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Iprodione - Pesticide Tolerance Petition Filing for Tangerines 1/97

CHEMICAL PROFILES/FUNGICIDE/iprodione
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ENVIRONMENTAL PROTECTION AGENCY
[PF-689; FRL-5582-7]
Rhone-Poulenc Ag Company; Pesticide Tolerance Petition Filing
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice of filing.
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SUMMARY: This notice announces the filing of a pesticide petition proposing
the extension of the temporary tolerances for the combined residues of the
fungicide iprodione [3-(3,5-dichlorophenyl)-N-(1- methylethyl)-2,4-dioxo-1-
imidazolidinecarboxamide], its isomer [3-(1- methylethyl)-N-(3,5-
dichlorophenyl)-2,4-dioxo-1- imidazolidinecarboxamide], and its metabolite [3-
(3,5-dichlorophenyl)- 2,4-dioxo-1-imidazolidinecarboxamide] (CAS Number 36734-
19-7, PC Code 109801) in or on the raw agricultural commodities tangerines and
tangelos at 3.0 ppm. The notice includes a summary of the petition prepared by
the petitioner, Rhone-Poulenc Ag Company. DATES: Comments, identified by the
docket control number [PF-689], must be received on or before, February 24,
1997.

ADDRESSES: By mail, submit written comments to: Public Response and Program
Resources Branch, Field Operations Division (7506C), Office of Pesticide
Programs, Environmental Protection Agency, 401 M St., SW., Washington, DC
20460. In person, bring comments to: Crystal Mall #2, Room 1132, 1921
Jefferson Davis Highway, Arlington, VA.

Comments and data may also be submitted electronically by sending electronic
mail (e-mail) to: opp-docket@epamail.epa. gov. Electronic comments must be
submitted as an ASCII file avoiding the use of special characters and any form
of encryption. Comments and data will also be accepted on disks in WordPerfect
in 5.1 file format or ASCII file format. All comments and data in electronic
form must be identified by the docket control number [PF-689]. Electronic
comments on this notice may be filed online at many Federal Depository
Libraries. Additional information on electronic submissions can be found below
in this document.

Information submitted as comments concerning this document may be claimed
confidential by marking any part or all of that information as "Confidential
Business Information" (CBI). The CBI should not be submitted through e-mail.
Information marked as CBI will not be disclosed except in accordance with
procedures set forth in 40 CFR part 2. A copy of the comment that does not
contain CBI must be submitted for inclusion in the public record. Information
not marked confidential may be disclosed publicly by EPA without prior notice.
All written comments will be available for public inspection in Room 1132 at
the address given above, from 8:30 a.m. to 4 p.m., Monday through Friday,
excluding legal holidays.

FOR FURTHER INFORMATION CONTACT: By mail: Connie Welch, Product Manager (PM
21), Registration Division (7505C), Office of Pesticide Programs,
Environmental Protection Agency, 401 M St., SW., Washington, DC 20460. Office
location, telephone number, and e-mail address: Crystal Mall #2, Room 227,
1921 Jefferson Davis Highway, Arlington, VA, 703-305-6226, e- mail:
welch.connie@epamail.epa.gov.

SUPPLEMENTARY INFORMATION: EPA has received a pesticide petition (PP 3G4210)
from Rhone-Poulenc Ag Company (Rhone-Poulenc), P.O. Box 12014, T.W. Alexander
Drive, Research Triangle Park, NC 27709 proposing pursuant to section 408(d)
of the Federal Food, Drug and Cosmetic Act (FFDC), 21 U.S.C. 346(d), to extend
the temporary tolerances for the fungicide iprodione [3-(3,5-dichlorophenyl)-
N-(1-methylethyl)-2,4- dioxo-1-imidazolidinecarboxamide], its isomer [3-(1-
methylethyl)-N- (3,5-dichlorophenyl)-2,4-dioxo-1-imidazolidinecarboxamide],
and its metabolite [3-(3,5-dichlorophenyl)-2,4-dioxo-1-
imidazolidinecarboxamide] in or on the raw agricultural commodities tangerines
and tangelos at 3.0 ppm. The current temporary tolerances expire on April 15,
1997. EPA has determined that the petition contains data or information
regarding the elements set forth in section 408(d)(2) of the FFDC; 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. As required by section 408(d) of the
FFDC, as recently amended by the Food Quality Protection Act (FQPA), Pub. L.
104-170), Rhone-Poulenc included in the petition a summary of the petition and
authorization for the summary to be published in the Federal Register in a
notice of receipt of the petition. The summary represents the views of Rhone-
Poulenc. EPA is in the process of evaluating the petition. As required by
section 408(d)(3) of the FFDC, EPA is including the summary as a part of this
notice of filing. EPA may have made minor edits to the summary for the purpose
of clarity.

I. Petition Summary

There is an extensive data base supporting the registration of iprodione. All
the studies required under the reregistration process mandated by FIFRA 88
have been submitted. Most of these studies have been reviewed by the Agency
and accepted.

The temporary tolerances for iprodione on tangelos and tangerines at 3.0 ppm
are considered adequate to cover residues resulting from the limited use of
iprodione in the proposed experimental use program. The tolerance level is
based on field trial data with an overall mean residue of 1.19 ppm for
tangelos and tangerines. The nature of the residue in plants is adequately
defined. Plant metabolism studies have been reviewed in connection with
previous petitions for tolerances. The residues of concern are iprodione, its
isomer RP 30228, and its metabolite RP 32490. The Phase IV Review concluded
that additional plant metabolism studies are not needed.

The nature of the residue in animals is adequately understood considering the
limited use of iprodione on tangerines and tangelos as proposed in the
experimental use permit (EUP). The residues of concern in animals are
iprodione, its isomer RP 30228, its metabolites RP 32490 and RP 36114. The
established tolerances for iprodione and its metabolites in meat, milk,
poultry, and eggs are adequate to cover secondary residues in animal
commodities resulting from the experimental use on tangerines and tangelos.
Citrus feedstuff theoretically accounts only for a maximum of 20% of beef and
dairy cattle diet. Citrus feedstuff is not fed to poultry and swine. Since the
EUP covers only a maximum of 4,000 acres which represents less than 0.4% of
total U.S. bearing citrus fruit production for 1996, the actual iprodione
contribution to the diet of livestock is not significant.

An adequate analytical method, gas liquid chromatography using an electron-
capture detector, is available in the Pesticide Analytical Manual, Vol. II,
for enforcement purposes. In the Phase IV Review, EPA requested that a
substitute for benzene be used in the method of analysis used in new crop
field trials. In response to this request, Rhone-Poulenc developed a common
moiety GC method with a 0.05 ppm limit of quantitation (LOQ). An Independent
Laboratory Validation for this method was submitted.

Iprodione is an important product for growers of several minor crops. These
include garlic, ginseng, chinese mustard, broccoli, caneberries (blackberries,
loganberries, and raspberries), and bushberries (blueberries, currant,
elderberries, gooseberries, and huckleberries).

There are no Codex tolerances for iprodione on citrus commodities. The
following mammalian toxicity studies have been conducted to support the
extension of the temporary tolerances for iprodione on tangerines and
tangelos.

A. Toxicological Profile

1. Acute toxicity. A complete battery of acute toxicity studies for iprodione
were completed. Iprodione has low acute toxicity. The acute oral toxicity
study in the rat resulted in LD50s of 3,629 mg/kg and 4,468 mg/kg for females
and the combined sexes, respectively. The acute dermal LD50 in both rats and
rabbits is >2,000 mg/kg. The acute inhalation LC50 for a 4-hour exposure to
rats is >5.16 mg/L. No skin or eye irritation or dermal sensitization are
produced by iprodione. Based on the results of these studies, iprodione was
placed in toxicity category III.

Conclusion. Based on the acute toxicity data cited above, Rhone-Poulenc
believes that iprodione does not pose any acute dietary risks.

2. Mutagenicity. Mutagenicity studies completed include Salmonella typhimurium
and Escherichia coli reverse mutation (all negative), induction tests with
Escherichia coli (all negative), DNA repair test in Escherichia coli
(negative), DNA damage in Bacillus subtilis (positive), Rec assay in Bacillus
subtilis (negative), mutagenicity in Saccharomyces cerevisiae D7 (negative),
forward mutation in CHO/HGPRT assay (negative), chromosome aberrations in CHO
cells (negative), sister chromatid exchange in CHO cells (negative), in vivo
micronucleus test (negative), in vivo host mediated assay with Salmonella
typhimurium G46 (negative) and dominant lethal test in male mice (negative).
Conclusion. Based on the data cited above, Rhone-Poulenc believes that the
weight of evidence indicates that iprodione does not pose a mutagenic hazard
to humans.

3. Rat metabolism. 14C-Iprodione was absorbed readily from the
gastrointestinal tract, metabolized, and excreted by rats of both sexes
following single low [50 mg/kg] and high [900 mg/kg] oral doses and 14
repeated low [50 mg/kg] doses. Peak blood levels were observed at 4 and 2
hours, respectively, in low-dose males and females and at 6 hours in high-dose
rats of both sexes. The elimination of 14C from the blood was slower in males
than females. There were both dose and sex- related differences noted in
absorption: males absorbed a greater percentage of the low and repeated doses
than females. Although levels of 14C were found in most tissues monitored, the
levels were ≤0.5% of the total amount administered. It is to be
noted that the testes of the low-dose [50 mg/kg] males showed no detectable
amount of 14C; the high dose in the rat chronic toxicity/ carcinogenicity
study where testicular tumors were observed was 69 mg/ kg. The primary route
of elimination of 14C following single and repeat low-dose exposure was the
urine, and the feces was the primary route following high-dose exposure.
Dealkylation and cleavage of the hydantoin ring were the two primary steps in
the metabolism of iprodione. Hydroxylation of the phenyl ring and oxidation of
the alkyl chain also occurred. The primary metabolites recovered from the
urine [both sexes] included a dealkylated derivative of iprodione and two
polar but unidentified compounds. Males produced larger amounts of a hydantoin
ring-opened metabolite than females, and the urine of the females contained a
higher proportion of unchanged parent compound than that of the males. Several
urinary metabolites were not identified. The feces contained much larger
amounts of unchanged parent compound than the urine, which the authors
suggested was unabsorbed iprodione and metabolites or hydrolyzed conjugates of
absorbed material.

In another single oral administration study in rats using 50 mg/kg, no sex
differences were apparent in the excretion profile, and both urinary
elimination [37%M/28%F] and fecal excretion [56%M/50%F] are major routes of
excretion. The metabolism of iprodione was extensive and characterized by the
large number of metabolites formed. In the urine, RP 36115, RP 32490, RP
36112, RP 36119, and RP 30228 were either confirmed or indicated. The feces
contained a large proportion of parent compound; the major fecal metabolites
were RP 36115, RP 36114, RP 32490, and RP 30228. 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.

4. Chronic effect. The chronic toxicity of iprodione has been extensively
studied in three species, i.e. dog, rat, and mouse:

a. Dog--i. In the first study, conducted at dose levels of 100, 600, and 3,600
ppm a clear no observed effect level (NOEL) was established at 100 ppm (4.2
mg/kg/day). The lowest effect level (LEL) was set at 600 ppm based on
equivocal effects such as decreased prostate weight and an increased incidence
of Heinz bodies in erythrocytes in males.

ii. A second study (MRID 00144391, 41327001, 42211101), conducted at dose
levels of 200, 300, 400, and 600 ppm, was performed as a bridging study for
EPA in order to establish a higher NOEL. In this study no clear indications of
any toxicological effects were noted.

From the results of the two complementary studies, a conservative NOEL
of 400 ppm (17.5 mg/kg/day in males and 18.4 mg/kg/day in females) and a LEL
of 600 ppm (24.6 mg/kg/day in males and 26.4 mg/kg/day in females) based on
depressed blood cell parameters were established.

b. Rat--i. In an initial study, Charles River outbred CD albino rats were fed
diets containing 125, 250, or 1,000 ppm (6.25, 12.5, and 50 mg/kg/day) of
iprodione technical for 24 months. In this study, the NOEL of iprodione in
rats was observed to be greater than 1,000 ppm (i.e. >50 mg/kg/day).

ii. In a repeat study, Sprague Dawley rats were administered 150, 300, or
1,600 ppm iprodione technical in the diet for 24 months. The NOEL for chronic
toxicity was set at 150 ppm (mean intake of males and females was 7.25
mg/kg/day) and the LEL was 300 ppm (12.4 mg/kg/day for males and 16.5
mg/kg/day for females).

c. Mouse--i. In an initial study, Carworth CF-1 outbred albino mice were fed
diets containing 200, 500, 1,250 ppm (28.6, 71.4, and 178.6 mg/kg/day) of
iprodione technical for 18 months. In this study, the NOEL of iprodione in
mice was greater than 1,250 ppm (i.e. >178.6 mg/ kg/day).

ii. In a repeat study, iprodione technical was administered at dietary
concentrations of 160, 800, or 4,000 ppm to CD-1 mice for 99 weeks. The NOEL
for chronic toxicity was set at 160 ppm (23 mg/kg/day for males and 27
mg/kg/day for the females) and the LEL at 800 ppm (115 mg/kg/day for males and
138 mg/kg/day for females).

Conclusion. The chronic reference dose (RfD) for iprodione is 0.0725
mg/kg/day. This RfD is based on the NOEL of 7.25 mg/kg/day determined from the
rat combined chronic toxicity and carcinogenicity study. An uncertainty factor
of 100 has been included in the RfD value to account for inter and intra-
species variations.

5. Carcinogenicity--a. Rat--i. In the initial 2-year combined
toxicity/carcinogenicity study, Charles River outbred CD albino rats were fed
diets containing 125, 250, or 1,000 ppm of iprodione technical. In this study,
no increase in neoplastic lesions were observed at any of the treatment
levels. The NOEL for oncogenicity in rats was observed to be greater than
1,000 ppm (>50 mg/kg/day).

ii. In the repeat study conducted with Sprague Dawley rats administered 150,
300, or 1,600 ppm iprodione technical in the diet, no increase in tumor
incidence was noted at interim sacrifice. Microscopic examination of animals
found dead, sacrificed in extremis, or killed at termination after 104 weeks
revealed an increased incidence of benign interstitial cell tumors in rats
treated with 1,600 ppm (29/60 animals) compared with controls (3/60). No
increased incidence of any other tumor type was recorded. No treatment-related
neoplastic lesions were observed in the 150 or 300 ppm treatment groups. The
NOEL for oncogenicity in males in this study was 300 ppm (12.4 mg/kg/day) and
the LEL 1,600 ppm (69 mg/kg/day). There was no indications of oncogenicity in
females at any dose level.

b. Mouse--i. In the initial study, Carworth CF-1 outbred albino mice were fed
diets containing 200, 500, 1,250 ppm of iprodione technical for 18 months. In
this study, no increase in neoplastic lesions were observed at any of the
treatment levels. The NOEL for oncogenicity in mice was observed to be greater
than 1,250 ppm (>178.6 mg/kg/day).

ii. In the repeat mouse oncogenicity study, iprodione technical was
administered at dietary concentrations of 0, 160, 800, or 4,000 ppm to CD-1
mice for 99 weeks. Microscopic examination of animals found dead, sacrificed
in extremis, or killed at termination after 99 weeks revealed an increased
incidence of benign and malignant liver cell tumors in both sexes. A slight
increase in the incidence of luteomas in the ovaries of females was also noted
at 4,000 ppm. No increased incidence of any other tumor type was recorded. No
treatment-related neoplastic lesions were observed in the 160 or 800 ppm
treatment groups. The NOEL for oncogenicity in this study was 800 ppm (115
mg/kg/ day in males and 138 mg/kg/day in females) and the LEL was 4,000 ppm
(604 mg/kg/day in males and 793 mg/kg/day in females).

Discussion. A number of mechanistic studies have been conducted in order to
elucidate the mechanism of testicular toxicity and carcinogenicity in the rat
and hepatic toxicity and carcinogenicity in the mouse.

c. Testicular toxicity and carcinogenicity in the rat. The results of recently
completed mechanistic studies have further elucidated the mechanism of
iprodione testicular toxicity. The available evidence suggests that the
primary mode of action of iprodione in the testes is via a disruption of
testosterone biosynthesis in the interstitial cells. The resulting reduction
in testosterone secretion may lead to a compensatory hyperplasia in order to
maintain normal hormonal homeostasis. Tumors may then develop in sensitive
species, such as the rat, due to the persistent hyperplasia. The evidence
supporting such a mechanism of action can be summarized as follows:

• Iprodione and certain metabolites (RP 36112 and RP 36115) have been
shown to inhibit testosterone secretion from cultures of porcine Leydig cells.
Recently, it has been demonstrated that iprodione inhibits testosterone
synthesis and release from rat testicular sections in vitro.

• The site of action whereby iprodione and its metabolites (RP 36112
and RP 36115) appear to modulate Leydig cell steroidogenesis has recently been
identified using porcine Leydig cell cultures. Iprodione appears to act
through a rapid, reversible, interaction with cholesterol and/or steroid
hormones at the level of some transport proteins and/or steroidogenic enzymes.
• Hormonal perturbation has been observed in a rat in vivo study with
iprodione. These were however limited to increases in LH and FSH levels
following 15 days of iprodione treatment and slight differences in the
secretion pattern of LH and testosterone following 30-days of treatment. In
the same study, decreases in absolute and relative weights of total accessory
sex organs and seminal vesicles (but not the prostate or epididymides) were
noted at final sacrifice. By contrast, treatment with flutamide induced marked
and persistent increases in plasma levels of testosterone, estradiol, LH and
FSH and these were associated with marked decreases in the epididymides and
accessory sex organs weights (ventral prostate and seminal vesicles).
• Data from subchronic and chronic toxicity studies show that several
major target organs (adrenals, testicular and ovarian interstitial cells) are
tissues which secrete steroid hormones.

-- No clear evidence of competitive binding to the androgen receptor was found
for iprodione or its major metabolites (RP 32490, RP 36114, RP 36118, and RP
36119). Several minor metabolites did exhibit a binding activity close to the
reference compound flutamide. However, it is generally accepted that the anti-
androgenic activity of flutamide is due to its major metabolite
hydroxyflutamide, which binds to the androgen receptor with a greater affinity
than flutamide (Simard et al, 1986).

It is well established that a threshold can be expected for hormonally
mediated oncogenic mechanisms. In the rat chronic/ oncogenicity study, Leydig
cell tumors were only observed at highly toxic dose levels which were at or
above the MTD (mean body weight gains were reduced from 13.7% to 16.4% between
weeks 0 to 12, 12 to 22, and 0 to 104 of the study in high dose males) and
clear thresholds exist for both non-neoplastic lesions and tumors. In
addition, the cellular effects of iprodione have been demonstrated to be
reversible since the inhibition of testosterone biosynthesis in porcine Leydig
cells was removed following removal of the iprodione from the cell culture. It
can also be noted that the rat appears to be one of the most sensitive species
to benign interstitial cell tumors. They are, however, a very uncommon tumor
type in humans. It is evident that the rat is much more sensitive to chemical
insult of the Leydig cells than is man and, consequently, that humans are at
less risk for Leydig cell testicular tumors than rats. This implies that the
threshold dose for humans would be greater than for rats (See C. C. Capen,
Leydig Cell Tumors: Pathology, Physiology, and Mechanistic Considerations in
Rats, The Toxicology Forum, 1994 Annual Summer Meeting, p. 110).

d. Hepatotoxicity and carcinogenicity in male and female mice. In the mouse
oncogenicity study, the development of hepatocellular tumors in mice appeared
secondary to hepatic toxicity at a dose level at which body weight gain was
severely reduced indicating that the MTD was probably exceeded (over the
duration of the study, weight gain was reduced 14% and 11% in high dose males
and females respectively. During weeks 18 to 45, weight gain was reduced 44%
and 47%, respectively. This severity of the weight gain decrement is
compounded by the fact that the livers in these animals weighed more than
double their respective controls, i.e., the weight gain decrement is even more
serious than the body weights alone would indicate). The animals at the
highest dose level, and to a lesser extent, the mid-dose group, exhibited
signs of liver toxicity, including increased liver weights, hepatocytic
hypertrophy, enlarged eosinophilic hepatocytes, pigmented macrophages,
centrilobular necrosis, amyloid deposits, and statistically significant
increases in levels of the liver enzymes GPT and GOT. Clear NOELs exist for
these effects. In a recently completed 14-day toxicity study in male mice,
dose levels similar to those at which tumors were observed in the mouse
carcinogenicity study induced a number of hepatic changes including the
induction of Cytochrome P450 isoenzymes and cellular proliferation.

The HED Carcinogenicity Peer Review Committee (CPRC) met in 1994 and
determined that iprodione should be classified a group B2 carcinogen. The CPRC
recommended that a low dose quantitative risk assessment for iprodione be
estimated from the benign rat interstitial cell tumors of the testes, and also
from the mouse male and female liver tumors separately. It is the opinion of
Rhone-Poulenc that the B2 classification as well as the use of low dose
quantitative risk assessment for iprodione is inappropriate.

The male interstitial cell tumors seen only at the high dose in the lifetime
rat study with iprodione were due to a mode of action with a clear threshold.
This conclusion is based on the following rationale: (i) The tumors were
benign and only observed at a dose level at or above the MTD, (ii) the
mechanistic toxicological research designed to elucidate the biochemical mode
of action, and (iii) the consensus of scientific experts that benign Leydig
cell tumors in the rat are not useful predictors of human disease. Thus,
because the mechanism of action shows a clear threshold, and because the
potential toxicological hazard has no direct relevance for human health,
Rhone-Poulenc believes that the dose response assessment for the benign
interstitial cell effects in the rat testes should rely on threshold, non-
linear, margin of exposure procedures and not on linear low dose
extrapolations.

The mouse liver tumors also arose from a toxicological mechanism having a
clear threshold. A study conducted to elucidate the mode of action of the
mouse liver tumorigenesis has been described above. The relationship between
hormonally active compounds and the etiology of mouse liver cancer is well
established. Rhone-Poulenc therefore contends that a complete evaluation of
the carcinogenicity issue indicates that iprodione is a threshold carcinogen
acting through a non-genotoxic mechanism of toxicity. The application of a low
dose quantitative risk assessment for iprodione is inappropriate. Rhone-
Poulenc therefore recommends the use of an uncertainty factor approach and a
RfD of 0.0725 mg/kg/day.

6. Teratology rat--a. The embryo/fetal toxicity and teratogenicity of
iprodione were evaluated in Sprague-Dawley rats at oral (gavage) dose levels
of 40, 90, or 200 mg/kg/day. Iprodione showed no embryotoxicity or
teratogenicity at any of the dose levels examined. Although no maternal
effects were detected at any treatment level in the definitive study, dose
selection was justified from the pilot study in which maternal toxicity was
noted at 120 and 240 mg/kg/day. In addition, an increase in the average number
of late resorptions per litter was observed at 240 mg/kg/day. A clear and
conservative developmental and maternal NOEL was observed at 90 mg/kg/day.

b. Rabbit. The embryo/fetal toxicity and teratogenicity of iprodione were
evaluated in rabbits at oral (gavage) dose levels of 20, 60, or 200 mg/kg/day.
No treatment-related embryotoxicity or teratogenicity was noted at doses of 20
or 60 mg/kg/day. Even though iprodione at 200 mg/kg/day was too maternally
toxic for a complete teratologic evaluation, no malformations were observed in
the fetuses examined from this group. The developmental NOEL was 60 mg/kg/day
and the maternal NOEL was 20 mg/kg/day based decreases in maternal body weight
gain.

Conclusion. Based on the studies cited above, iprodione is not a developmental
toxicant.

7. Reproductive effects. In a multi-generation study, iprodione was
administered to male and female Sprague-Dawley rats via dietary admixture at
dose levels of 300, 1,000, or 2,000/3,000 ppm (for males 18.5, 61.4, and 154.8
mg/kg/day and for females 22.49, 76.2, and 201.2 mg/kg/day, respectively). It
was necessary to reduce the high dose from 3,000 to 2,000 ppm following the
first mating period of the F1 parents owing to excessive toxicity. No effects
on reproductive performance were observed at any of the treatment levels.
Parental toxicity, as evidenced by reduced body weight, body weight gain and
food consumption was observed at dietary levels of 1,000 ppm and higher.
Effects on pup viability and pup weight were noted at 2,000/3,000 ppm. The
NOELs for parental and offspring toxicity were 300 ppm and 1,000 ppm,
respectively.

Conclusion. Based on the study cited above, Rhone-Poulenc believes that
iprodione is not a reproductive toxicant.

8. Neurotoxicity. Iprodione does not have a chemical function associated with
neurotoxicity. No neurotoxic symptoms have been recorded in any toxicity study
conducted with iprodione. Iprodione is therefore not considered to be a
neurotoxin.

B. Aggregate Exposure

In addition to dietary exposure, the FQPA lists three potential sources of
exposure to the general population that must be addressed. These are
pesticides in drinking water, exposure from non-occupational sources, and the
potential cumulative effect of pesticides with similar toxicological modes of
action.

1. 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 provides support for this conclusion.
There is no established Maximum Concentration Level or Health Advisory Level
for iprodione under the Safe Drinking Water Act.

2. Non-occupational exposure discussion. Iprodione is included in a number of
formulations used for professional treatment of golf-courses and turf. Posting
and notification procedures ensure that there is no exposure to the general
public either during or following treatment.

A single granular formulation containing low quantities of iprodione (1.02%)
is available to the homeowner for use on residential ornamentals and lawns.
Treatment rates (1.25 oz a.i./2,500 - 5,000 sq. ft.) and the number of
treatments allowed per year (2-3 max.) are low. Rhone-Poulenc believes that
this minor use will not impact significantly on the aggregate exposure to
iprodione since it represents less than 4% of total iprodione use. Two
formulations are registered for home and garden use but they have not been
commercialized. They therefore do not need to be included in the aggregate
exposure risk estimate for iprodione.

Conclusion. Rhone-Poulenc does not expect that the ornamental and turf uses
add significantly to the aggregate exposure for iprodione; thus, dietary
exposure is the main consideration for risk assessment purposes.

3. Common mechanism of action discussion. Risk assessment based on exposure to
multiple chemicals is not appropriate for the following reasons:

-- Similar toxicological end-points may be induced by a number of different
mechanisms of action that are unlikely to be additive.

-- Toxicological end-points for RfD setting may be different even between
chemicals acting via a common mechanism.

-- Margins between NOELs and LELs may be large and variable from chemical to
chemical.

-- Multiple chemical dietary exposures are low and infrequent.

-- For a majority of chemicals insufficient or incomplete data is available to
identify a common mechanism of action.

However, 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. In multi-generation
studies, iprodione had no adverse effects on reproductive performance,
fertility, fecundity, or sex ratio, even at dose levels that induced dramatic
parental toxicity. However in similar types of studies, procymidone induced
adverse effects on fertility and abnormalities of male sex organs and
vinclozolin induced infertility, genital and reproductive tract malformations
and pseudohermaphroditism in male rats.

Vinclozolin and procymidone are known to exert their endocrine effects via a
blockage of the androgen receptor in a similar way to the potent anti-androgen
flutamide (Hosokawa et al, 1993a and 1993b, Kelce et al, 1994). 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 in
a similar manner to ketoconazole; a therapeutic agent that also has no effects
on fertility or fecundity (Heckman et al, 1992). Subsequently, iprodione only
appears to induce transient changes in plasma hormone levels until
compensatory mechanisms take effect. Consequently, iprodione does not possess
the potent anti-androgenic activity of flutamide (or its structural analogs).

Conclusion. Therefore, Rhone-Poulenc believes that consideration of a common
mechanism of toxicity is not appropriate at this time since there are no

reliable data to indicate that the toxic effects caused by iprodione would be
cumulative with those of any other compound. Based on this point, Rhone-
Poulenc has considered only the potential risks of iprodione in its exposure
assessment.

C. Safety Determination

1. DRES-U.S. population-infants-children (1-6 yrs old). According to EPA's
Dietary Risk Evaluation System (DRES) chronic analysis, the % RfD falls within
a safe margin even when considering tolerance levels and 100% crop treated.
For the overall U.S. population, dietary exposure to iprodione uses 0.353% of
the RfD when using Anticipated Residue Contribution (ARC) or 54.22 % of the
RfD when using tolerance levels. Exposure to iprodione resulting from the use
of the product on tangelos and tangerines is negligible considering the low
residues and limited acreage covered in the EUP (maximum of 4,000 acres).
Dietary contribution from tangerines and tangelos accounts for less than 1% of
total exposure and the cancer risk for these uses is estimated to be less than
5 x 10**-8.

A DRES detailed acute exposure analysis was performed by EPA using
conservative values. The resulting high end Margin of Exposure value of 100
for the DRES subgroup of concern (females 13 + years) is above the acceptable
level and demonstrates no acute dietary concern.

For the reasons stated earlier (see Unit A.5.) Rhone-Poulenc considers the use
of a low dose quantitative risk assessment for iprodione to be inappropriate.
As previously indicated Rhone-Poulenc recommends the use of a safety factor
approach and a RfD of 0.0725 mg/kg/day. The use the Q* (Q star) value of
0.0439 (mg/kg/day)-1 previously calculated by EPA represents a very
conservative estimate of the lifetime cancer risk from potential residues of
iprodione.

Nevertheless, an assessment of the lifetime cancer risk from iprodione
residues in food using a Q* value of 0.0439 (mg/kg/day)- 1 has been conducted.
This assessment indicates the total cancer risk to be in the de minimus range
of 10 to the -6, even with a very conservative Q* value. Based on results of
the analyses, iprodione residues in currently registered foods would not be
expected to result in significant levels of chronic toxicity to any segment of
the U.S. population. The upper bound cancer risk attributed to the use of
iprodione on tangerines and tangelos is calculated to be negligible.
Therefore, the added use will not measurably increase the cancer risk estimate
for any population subgroup.

2. Infants and children-adequate margin of safety. 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 lowest observed effect levels (LOELs) were generally
comparable indicating no increased susceptibility of developing organisms.
Multi-generation 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, Rhone-Poulenc believes that 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.

3. Endocrine discussion and conclusion. As indicated in unit A. 5., the
primary lesion at the level of the target organs (testes, ovaries, and
adrenals) is likely to be related to an inhibition of steroid/ androgen
biosynthesis. The resulting endocrine toxic effect due to iprodione is fairly
moderate compared to that produced by potent endocrine disruptors such as
flutamide (and other structural analogs) and is insufficiently potent to
produce effects on reproduction or development.

The increased incidence in tumors in both rats and mice was only observed when
animals were treated at or above the MTD. For all three tumor sites (testes,
liver, ovary) tumors only develop on pre-existing non-neoplastic lesions (cell
hypertrophy/vacuolation, hyperplasia) and a clear threshold level exist for
both non-neoplastic lesions and tumors. Those thresholds are far in excess of
those levels of iprodione that the general public would be exposed to.

Conclusion. Rhone-Poulenc believes that iprodione would not be expected to
induce any adverse effects related to endocrine disruption in members of the
general population via the consumption of food crops containing residues of
this compound.

II. Public Record

EPA invites interested persons to submit comments on this notice of filing.
Comments must bear a notation indicating the docket control number, [PF-689].

A record has been established for this notice of filing under docket control
number [PF-689] (including comments and data submitted electronically as
described below). A public version of this record, including printed, paper
versions of electronic comments, which does not include any information
claimed as CBI, is available for inspection from 8:30 a.m. to 4 p.m., Monday
through Friday, excluding legal holidays. The public record is located in Room
1132 of the Public Response and Program Resources Branch, Field Operations
Division (7506C), Office of Pesticide Programs, Environmental Protection

Agency, Crystal Mall #2, 1921 Jefferson Davis Highway, Arlington, VA.

Electronic comments can be sent directly to EPA at: opp-docket@epamail.epa.gov

Electronic comments must be submitted as ASCII file avoiding the use of
special characters and any form of encryption.

The official record for this notice of filing, as well as the public version,
as described above will be kept in paper form. Accordingly, EPA will transfer
all comments received electronically into printed, paper form as they are
received and will place the paper copies in the official rulemaking record
which will also include all comments submitted directly in writing. The
official rulemaking record is the paper record maintained at the address in
"ADDRESSES" at the beginning of this document.

List of Subjects

Environmental protection, Administrative practice and procedure, Agricultural
commodities, Pesticides and pests, Reporting and recordkeeping requirements.

Dated: January 15, 1997.

Stephen L. Johnson, Director
Registration Division
Office of Pesticide Programs

[FR Doc. 97-1752 Filed 1-23-97; 8:45 am]
[Federal Register: January 24, 1997 (Volume 62, Number 16)] [Notices]
[Page 3700-3701]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]