[Federal Register Volume 66, Number 135 (Friday, July 13, 2001)]
[Notices]
[Pages 36769-36777]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 01-17634]


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ENVIRONMENTAL PROTECTION AGENCY

[PF-1028; FRL-6785-8]


Notice of Filing a Pesticide Petition to Establish a Tolerance 
fora Certain Pesticide Chemical in or on Food

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

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SUMMARY: This notice announces the initial filing of a pesticide 
petition proposing the establishment of regulations for residues of a 
certain pesticide chemical in or on various food commodities.

DATES: Comments, identified by docket control number PF-1028, must be 
received on or before August 13, 2001.

[[Page 36770]]


ADDRESSES: Comments may be submitted by mail, electronically, or in 
person. Please follow the detailed instructions for each method as 
provided in Unit I.C. of the SUPPLEMENTARY INFORMATION. To ensure 
proper receipt by EPA, it is imperative that you identify docket 
control number PF-1028 in the subject line on the first page of your 
response.

FOR FURTHER INFORMATION CONTACT: By mail: Mary L. Waller, Registration 
Division (7505C), Office of Pesticide Programs, Environmental 
Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460; 
telephone number: (703) 308-9354; e-mail address: [email protected].

SUPPLEMENTARY INFORMATION:

I. General Information

A. Does this Action Apply to Me?

    You may be affected by this action if you are an agricultural 
producer, food manufacturer or pesticide manufacturer. Potentially 
affected categories and entities may include, but are not limited to:

------------------------------------------------------------------------
                                                          Examples of
           Categories                 NAICS codes         potentially
                                                       affected entities
------------------------------------------------------------------------
Industry                          111                 Crop production
                                  112                 Animal production
                                  311                 Food manufacturing
                                  32532               Pesticide
                                                       manufacturing
------------------------------------------------------------------------

    This listing is not intended to be exhaustive, but rather provides 
a guide for readers regarding entities likely to be affected by this 
action. Other types of entities not listed in the table could also be 
affected. The North American Industrial Classification System (NAICS) 
codes have been provided to assist you and others in determining 
whether or not this action might apply to certain entities. If you have 
questions regarding the applicability of this action to a particular 
entity, consult the person listed under FOR FURTHER INFORMATION 
CONTACT.

B. How Can I Get Additional Information, Including Copies of this 
Document and Other Related Documents?

    1. Electronically. You may obtain electronic copies of this 
document, and certain other related documents that might be available 
electronically, from the EPA Internet Home Page at http://www.epa.gov/. 
To access this document, on the Home Page select ``Laws and 
Regulations,'' ``Regulations and Proposed Rules,'' and then look up the 
entry for this document under the ``Federal Register--Environmental 
Documents.'' You can also go directly to the Federal Register listings 
at http://www.epa.gov/fedrgstr/.
    2. In person. The Agency has established an official record for 
this action under docket control number PF-1028. The official record 
consists of the documents specifically referenced in this action, any 
public comments received during an applicable comment period, and other 
information related to this action, including any information claimed 
as confidential business information (CBI). This official record 
includes the documents that are physically located in the docket, as 
well as the documents that are referenced in those documents. The 
public version of the official record does not include any information 
claimed as CBI. The public version of the official record, which 
includes printed, paper versions of any electronic comments submitted 
during an applicable comment period, is available for inspection in the 
Public Information and Records Integrity Branch (PIRIB), Rm. 119, 
Crystal Mall #2, 1921 Jefferson Davis Highway, Arlington, VA, from 8:30 
a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The 
PIRIB telephone number is (703) 305-5805.

C. How and to Whom Do I Submit Comments?

    You may submit comments through the mail, in person, or 
electronically. To ensure proper receipt by EPA, it is imperative that 
you identify docket control number PF-1028 in the subject line on the 
first page of your response.
    1. By mail. Submit your comments to: Public Information and Records 
Integrity Branch (PIRIB), Information Resources and Services Division 
(7502C), Office of Pesticide Programs (OPP), Environmental Protection 
Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460.
    2. In person or by courier. Deliver your comments to: Public 
Information and Records Integrity Branch (PIRIB), Information Resources 
and Services Division (7502C), Office of Pesticide Programs (OPP), 
Environmental Protection Agency, Rm. 119, Crystal Mall #2, 1921 
Jefferson Davis Highway, Arlington, VA. The PIRIB is open from 8:30 
a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The 
PIRIB telephone number is (703) 305-5805.
    3. Electronically. You may submit your comments electronically by 
e-mail to: [email protected], or you can submit a computer disk as 
described above. Do not submit any information electronically that you 
consider to be CBI. Avoid the use of special characters and any form of 
encryption. Electronic submissions will be accepted in Wordperfect 6.1/
8.0 or ASCII file format. All comments in electronic form must be 
identified by docket control number PF-1028. Electronic comments may 
also be filed online at many Federal Depository Libraries.

D. How Should I Handle CBI That I Want to Submit to the Agency?

    Do not submit any information electronically that you consider to 
be CBI. You may claim information that you submit to EPA in response to 
this document as CBI by marking any part or all of that information as 
CBI. Information so marked will not be disclosed except in accordance 
with procedures set forth in 40 CFR part 2. In addition to one complete 
version of the comment that includes any information claimed as CBI, a 
copy of the comment that does not contain the information claimed as 
CBI must be submitted for inclusion in the public version of the 
official record. Information not marked confidential will be included 
in the public version of the official record without prior notice. If 
you have any questions about CBI or the procedures for claiming CBI, 
please consult the person identified under FOR FURTHER INFORMATION 
CONTACT.

E. What Should I Consider as I Prepare My Comments for EPA?

    You may find the following suggestions helpful for preparing your 
comments:
    1. Explain your views as clearly as possible.
    2. Describe any assumptions that you used.
    3. Provide copies of any technical information and/or data you used 
that support your views.
    4. If you estimate potential burden or costs, explain how you 
arrived at the estimate that you provide.
    5. Provide specific examples to illustrate your concerns.
    6. Make sure to submit your comments by the deadline in this 
notice.
    7. To ensure proper receipt by EPA, be sure to identify the docket 
control number assigned to this action in the subject line on the first 
page of your response. You may also provide the name, date, and Federal 
Register citation.

II. What Action is the Agency Taking?

    EPA has received a pesticide petition as follows proposing the 
establishment and/or amendment of regulations for

[[Page 36771]]

residues of a certain pesticide chemical in or on various food 
commodities under section 408 of the Federal Food, Drug, and Comestic 
Act (FFDCA), 21 U.S.C. 346a. EPA has determined that this petition 
contains data or information regarding the elements set forth in 
section 408(d)(2); however, EPA has not fully evaluated the sufficiency 
of the submitted data at this time or whether the data support granting 
of the petition. Additional data may be needed before EPA rules on the 
petition.

List of Subjects

    Environmental protection, Agricultural commodities, Feed additives, 
Food additives, Pesticides and pests, Reporting and recordkeeping 
requirements.


    Dated: June 20, 2001.
Peter Caulkins,
Acting Director, Registration Division, Office of Pesticide Programs.

Summary of Petition

    The petitioner summary of the pesticide petition is printed below 
as required by section 408(d)(3) of the FFDCA. The summary of the 
petition was prepared by the petitioner and represents the view of the 
petitioners. EPA is publishing the petition summary verbatim without 
editing it in any way. The petition summary announces the availability 
of a description of the analytical methods available to EPA for the 
detection and measurement of the pesticide chemical residues or an 
explanation of why no such method is needed.

Aventis CropScience

PP 4F4281 and PP 0F6126

    EPA has received pesticide petitions (PP 4F4281 and PP 0F6126) from 
Aventis CropScience, P.O. Box 12014, 2 T.W. Alexander Drive, Research 
Triangle Park, NC 27709 proposing, pursuant to section 408(d) of the 
Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to 
amend 40 CFR part 180 by establishing a tolerance for residues of 
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-imidaxolidinecarboxamide and its 
metabolite,3-(3,5-dichlorophenyl)-2,4-dioxo-1-imidazolidine carboxamide 
in or on the raw agricultural commodity rapeseed (canola) at 1.0 part 
per million (ppm)(4F4281) and increasing the tolerance in or on the 
commodity almond hulls to 5.0 ppm (0F6126). EPA has determined that the 
petition contains data or information regarding the elements set forth 
in section 408(d)(2) of the FFDCA; however, EPA has not fully evaluated 
the sufficiency of the submitted data at this time or whether the data 
supports granting of the petition. Additional data may be needed before 
EPA rules on the petition.

A. Residue Chemistry

    1. Plant metabolism. The 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-imidazolidinecarboxamide, and its metabolite 3-(3,5-
dichlorophenyl)-2,4- dioxo-1-imidazolidinecarboxamide.
    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 --i. Canola. a. Foliar application. 
Residue data were reported for 11 field trials conducted in the major 
canola production areas of Canada. Most of the trial locations also 
represent major canola production areas of the United States. Residues 
ranged from 0.05 ppm to 0.62 ppm.
    b. Seed treatment. Residue data were reported for 8 field trials 
conducted in EPA Regions II, V, VII, and XI. The seed were treated with 
iprodione and planted with equipment customarily used for canola seed. 
Mature canola seed generated from the treated seed was collected at 
normal commercial harvest and analyzed. Iprodione residues were non-
detectable in all samples. The LOD was estimated to be 0.005 ppm.
    c. Processing. A canola processing study was found to be adequate 
by the Agency to support a tolerance on canola. Combined residues do 
not concentrate in canola meal, crude oil, or refined oil. Food or feed 
additive tolerances are not necessary.
    ii. Almonds. A residue study was conducted at five field trial 
locations in California, the only state with commercial almond 
production. The product was applied four times as airblast applications 
using equipment customarily used to apply pesticides to almonds at a 
nominal rate of 1.0 lb ai/A per application. This represents a rate 
increase compared to thecurrent label rate of 0.5 lb ai/A per 
application. All resulting iprodione residues in/on almond nutmeat 
samples were below the current tolerance of 0.3 ppm. Residues in almond 
hull samples ranged from 1.6 ppm to 3.9 ppm.

B. Toxicological Profile

    1. Acute toxicity. A complete battery of acute toxicity studies for 
iprodione was completed. Iprodione has low acute toxicity. The acute 
oral toxicity study in the rat resulted in LD50 of 3,629 
milligrams/kilograms 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 
four hour exposure to rats is > 5.16 mg/L. No skin or eye irritation or 
dermal sensitization is produced by iprodione. Based on the results of 
this study iprodione was placed in toxicity category III.
    2. Genotoxicty. Mutagenicity studies completed includeSalmonella 
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). Based on these data, the weight of evidence indicates that 
iprodione does not pose a mutagenic hazard to humans.
    3. Reproductive and developmental toxicity. The embryo/fetal 
toxicity and teratogenicity of iprodione were evaluated in Sprague-
Dawley rats at oral (gavage) dose levels of 0, 40, 90 or 200 mg/kg/day 
by gavage from day 6 through 15 of gestation. 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 NOAEL was observed at 90 mg/kg/day.
    The potential effects of iprodione on pregnancy and on parameters 
of sex differentiation have been investigated in the rat. Iprodione was 
administered by gavage at dose levels of 0, 20, 120 or 250 mg/kg/day to 
pregnant female Sprague -Dawley rats on days 6 to 19 of

[[Page 36772]]

gestation. Iprodione induced severe maternal toxicity, including 
mortality, at 250 mg/kg/day. Maternal body weight gain was reduced 
during the treatment period at 120 and 250 mg/kg/day. Mean fetal 
bodyweight was reduced at 250 mg/kg/day in both sexes. In the final 
report of the FQPA Safety Factor Committee, April 14, 1998, EPA 
concluded that for developmental toxicity, the NOAEL was 20 mg/kg/day 
and the LOAEL was 120 mg/kg/day based on decreased anogenital distance 
in the male pups. Aventis CropScience disagrees with EPA's evaluation 
of the study findings. The effects observed on AGD at 120 mg/kg/day are 
marginal (4.5% decrease) and of extremely doubtful biological 
significance considering the presence of substantial maternal toxicity 
(28% decrease in maternal body weight gain on GD 16-20). Nevertheless, 
it should be noted that since the completion of the FQPA Safety Factor 
Committee, April 14, 1998, EPA Dr. Earl Gray published in the January-
March 1999 issue of Toxicology and Industrial Health An International 
Journal, findings from a sex differentiation study conducted with 
iprodione. Dr. Gray reports no decrease in AGD in male rats when 
iprodione is administered at 100 mg/kg/day from gestational day 14 to 
postnatal day 3. EPA's findings support a change in the NOAEL to 100 
mg/kg/day. Additionally, EPA has relied and used the data generated by 
Dr. Gray to regulate the product, vinclozolin. The Agency should handle 
iprodione in a similar fashion and use the data generated by Dr. Gray 
at the 100 mg/kg/day dose level to regulate iprodione concerning this 
endpoint.
    The embryo/fetal toxicity and teratogenicity of iprodione were 
evaluated in rabbits dosed by gavage at levels of 0, 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 NOAEL was 60 mg/kg/day and the maternal NOAEL was 20 
mg/kg/day based on decreases in maternal body weight gain.
    In a multi-generation study, iprodione was administered to male and 
female Sprague-Dawley rats via dietary admixture at dose levels of 0, 
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 
bodyweight, 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 NOAELs for parental and 
offspring toxicity were 300 ppm and 1,000 ppm, respectively. Based on 
these data, it is concluded that Iprodione is not a reproductive 
toxicant.
    4. Subchronic toxicity. In a dermal toxicity study, rabbits were 
administered iprodione on the skin at dose levels of 0, 100, 500, and 
1,000 mg/kg/day for 21 days. There were no deaths or clinical signs of 
toxicity and no adverse effects were observed on body weight, food 
consumption, the skin, liver or kidneys. The NOAEL was 1,000 mg/kg/day, 
the highest dose tested (HDT).
    In a 90-day subchronic feeding study, rats were administered 
iprodione in the diet at doses of 0, 1,000, 2,000, 3,000, and 5,000 ppm 
(0, 78, 151, 252, and 355 mg/kg/day for males and 0, 89, 189, 266, and 
408 mg/kg/day for females). The NOAEL in this study was 1,000 ppm (78 
mg/kg/day for males and 89 mg/kg/day for females). The LOAEL was 2,000 
ppm (151 mg/kg/day for males and 189 mg/kg/day for females), based on 
decreased body weight gain, decreased food consumption and food 
utilization, organ weight effects, and microscopic lesions in the sex 
organs.
    5. Chronic toxicity and carcinogenicity- i. Non-rodent dog. In a 
first chronic feeding study, 6 Beagle dogs/sex/group were administered 
iprodione in the diet at dose levels of 0, 100, 600 and 3,600 ppm 
(equivalent to 0, 4.2, 26.6, and 148.9 mg/kg/day) for 12 months. There 
were no teatment-related for body weight, food consumption, or clinical 
signs observed in either male or female dogs. In the 3,600 ppm dose 
group, increases in alkaline phoshatase, SGOT, SGTP, and LDH levels 
were observed in both male and female dogs. Increases in absolute and 
relative liver and adrenal weights were observed in both male and 
female in the 3,600 ppm dose level. Increased erthrocytes with Heinz 
bodies were observed in the male dogs at both the 600 and 3,600 ppm 
dose groups. Additionally decreased prostate weights were seen in these 
same male dogs. A clear NOAEL was established at 100 ppm (4.2 mg/kg/
day). The LOAEL 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.
    A second chronic feeding study designed to complement the above 
study in dogs was conducted at dose levels of 0, 200, 300, 400 and 600 
ppm. In this study no clear indications of any toxicological effects 
were noted with the exception of minor effects seen at the 600 ppm dose 
group, which consisted of decreased red blood cell parameters. From the 
results of the two complementary studies, a conservative NOAEL of 400 
ppm (17.5 mg/kg/day in males and 18.4 mg/kg/day in females) and a LOAEL 
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.
    ii. Rodent --Rat. a. Study A. In the initial chronic/
carcinogenicity 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, no treatment-related 
effects were observed for parameters measured (i.e., body weight, 
clinical signs, and etc.) No treatment-related tumors were observed in 
this study. The NOAEL of iprodione in rats was observed to be greater 
than 1,000 ppm (i.e. >50 mg/kg/day), the HDT. Therefore, the rat 
chronic/ carcinogenicity study discussed below was repeated to comply 
with EPA guidelines as in the initial study a MTD was not attained.
    b. Study B. In the second study, Sprague Dawley rats were 
administered 150, 300, or 1,600 ppm iprodione technical in the diet for 
24 months. The NOAEL 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). The NOEL for 
carcinogenicity in males in this study was 300 ppm (12.4 mg/kg/day) and 
the LEL was 1,600 ppm (69 mg/kg/day). There was no indication of 
carcinogenicity in females at any dose levels.
    The following summarizes the findings at the mid and high dose 
levels in this study:
    In the high dose group 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.
    Terminal sacrifice: Increased relative liver weight was noted in 
males receiving 300 or 1,600 ppm, significantly increased testes weight 
were recorded at 1,600 ppm and slight increases in relative adrenal and 
thyroid weights in males were recorded at 1,600 ppm.
    Interim sacrifice: An increased incidence of centrilobular 
hepatocyte

[[Page 36773]]

enlargement was seen in males at 300 and 1,600 ppm and an increased 
incidence of extramedullary haemopoiesis and haemosiderosis was 
observed in female rats receiving 1,600 ppm. In the adrenals, 
generalized and/or focal enlargement of cells of the zona glomerulosa 
was observed in numerous male and female rats treated at 1,600 ppm. A 
high proportion of rats in this group revealed generalized rarefaction 
and fine vacuolation of zona fasciculata; only one female in the 300 
ppm group showed this latter change. A high proportion of male rats 
also showed a generalized fine vacuolation of zona reticularis.
    Terminal sacrifice: In the testes, interstitial cell hyperplasia 
was observed at 300 and 1,600 ppm and an increased incidence of atrophy 
of seminiferous tubules was noted in rats treated with 1,600 ppm. In 
the epididymides, reduced spermatozoa were noted at 300 and 1,600 ppm 
and an increased incidence of spermatozoa absent was noted in males 
treated with 1,600 ppm. An increased atrophy of the prostate was noted 
at 1,600 ppm. In seminal vesicles, secretory colloid was absent/empty 
in rats treated with 1600 ppm and reduced secretion was also observed 
at 300 ppm. In the spleen, the incidence of minimal haemosiderosis was 
increased amongst female rats treated with 300 or 1,600 ppm. In the 
adrenals, an increased incidence of either generalized or focal 
enlargement of cells of zona glomerulosa for males and females treated 
with 1600 ppm, often with generalized vacuolation of zona fasciculata 
and zona reticularis for males treated with 1,600 ppm were noted. 
Generalized vacuolation of zona reticularis was also observed in male 
rats treated at 300 ppm.
    No increase in tumor incidence was noted at interim sacrifice.
    Macroscopic examination of animals found dead or sacrificed in 
extremis did not show an increased incidence of any tumor type. In the 
high dose group there was an increase in the incidence of both 
unilateral and bilateral benign interstitial cell tumors in the testes 
of males. No treatment-related neoplastic lesions were observed in the 
150 or 300 ppm dose levels.
    iii. Rodent --Mouse. a. Study A. In the 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, no treatment-related effects were observed for 
parameters measured (i.e., body weight, clinical signs, and etc.). No 
treatment-related tumors were observed in this study. In this study, 
the NOAEL of Iprodione in mice was greater than 1,250 ppm (i.e. > 178.6 
mg/kg/day). Therefore, the mouse life-time feeding study discussed 
below was repeated to comply with EPA guidelines as in the initial 
study a MTD was not attained.
    b. Study B. In the second study (MRID 42825002), iprodione 
technical was administered at dietary concentrations of 160, 800 or 
4,000 ppm to CD-1 mice for 99 weeks. The NOAEL 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). The NOAEL 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).
    The following summarizes the findings at the mid and high dose 
levels in this study:
    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.
    Biochemistry investigations at week 52 revealed significant 
increases in GOT and GPT values in both sexes at 4,000 ppm.
    At interim sacrifice, Significantly higher liver weights and 
slightly higher adrenal weights were noted in animals of both sexes at 
4,000 ppm. A decrease in uterine and ovarian weights was also observed 
at 4,000 ppm although they were not statistically significantly reduced 
in comparison with the controls. At terminal sacrifice the following 
organ weight changes were noted at 4,000 ppm: Significant increases in 
liver weights in both sexes, marginal increases in thyroid weights in 
both sexes and significantly decreased uterus weights in females. A 
decrease in ovarian weights was also noted at 4,000 ppm, although the 
reduction was not statistically significant.
    At interim sacrifice, non-neoplastic findings were only observed in 
mice treated with 4,000 ppm. In the livers of both sexes an increase in 
the incidence and degree of centrilobular hepatocyte enlargement was 
observed with increased incidence of centrilobular hepatocyte 
vacuolation in females. In the adrenals, an increased incidence of 
hypertrophy of the cells of the zona fasciculata was observed in 
females. In the testes, generalized vacuolation and hypertrophy of the 
interstitial cells was observed in most males. In the ovaries, 
luteinisation of the interstitial cells and absence of corpora lutea 
were observed.
    At terminal sacrifice, the following non-neoplastic lesions were 
noted: In the liver, single and multiple areas of eosinophilic 
hepatocytes, focal fat containing hepatocytes and centrilobular 
hepatocyte enlargement were present more frequently in both sexes 
treated at 4,000 ppm with minimal centrilobular hepatocyte enlargement 
in female mice treated with 800 ppm. In male mice receiving 4,000 ppm, 
pigmented macrophages were more frequently observed. In the testes, an 
increased incidence of generalized vacuolation and hypertrophy of 
interstitial cells of the testes were noted in male mice treated with 
800 and 4,000 ppm. In the ovaries, luteinisation of the interstitial 
cells, absence of corpora lutea, arrest of follicular development were 
more frequently noted in female mice treated with 4,000 ppm. In the 
stomach, an increased incidence of hyperkeratosis of the non-glandular 
stomach was noted in male mice treated with 800 and 4,000 ppm. In the 
spleen, haemosiderosis was more frequent in females treated with 4,000 
ppm. In the kidneys amyloidosis/amyloid deposits and cortical scarring 
were noted in female mice treated with 4,000 ppm.
    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.
    c. Conclusion. The chronic reference dose (RfD) for iprodione 
should be 0.0725 mg/kg/day based on the NOEL of 7.25 mg/kg/day 
determined from the rat combined chronic toxicity and carcinogenicity 
study. Aventis CropScience believes that using an uncertainty factor of 
100 to account for inter- and intra-species variations is adequate to 
protect all population subgroups.
    Aventis CropScience have developed a complete and reliable database 
which demonstrates that pre-and/or postnatal exposure to iprodione does 
not result in an increased susceptibility to the developing organism in 
comparison to the adult.
    Iprodione has no teratogenic potential, even at maternally toxic 
dose levels. In addition the results of a recently completed study have 
confirmed that iprodione has no effects on sex differentiation. An 
acceptable two generation rat reproduction study indicated that 
iprodione has no adverse effects on reproductive performance,

[[Page 36774]]

fertility, fecundity, sex ratio or ano-genital distance. Effects on pup 
weight and viability were only noted in the presence of severe parental 
toxicity.
    These studies constitute a very stringent test of developmental and 
reproductive toxicity because of the types of dosing regimens employed 
(e.g. MTD throughout the sensitive period of organogenesis), the large 
numbers of animals examined, and the multiplicity of parameters 
measured.
    The Agency Hazard Identification Review Committee (HIARC) concluded 
``based on the weight-of-the-evidence of all available studies, the 
HIARC concluded that there is no increased susceptibility to rat and 
rabbit fetuses following in utero and/or post natal exposure to 
iprodione. Additionally, HED also stated that the special prenatal 
study in rats ...''demonstrated no indication of increased 
susceptibility. Therefore, based on these statements and available data 
base for iprodione, a standard 100-fold UF (10-fold for inter-species 
extrapolation and 10-fold for intra-species variability) is sufficient 
to assure protection for all population sub-groups, including females 
of child-bearing age, infants and children, to dietary, residential or 
occupational exposure to iprodione residues.
    iv. Supplementary information and 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.
    a. Background and introduction. 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.
    In November 1997, HED's Cancer Assessment Review Committee re-
affirmed its position for the risk characterization of iprodione on the 
basis that a definitive mode of action for the formation of either 
tumor type had not yet been provided.
    Aventis CropScience has since produced significant new data to 
address all the Agency's outstanding issues relative to the induction 
of rat Leydig cell tumors by iprodione. These data provide a definitive 
mode of action for the induction of rat Leydig cell tumors and support 
a move to a MOE (i.e. non-linear) approach for cancer risk assessment 
for this tumor type. Work has also been conducted on the mechanism of 
hepatic toxicity and carcinogenicity in the mouse.
    b. Mechanism of Leydig cell toxicity in the rat. Aventis 
CropScience 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. These 
conclusions are based on the available data from the following areas:
    (1) Genetic toxicity of iprodione. The genotoxicity of iprodione 
has been assessed in a large number of assays conducted using bacteria, 
yeast and mammalian cells and whole animals. A single positive result 
was observed in an outdated and deficient assay designed to assess DNA 
damage using Bacillus subtilis. All other genotoxicity assays, 
including those conducted in vivo, were found to be negative. This 
considerable body of data indicates that iprodione does not pose a 
mutagenic hazard to humans. A hormonally-mediated mechanism of 
carcinogenesis has therefore been investigated. In vivo mechanistic 
studies: Iprodione has recently been shown to decrease plasma 
testosterone levels significantly in rats in a dose-dependent manner at 
dose levels analogous to those at which tumors were induced in the rat 
bioassay (approx. 70 mg/kg/day). Following a single gavage 
administration of iprodione, plasma testosterone levels were reduced 2 
and 4 hours post dosing. Thereafter plasma testosterone levels returned 
to baseline, presumably as a consequence of the compensatory increase 
in plasma LH which was significantly increased 2 and 4 hours post 
dosing (MRID 44729201). This profile of transient hormonal changes 
mirrors that of the classic testosterone biosynthesis inhibitor 
ketoconazole.
    In previous in vivo studies in the rat, detectable hormonal changes 
have been limited to increases in LH and FSH levels following 14/15 
days of iprodione treatment and alterations in the secretion pattern of 
LH and testosterone following 30-days of treatment (MRID 43535002, 
44171903). The rapid reversibility of the hormonal changes observed in 
the recent study (MRID 44729201) helps to explain the absence of 
detectable decreases in testosterone levels in vivoin previous studies. 
In the 15-day gavage study, blood sampling was performed 12-14 hours 
following the final gavage (MRID 43535002). In the 14-day feeding 
study, blood samples were not taken until mid- to late morning i.e. 
several hours following the conclusion of the animals' anticipated 
nocturnal feeding (MRID 44171903). Since, in the recent study, plasma 
testosterone levels were observed to return to normal approximately 6 
hours post dosing (MRID 44729201) it is probable that no significant 
decreases in circulating testosteronelevels were demonstrated in 
earlier experiments due to inappropriate sampling times following 
iprodione administration.
    (2) Combined chronic toxicity/carcinogenicity studies. Pathologic 
evidence of a chronic perturbation of steroidogenesis and/or 
compromised testosterone availability was observed in the rat bioassay. 
An increased incidence of Leydig cell hyperplasia was observed both at 
the interim and terminal sacrifices. Other indicators of testosterone 
deficiency noted at terminal sacrifice included reductions in 
epididymal spermatozoa, reduced secretion in the seminal vesicles, and 
decreased weight of seminal vesicles.
    Similar effects on steroid hormone producing organs such as the 
adrenal cortex, testis and ovary have been observed in other subchronic 
and chronic studies conducted with iprodione in rodents and dogs. 
Hypertrophy and intracellular accumulation of lipid, most likely due to 
an interference with cholesterol utilization in steroidogenesis, was 
observed in the interstitial cells of the mouse ovary and in the zonal 
fasciculata of the adrenal cortex in rodents and dogs.
    (3) In vitro mechanistic studies. No clear evidence of competitive 
binding to the androgen receptor was found for iprodione or its major 
metabolites.
    Iprodione and certain metabolites (RP36112 and RP36115) have been 
shown to rapidly and reversibly inhibit testosterone secretion from 
cultures of porcine Leydig cells. Inhibition was found to occur at 
media concentration of 1-10 ug/ml. No inhibitory effects on 
testosterone secretion were noted at media concentrations of iprodione 
or its active metabolites below 1 ug/ml demonstrating a threshold for 
this effect. Iprodione has also been shown to inhibit testosterone 
secretion from rat testicular sections in vitro at similar media 
concentration.
    The mode of action whereby iprodione and its metabolites (RP36112 
and RP36115) modulates steroidogenesis in Leydig cells has been 
identified using porcine Leydig cell cultures. Iprodione and RP36112 
interfere with the active transport of cholesterol substrate into 
mitochondria while another metabolite RP36115 appears to inhibit 
steroidogenic enzymes.

[[Page 36775]]

    (4) Toxicokinetic study. Groups of male Sprague Dawley rats 
received a single oral administration of 14C-iprodione at 
the nominal rate of 70 mg/kg. Levels of iprodione and its metabolites 
RP36112 and RP36115 were estimated in the testes and plasma 0.5, 1, 2, 
4, 6, 10, 24, and 48 hours post dose.
    The results of this study indicate that the changes previously 
observed in plasma testosterone and LH levels at 70 mg/kg were most 
likely induced by the presence of RP36112, RP36115, and/or iprodione, 
which were present in the testes as early as 0.5 hours post dosing. At 
2 hours post dosing, when maximal changes in plasma testosterone levels 
were observed to have occurred, the concentrations of RP36115 and 
iprodione were already at, or near, peak values in the plasma and 
testes. These levels were maintained for at least 8 hours, after which 
the levels rapidly declined to very low concentrations by 24 hours post 
dosing. It is also noteworthy that the range of concentrations of 
iprodione and RP36115 achieved in the testes samples by 2 hours post 
dosing were of the order of 5.6-6.8 ug/g which fall within the range of 
concentrations known to provide inhibition of testosterone secretion in 
vitro (1-10 ug/ml).
    c. Hepatotoxicity and carcinogenicity in male and female mice. 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 NOAELs exist for these 
effects. In a 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 CYP 2B and CYP 3A and cellular proliferation 
in a similar manner to the well established liver promotor 
phenobarbital (MRID 44171902). This mechanism is not relevant to humans 
based on the pharmaceutical use of phenobarbital in humans for over 50 
years.
    d. Conclusion. As demonstrated above, the administration of 
iprodione to the Sprague Dawley rat results in transient hormonal 
imbalances in vivo (decreased plasma testosterone and increased plasma 
LH). It is well established that the chronic administration of a number 
of xenobiotic chemicals which cause similar changes to the 
hypothalamic-pituitary-gonodal axis result in the development of Leydig 
cell tumors in highly sensitive species, such as the rat. The dose-
response for this type of hormonally-mediated effect is expected to be 
non-linear
    The biochemical basis for this hormonal imbalance is an inhibition 
of testosterone biosynthesis by iprodione and its active 
metabolites(s). Testicular concentrations of iprodione, and at least 
one of its active metabolites, attained in vivo are within the range of 
those demonstrated to inhibit testosterone biosynthesis in Leydig cells 
in vitro. The mode of action whereby iprodione modulates Leydig cell 
steroidogenesis is via a reversible interference with the active 
transport of cholesterol into the mitochondria of Leydig cells as 
opposed to vinclozolin and procymidone which interact directly with the 
androgen receptor. As shown with vinclozolin and procymidone, direct 
interaction with the androgen receptor leads to marked effects on 
reproduction systems. However, iprodione does not lead to such marked 
reproductive effects. In fact, iprodione has no effects on reproductive 
parameters, sex differentiation, and other parameters measured in these 
study types.
    For iprodione, the male interstitial cell tumors seen only at the 
high dose in the lifetime rat study was due to 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 described above and (iii) the 
consensus of scientific experts that benign Leydig cell tumors in the 
rat are not valid predictors of human disease as will be discussed 
below.
    Furthermore, concerning the testicular tumors (Leydig cell tumors) 
and as stated in the recent Federal Register notice for Vinclozolin 
April 21, 2000 (65 FR 21427),(FRL-6555-6) ``the relevance of Leydig 
cell tumors to men should be seen in the light that this is a very rare 
human tumor and that the precursor change (i.e. Leydig cell 
hyperplasia) has not been observed in patients treated with flutamide. 
In addition, the toxicology of cimitidine, an H2-receptor antagonist 
with anti-androgenic properties results in a size reduction and atrophy 
of the prostate and seminal vesicles in chronic rat studies. Moreover, 
an increase in benign Leydig cell tumors, and a decrease in pituitary 
and mammary tumor incidence were noted; hence a toxicity potential not 
unlike that of vinclozolin is evident. Despite the fact that over 30 
million patients have been treated with cimitidine, this therapeutic 
agent has been demonstrated to be extremely safe, clearly indicating 
that the rat Leydig cell tumors have very little relevance for 
humans.'' A similar conclusion is drawn by other investigators ``Leydig 
cell tumors of the rat have limited significance because of the 
fundamental differences in testicular control mechanisms.'' It is 
therefore concluded that the observed neoplastic changes do not pose a 
relevant hazard to humans. EPA in the September 1996, Cancer Peer 
Review Document for vinclozolin, came to the same basic conclusion that 
the Leydig cell tumors are a very uncommon tumor type in humans which 
implies the threshold dose for humans would be greater than for rats. 
EPA based this conclusion on the work performed by Dr. Charles C. Capen 
(Professor Charles C. Capen, Leydig Cell Tumors: Pathology, Physiology, 
and Mechanistic Considerations in Rats, The Toxicology Forum, 1994 
Annual Summer Meeting, p. 110). Consistent with the data and the advice 
of the OPP Scientific Advisory Panel and using its Guidelines for 
Carcinogen Risk Assessment published September 24, 1986 (51 FR 33992), 
EPA has classified the potent anti- androgen, vinclozolin, as a Group C 
chemical-possible human carcinogen. The Agency Cancer Peer Review 
Committee (CPRC) chose an-linear approach margin (MOE) to regulate 
vinclozolin. More recently, the Agency in its recent Federal Register 
notice of May 26, 2000 (65 FR 34179),(FRL-6588-6) stated the following, 
``Vinclozolin is classified as a Group C carcinogen based on Leydig 
(interstitial testicular) cell tumors in a perinatal rat developmental 
toxicity study. A nonlinear (MOE) approach was determined to be 
appropriate based on the weight of the evidence conclusion that tumor 
induction is via an anti-androgenic effect mechanism.'' The

[[Page 36776]]

Agency should handle iprodione in a similar fashion and regulate 
iprodione via the MOE Approach.
    Supporting this position, Aventis CropScience notes, that the joint 
meeting of the Food and Agriculture Organization of the United Nations 
(FAO) Panel of Experts on Pesticide Residues and the World Health 
Organization (WHO) Expert Group on Pesticide Residues determined in 
1995 that a risk assessment utilizing a margin of safety approach with 
an uncertainty factor of 100 applied to the no oberserved adverse 
effect level (NOAEL) from the chronic rat study was appropriate to 
provide adequate dietary safety for Iprodione.
    Again, Aventis CropScience 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.
    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- 
imidazolidinecarboxamide, 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-imidazolidinecarboxamide, 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. The resulting endocrine toxic effect 
due to iprodione is fairly moderate compared to that produced by potent 
endocrine disruptors such as Flutamide, Vinclozolin (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 (testis, liver, ovary) tumors only develop on pre-existing 
non-neoplastic lesions (cell hypertrophy/vacuolation, hyperplasia) and 
Aventis CropScience concludes that 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. 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. Aventis CropScience expects that potential 
residues resulting from the proposed use of iprodione on canola and the 
increased application rate on almonds 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 reference dose (RfD). A chronic dietary exposure analysis for 
iprodione residues in canola only was conducted for the overall 
population and 0 26 population subgroups, including infants and 
children, to determine the incremental risk resulting from the proposed 
use on canola. Chronic exposure estimates from residues in canola only 
were less than 0.1% of the RfD for all population subgroups examined. 
The corresponding lifetime cancer risk was estimated to be 9.44 x 
10-9 or less for all lifetime population groups. Chronic 
exposure estimates from residues in almonds only were also less than 
0.1% of the RfD for all population subgroups examined. The 
corresponding lifetime cancer risk was estimated to be 2.23 x 
10-8 8 or less for all lifetime population groups. Thus, the 
incremental chronic dietary risk resulting from the proposed use on 
canola and the increased application rate on almonds does not increase 
the cancer risk to an unacceptable level.
    Acute dietary exposure was estimated for the population subgroup of 
concern, women 13 years of age and older. Utilizing the Tier 3 
methodology (Monte Carlo) for acute exposure, margins of exposure 
(MOEs) up to the 99.9th percentile of exposure for this population 
subgroup were at least 351 for currently registered crops. Adding 
residues in canola and residues in almonds that reflect the revised 
application rate resulted in MOEs of 351 and 366, respectively, at the 
99.9th percentile of exposure. The EPA has determined that a MOE of at 
least 300 is acceptable for iprodione.
    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: (a) 
Acute dietary; (b) chronic dietary; (c) cancer; (d) short-term; and (e) 
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 at this time.
    Since the completion of the RED, EPA recently 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. Aventis has since submitted to the Agency 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.
    Aventis CropScience expects that potential residues resulting from 
the proposed use of iprodione on canola and the proposed application 
rate increase on almonds will not significantly affect EPA's exposure 
and risk assessments for drinking water. Most of the use on canola will 
occur in the states of North Dakota and Minnesota. The amount of 
product that

[[Page 36777]]

will be used on canola is expected to be minimal compared to that used 
on currently registered crops. The total amount of product used on 
almonds is not expected to increase significantly.
    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, Aventis CropScience 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 compound.

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 reference dose (RfD). Chronic dietary 
exposure to iprodione residues in/on canola only was estimated to be 
less than 0.1% of the RfD for the general U.S. population and 26 
population subgroups. The lifetime cancer risk from potential iprodione 
residues in canola only was estimated to be 8.27 x 10-9 for 
the overall U.S. population. For the most highly exposed population 
subgroup, nonhispanics other than black or white, the cancer risk was 
estimated to be 9.44 x 10-9. Chronic dietary exposure to 
iprodione residues in/on almonds only was also estimated to be less 
than 0.1% of the RfD for the general U.S. population and 26 population 
subgroups. The lifetime cancer risk from potential iprodione residues 
in almonds treated at the increased application rate was estimated to 
be 1.36 x 10-8 for the overall U.S. population. For the most 
highly exposed population subgroup, those living in the Pacific region 
of the U.S., the cancer risk was estimated to be 2.23 x 
10-8. The cancer risk estimates for currently registered 
crops, drinking water, almonds treated at the proposed increased 
application rate, and the proposed use on canola are within the range 
the Agency generally considers negligible for excess life-time cancer 
risk.
    For crops with existing tolerances, acute dietary exposure at the 
99.9th percentile for women 13 years of age and older resulted in a MOE 
of 351. Separate acute exposure analyses conducted for (i) all 
registered crops including almonds treated at the increased application 
rate and (ii) all registered crops and canola, resulted in MOEs of 351 
and 366, respectively, for this subgroup. Iprodione uses are not 
expected to impact ground water. Upper bound estimates of iprodione in 
surface waters from conservative screening models indicate 
concentrations of a few parts per billion.
    Both the chronic and acute dietary exposure assessments clearly 
demonstrate a reasonable certainty that no harm will result from the 
use of iprodione on currently registered crops, including almonds 
treated at the increased application rate, and canola.
    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 NOAELs and LOAELs 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. Chronic dietary 
exposure to iprodione residues in/on canola only was estimated to be 
less than 0.1% of the RfD. Chronic dietary exposure to iprodione 
residues in/on almonds only (treated at the increased application rate) 
was also estimated to be less than 0.1% of the RfD. EPA generally has 
no concern for exposures below 100% of the RfD. 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 use on canola and for the increased application rate on 
almonds. 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 for iprodione on rape seed is established at 0.5ppm. In 
Canada, PMRA supports the establishment of a MRL of 1.0 ppm for 
iprodione on canola and a temporary registration was granted. A Codex 
MRL for iprodione on almonds is established at 0.2 ppm.
[FR Doc. 01-17634 Filed 7-12-01;8:45 am]
BILLING CODE 6560-50-S