[Federal Register Volume 62, Number 16 (Friday, January 24, 1997)]
[Notices]
[Pages 3691-3696]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-1752]
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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
[[Page 3692]]
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).
[[Page 3693]]
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).
[[Page 3694]]
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
[[Page 3695]]
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 10-6, 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.
[[Page 3696]]
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]
BILLING CODE 6560-50-F
