Document ID: EPA-HQ-OPP-2009-0550-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-09-08T04:00Z

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

<EPA Registration Division contact: Mary Waller, 703-308-9354

 

<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:>

Devgen US, Inc.

Pesticide Petition No. 

<	EPA has received a pesticide petition ([insert petition number]) from
Devgen US, Inc., 413 McFarlan Road, Suite B, Kennett Square, PA 19348
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 180.399>

<(Options (pick one)>

<	1. by establishing a tolerance for residues of>

<	iprodione in or on the raw agricultural commodity cucurbit crop group
and fruiting vegetable crop group at 0.3 and 2.0 parts per million
(ppm), respectively.  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.>

<A. Residue Chemistry>

<	1. Plant metabolism.>  The metabolism of iprodione in plants is well
understood. EPA concluded that the residues of concern in plants are the
parent, its isomer 

 
3-(1-methylethyl)-N-(3,5-dichlorophenyl)-2,4-dioxo-1-imidazolidinecarbox
amide (RP-30228), and its metabolite 3-(3,5-dichlorophenyl)-2,4-
dioxo-1-imidazolidinecarboxamide (RP-32490).

<	2. Analytical method. An adequate analytical method, gas liquid
chromatography using an electron-capture detector, is available in the
Pesticide Analytical Manual, Vol. II, for enforcement purposes. 

<	3. Magnitude of residues. Cucumber, muskmelon, and summer squash are
the representative crops for EPA Crop Group No. 9 – Cucurbit
Vegetables.  A total of 19 field trials were conducted in the US to
develop residue data in support of the proposed tolerances, 6 trials on
cucumbers, 8 trials on melons and 5 trials on squash.  EPA guidelines
specify 6 trials for cucumbers, 6 trials for melons and 5 trials for
squash.

Iprodione residues in cucumbers ranged from <0.01 ppm to 0.12 ppm; for
RP-30228 from <0.01 to 0.01 ppm , and for RP-32490 <0.01 ppm (method
LOQ).

Residues in melons and squash were all <0.01 ppm for iprodione, RP-30228
and RP-32490.  

Tomatoes and peppers (non-bell and bell) are the representative crops
for EPA Crop Group No. 8 – Fruiting Vegetables (except cucurbits).  A
total of 21 field trials were conducted in the US to develop residue
data, 12 trials in tomatoes, 6 trials were conducted in bell peppers and
3 trials in non-bell peppers.  EPA guidelines specify 12 trials for
tomatoes, and 9 trials for peppers.

Iprodione residues in tomatoes ranged from <0.01 to 1.36 ppm, RP-30228
residues were all <0.01 ppm and RP-32490 residues ranged from <0.01 to
0.06 ppm.  Iprodione residues in peppers ranged from 0.06 to 1.33 ppm,
RP-30228 residues ranged from <0.01 to 0.02 ppm and RP-32490 residues
ranged from <0.01 to 0.10 ppm.  

Processing.  A tomato processing study was found to be adequate to
support a tolerance on tomatoes. Residues of iprodione, RP-30228 or
RP-32490 do not concentrate in tomato puree or paste. Food or feed
additive tolerances are not necessary.

<B. Toxicological Profile>

<	1. Acute toxicity.  Iprodione is of low acute toxicity placing the
active ingredient in Toxicity Category III and IV. Iprodione is
non-irritating to the eyes and skin and is not a skin sensitizer. 

<	2. Genotoxicty. Iprodione has been evaluated through a full battery of
mutagenicity assays. Iprodione was not mutagenic or genotoxic in any
assay in either the presence or absence of metabolic activation. 

<	3. Reproductive and developmental toxicity. 

a. Teratology - Rat. In a developmental toxicity study, pregnant rats
were administered iprodione at dose levels of 0, 40, 90, and 200
mg/kg/day via gavage from day 6 through 15 of gestation. The dams were
sacrificed on day 20 of gestation. There were no deaths. Body weights
were comparable among the groups. There were no significant differences
observed in the mean number of viable fetuses, implantations, corpora
lutea, resorptions, and pre- and postimplantation losses were comparable
among the groups. The developmental NOAEL was 90 mg/kg/day. A special
prenatal developmental toxicity study, pregnant rats received iprodione
via gavage at dose levels of 0, 20, 120, or 250 mg/kg/day during
gestation days 6 through 19. For maternal toxicity, the NOAEL was 20
mg/kg/day and for developmental toxicity, the NOAEL was 20 mg/kg/day.

b. Teratology - Rabbit. In a developmental toxicity study, artificially
inseminated female

rabbits were administered iprodione at dose levels of 0, 20, 60, and 200
mg/kg/day via gavage from day 6 through 18 of gestation. On day 29 of
gestation, the does were sacrificed. Seven high-dose does aborted
between days 17 and 23 of gestation, and prior to aborting all had
displayed decreased urination and defecation. One mid-dose doe [day 28]
and one control doe [day 20] also aborted. All other does survived until
study termination, and nine of the high-dose does that did not abort
displayed decreased urination and defecation. During the dosing period,
the mid-dose does gained less weight than the control, and the high-dose
does lost weight. The maternal NOAEL is 20 mg/kg/day and the
developmental toxicity NOAEL was 60 mg/kg/day.

c. Two-Generation Reproduction - Rat. In a 2-generation reproduction
study, 28 rats/sex/group were administered iprodione via the diet at
dose levels of 0, 300 ppm, 1000 ppm, and 3000/2000 ppm for two
generations. The systemic maternal/parental NOAEL was 300 ppm, and the
LOAEL was 1000 ppm, based on decreased body weight, body-weight gain,
and food consumption in both sexes and both generations. The
reproductive [offspring] NOAEL was 1000 ppm, and the reproductive LOAEL
was 2000 ppm, based on decreased pup viability. 

<	4. Subchronic toxicity. a. 90 Day Dietary - Rat. In a subchronic
feeding study, 10

rats/sex/group were administered iprodione via the diet at dose levels
of 0, 1000 ppm, 2000 ppm, 3000 ppm, and 5000 ppm for 90 days. The 5000
ppm dose group was terminated early [week 8]. Dose-related microscopic
lesions were observed in the sex organs and adrenals of both sexes at
the 2000, 3000, and 5000 ppm dose levels. The NOAEL is 1000 ppm.  

b. 90 Day oral - Dog. In a subchronic feeding study, 2 Beagle
dogs/sex/group were

administered iprodione via the diet at dose levels of 0, 800 ppm, 2400
ppm, and 7200 ppm for 90 days. Body weights were comparable among the
groups in both sexes. High-dose dogs displayed increased alkaline
phosphatase and transaminase values compared to the controls. There were
no effects reported in clinical chemistry and urinalysis. No
treatment-related microscopic lesions were observed. The NOAEL is 2400
ppm. 

<	5. Chronic toxicity. 

a. Chronic Toxicity - Dog. In a chronic feeding study, 6 Beagle
dogs/sex/group were administered iprodione via the diet at dose levels
of 0, 100 ppm, 600 ppm, and 3600 ppm for 12 months. There were no
treatment-related deaths, and no adverse effects were observed on body
weight, food consumption, or clinical signs in either sex. At the
highdose level, there were increases in absolute and relative liver
weight, alkaline phosphatase, SGOT, SGPT and LDH enzyme levels, and
increased absolute and relative adrenal weights. At 4 the mid-and
high-dose levels, males displayed an increased number of erythrocytes
with Heinz bodies and decreased prostate weights. The NOAEL is 100 ppm.
In a second chronic feeding study designed to complement the study cited
above, 6 dogs/sex/group were administered iprodione via the diet at dose
levels of 0, 200 ppm, 300 ppm, 400 ppm, and 600 ppm for 12 months. There
were no treatment-related deaths, and no adverse effects were observed
on clinical signs, body weight/gain, and food consumption in either sex.
At the high-dose level, decreases were observed in the red blood cell
parameters. The NOAEL for is 400 ppm.  

b. Combined Chronic Toxicity/Oncogenicity - Rat. In the combined chronic
toxicity/

carcinogenicity study in rats, iprodione was administered to 60
rats/sex/dose via the diet at dose levels of 0, 150, 300, and 1600 ppm
for 24 months. Body-weight gains were decreased in both sexes at the
high-dose level compared to the controls. There were no
treatment-related clinical pathology findings in either sex. At the
terminal sacrifice, increased liver weight was observed in males at the
mid- and high-dose levels. At the high-dose level in males, testes with
epididymides and thyroid weights were increased at the terminal
sacrifice. At the terminal sacrifice, interstitial cell hyperplasia in
the testes, reduced spermatozoa in the epididymides, and absent/empty
secretory colloid cells or reduced secretion in the seminal vesicles
were observed in the mid- and high-dose males. Atrophy of the
seminiferous tubules in the testes, with atrophy of the prostate and
absence of spermatozoa in the epididymides were observed at the
high-dose level. Adrenal lesions were observed in both sexes at the mid-
and high-dose levels, although the males displayed more lesions than the
females. There was an increase in the incidence of both unilateral and
bilateral benign interstitial cell tumors in the testes of males at the
1600 ppm dose level, however this effect should be considered a
threshold phenomenon and not relevant at lower doses. The NOAEL is 150
ppm.

c. Oncogenicity - Mouse. Iprodione was administered in the diet to 50
mice/sex/dose for 99 weeks at dose levels of 0, 160 ppm, 800 ppm, and
4000 ppm. Decreased body- weight gains were observed in both sexes at
the highest dose level. There was an increase in the incidence of liver
tumors in both sexes at the high-dose level, which was accompanied by
increases in several liver lesions. SGOT and SGPT levels were elevated
at the high-dose level in both sexes compared to the controls at the
interim sacrifice. Liver weight was increased at the high-dose level in
both sexes at both the interim and terminal sacrifices. The NOAEL is 160
ppm.

<	6. Animal metabolism. A general metabolic pathway for Iprodione in the
rat indicates that biotransformation results in hydroxylation of the
aromatic ring, degradation of the isopropylcarbamoyl chain and
rearrangement followed by cleavage of the hydantoin moiety. 
Additionally, structural isomers of Iprodione resulting from molecular
rearrangement, as well as intermediates in the pathway, were detected.

 

<	7. Metabolite toxicology. The residues of concern in plants for
tolerance setting purposes are the parent, its isomer
3-(1-methylethyl)-N-(3,5-dichlorophenyl)-2,4-dioxo-1-imidazolidinecarbox
-amide, and its metabolite 3-(3,5-dichlorophenyl)-2,4- dioxo-1-

imidazolidinecarboxamide. In animal commodities, tolerances are
established on the parent, its isomer
3-(1-methylethyl)-N-(3,5-dichlorophenyl)-2,4-dioxo-1-imidazolidinecarbox
amide, its metabolite 3-(3,5-dichlorophenyl)-2,4-
dioxo-1-imidazolidinecarboxamide, and an additional metabolite
N-(3,5-dichloro-4-hydroxyphenyl)-ureidocarboxamide. 

<	8. Endocrine disruption. In the carcinogenicity studies conducted for
iprodione, the primary lesion at the level of the target organs (testes,
ovaries & adrenals) is likely to be related to an inhibition of
steroid/androgen biosynthesis. This inhibition of steroid/androgen
biosynthesis occurs only at high dose levels and is reversible within 24
hours. Iprodione is not expected to induce any adverse effects related
to endocrine disruption in members of the general population via the
consumption of food containing residues of this compound. 

<C. Aggregate Exposure>

<	1. Dietary exposure. 1. Dietary exposure. Devgen US, Inc. expects that
potential residues resulting from the proposed use of iprodione on
cucurbit or fruiting vegetable crop groups will not significantly affect
EPA’s exposure and risk assessments for currently registered uses of
iprodione.

<	i. Food. Dietary exposures for iprodione were reevaluated by EPA as
part of the

reregistration process (1998). The lifetime cancer risk from potential
iprodione residues in foods with existing tolerances and drinking water
was estimated to be 1.8 x 10-6. This cancer risk corresponds to a
dietary exposure of 0.000041 mg/kg/day or 0.2% of the chronic reference
dose (RfD). 

<	ii. Drinking water. Iprodione, applied according to labeled use and
good agricultural management practices, is predicted and demonstrated to
present no significant, if any, concentrations in drinking water
sources. Iprodione’s physical-chemical properties and actual measured
environmental concentrations in field dissipation/monitoring studies
provide support for this conclusion. Five conservative aggregate
exposure and risk assessments were conducted by EPA for the Iprodione
RED. These risk assessments include combined exposures to iprodione
through food and water in the diet: i) acute dietary; ii) chronic
dietary; iii) cancer; iv) short-term; and v) intermediate-term risk. EPA
concludes in the RED document that residues of 

iprodione are not expected to exceed the Agency’s drinking water level
of concern for either acute or chronic exposure. EPA also concluded with
reasonable certainty that residues of iprodione in drinking water (when
considered along with exposure from food) would not result in
unacceptable short-term and intermediate term aggregate human health
risk estimates. Since the completion of the RED, EPA issued a Data
Call-In requiring the submission of 3,5-dichloroaniline
(3,5-DCA)-targeted surface and ground water monitoring studies relating
to golf course use of iprodione products. 

Data has since submitted to the Agency for an aerobic soil metabolism
study and a soil adsorption/desorption study conducted with 3,5-DCA.
Risk analyses using these recent data and EPA’s standard operating
procedures confirm that there is no concern for contamination of
drinking water resulting from the use of iprodione products on

golf courses.  Devgen US, Inc. expects that potential residues resulting
from the proposed use of iprodione on cucurbit and fruiting vegetable
crop groups will not significantly affect EPA’s exposure and risk
assessments for drinking water. 

<	2. Non-dietary exposure. This assessment is not applicable since all
residential uses of iprodione products have been cancelled.

<D. Cumulative Effects>

The Agency has previously noted both structural and toxicological
similarities between

iprodione, procymidone and vinclozolin. There are clear differences in
both the type and

magnitude of effects observed after exposure to iprodione in contrast to
vinclozolin and

procymidone. Vinclozolin and procymidone are known to exert their
identical endocrine effects via a blockage of the androgen receptor. By
contrast, iprodione has poor binding affinity to the androgen receptor
and the primary lesion appears to be a blockage of testosterone
biosynthesis and secretion. Subsequently, Iprodione only appears to
induce transient changes in plasma hormone levels until compensatory
mechanisms take effect. Consequently, Devgen US, Inc. concludes that
consideration of a common mechanism of toxicity is not appropriate at
this time since there is no reliable data to indicate that the toxic
effects caused by Iprodione would be cumulative with those of any other
compounds.

<E. Safety Determination>

<	1. U.S. population. Dietary exposures for iprodione were reevaluated
by EPA as part of the reregistration process (1998). The lifetime cancer
risk from potential iprodione residues in foods with existing tolerances
and drinking water is estimated to be 

1.8 x 10-6.  This cancer risk corresponds to a dietary exposure of
0.000041 mg/kg/day or 0.2% of the chronic reference dose (RfD).  Devgen
US, Inc. concludes that the proposed use on cucurbit and tomato crop
groups will not increase the overall risk significantly. It is expected
that the cancer risk estimates for currently registered crops, drinking
water, and the proposed uses are within the range the Agency considers
acceptable for excess life-time cancer risk. 

<	2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of Iprodione the
available teratology and reproductive toxicity studies and the potential
for endocrine modulation by Iprodione were considered. Developmental
studies in two species indicate that Iprodione has no teratogenic
potential, even at maternally toxic dose levels. Maternal and
developmental NOELs and LOELs were generally comparable indicating no
increased susceptibility of developing organisms. In addition the
results of a recently completed study have confirmed that Iprodione has
no effects on sex differentiation.  Multigeneration rodent reproduction
studies indicated that Iprodione has no adverse effects on reproductive
performance, fertility, fecundity or sex ratio. Effects on pup weight
and viability were only noted in the presence of severe parental
toxicity. The mechanism of endocrine modulation associated with
Iprodione (inhibition of testosterone biosynthesis) appears to be
distinct from that of anti-androgens acting at the level of the androgen
receptor and may help to explain the lack of adverse effects on
reproductive function observed with Iprodione. 

Therefore, based upon the completeness and reliability of the toxicity
data and the conservative exposure assessment, there is a reasonable
certainty that no harm will result to infants and children from exposure
to residues of Iprodione and no additional uncertainty factor is
warranted. The EPA Health Effects Division (HED) determined that the
developmental NOAEL for iprodione was relevant only to women of
childbearing age and concluded that the developmental NOAEL is not
relevant to acute dietary exposures to infants and children. Because no
non-developmental acute effects have been identified, there is no acute
toxicological endpoint to assess acute dietary risk to infants and
children.  Based on the chronic exposure assessment conducted by EPA for
uses currently registered, aggregate exposure to iprodione from food
utilizes 1.6% of the RfD for non-nursing infants less than 1 year old
and less than 1% for all other population subgroups.  

Since the potential for exposure to iprodione in drinking water is low
and there is no risk from non-dietary, non-occupational exposure, the
aggregate exposure is expected to be well below 100% of the RfD when
accounting for the proposed uses on cucurbits and fruiting tomato crop
groups. Thus, there is a reasonable certainty that no harm will result
to infants and children from aggregate exposure to iprodione residues.

<F. International Tolerances>

A Codex MRL of 5.0 ppm is established for iprodione in tomato and 2.0
ppm in cucumber. A Codex MRL is not established for iprodione on melons
or squash. 

An MRL of 0.5 ppm is established in Canada for iprodione in cucumber and
tomatoes.  An MRL is not established in Canada for iprodione on melons
or squash.

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