Bayer CropScience Report NO.

Page

111 1 , 72,

Test Order/DCI # EDSP-109801-174

Title:

150-DAY RESPONSE TO EPA'S TEST ORDER FOR

ENDOCRINE SCREENING ON IPRODIONE

Volume 1 of 2

Guideline:

OPPTS 890 Guideline Series

Authors:

Joseph M. Breier, Ph.D.

Date:

June 16, 2010

Report ID:

US0059

Bayer CropScience

P.O. Box 12014

Research Triangle Park, NC 27709

• * •

Page 1 of 47
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STATEMENT OF DATA CONFIDENTIALITY CLAIMS

No claim of confidentiality is made for any information contained in this document on the basis of

its falling within the scope of FIFRA, Section 10(d)(l)(A)(B), or (C). This statement supersedes any

other confidentiality claims appearing on title pages of study reports in Appendix 1.

Robyn Kneen, Registration Manager

Company Agent: Robyn Kneen

Bayer CropScience

Regulatory Manager

Signature/Date: _ _ June 16,2010
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GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT

This report is not subject to the principles of 40 CFR 160, Good Laboratory Practices

Standards (FIFRA), as promulgated in Federal Register, final rule, August 17,1989.

June 16, 2010

Joseph M. Breier, Ph.D. Date

Toxicologist

Bayer CropScience

June 16, 2010

Robyn Kneen

 Date

Sponsor / Submitter

Bayer CropScience
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150-DAY RESPONSE TO ERA'S TEST ORDER FOR

ENDOCRINE SCREENING ON IPRODIONE

On January 7, 2010, EPA issued a Test Order for endocrine screening on iprodione. In this Order,

EPA provides the option to cite or submit existing data to satisfy part or all of the testing.

Specifically, EPA states, "... such hazard-related data would be of high quality and achieves the

objective of Tier 1 assays to provide reasonable assurance that a chemical does or does not have the

potential to interact with the estrogen, androgen, or thyroid systems." In response to the Order,

Bayer CropScience (BCS) believes that existing data on iprodione are adequate to assess the

potential for this compound to interact with estrogen, androgen and thyroid systems. Much of this

existing data comes from high quality regulatory studies which have been reviewed by EPA and are

classified as acceptable. The whole organism apical endpoints in these studies, such as reproduction

parameters, organ weights, histopathology, and sexual development, reflect the culmination of any

effects on the biological endpoints being assessed in EPA's Tier 1 endocrine screening battery.

Endocrine-related apical endpoints, which have been assessed in the Guideline studies on iprodione

that are functionally equivalent to endpoints assessed in EPA's Tier 1 endocrine screening battery,

are summarized in Tables la and Ib. Functionally equivalent, in this context, refers to data of a

suitable nature and quality to provide the same essential predictive information on a chemical, even

if different methods and procedures were used.

In addition to considering data provided by high quality Guideline studies, BCS has evaluated

information reported in the literature when available. In general, the approach of Klimisch et al.

(1997) has been utilized to evaluate systematically the quality of work reported in the literature.

This approach is recognized and used by regulatory authorities including its use in Europe in

developing the International Uniform Chemical Information Database (IUCLID). The data reliability

criteria presented by Klimisch etal. are similar to the criteria recommended by EPA in the High

Production Volume Program under TSCA. Assays reported in the literature have also been

compared to the relevant assay described in the OPPTS 890 Guideline Series to identify major

differences between the specific assay included in EPA's validation program for Tier 1 screening and

the one reported in the literature.

Estrogen System

Several assays (estrogen receptor (ER) binding, ERtranscriptional activation, uterotrophic, pubertal

female, and fish short-term reproduction) have been included in the EDSP Tier 1 battery to assess

the potential of a chemical to affect the estrogen signaling pathway. While the assays described in

EPA's OPPTS 890 Guideline Series have not been conducted with iprodione, adequate information

exists to assess its potential to interfere with the estrogen system. As summarized in Tables la and

Ib, relevant and sufficient data are available from many guideline toxicology studies, including

multi-generation rat reproduction, developmental toxicity (rat and rabbit), and developmental

neurotoxicity studies, as well as subchronic and chronic feeding studies in the rat, mouse, and dog.

These studies were conducted in accordance with US EPA Guidelines, under GLP conditions, and

have been reviewed and classified as acceptable by the EPA.
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Other Scientifically-Relevant Information - in vivo studies:

Endpoints from guideline studies that are relevant to assess a compound's potential for estrogenic

or anti-estrogenic activity are listed in Tables la and Ib. This includes the results from a multigeneration reproduction study in rats (Henwood, 1991), a sex differentiation study in rats (RepettoLarsay, 1997), developmental toxicity studies in rats (Tesh et al., 1986) and rabbits (Rodwell, 1985),

subchronic toxicity studies in mice (Fryer et al., 1990a) and rats (Fryer et al., 1990b), and chronic

toxicity studies in mice (Chambers et al., 1993), rats (Chambers et al., 1992), and dogs

(Broadmeadow, 1984; Kangas, 1991). Key design elements and results from these studies are

described below.

In a two-generation rat reproduction study (Henwood, 1991) conducted according to EPA Guideline

83-4, two litters per generation were produced, allowing extensive evaluation of the test substance

on reproduction and offspring development. In this study, FO adults were exposed to iprodione in

the diet for 10 weeks prior to mating and then throughout mating, gestation, and lactation periods.

Indirect exposure of the Fl offspring covers the in utero and lactation periods, with direct

consumption of the treated diet by the pups starting around PND 12, continuing after weaning on

PND 21 for 10 weeks before mating, and throughout mating, gestation, and lactation for pups

selected to become Fl parents. Since the exposure duration for the Fl generation exceeded that

required by the pubertal assay, this study provides a more rigorous assessment of a compound's

potential to affect endocrine-related endpoints. The highest dose level tested in this reproduction

study was 3000 ppm iprodione in the diet, but due to the level of toxicity observed, the level was

decreased to 2000 ppm at pairing of the Fl adults for the F2 litters. Therefore, Fl adults received

2000 ppm iprodione in the diet throughout mating, gestation, and lactation for the F2 litters. The

high dose of iprodione administered corresponded to 157.7 mg/kg/day for FO males, 212.6

mg/kg/day for FO females, 151.9 mg/kg/day for Fl males, and 189.7 mg/kg/day for Fl females.

Treatment with iprodione did not affect mating, or male or female fertility in any generation.

However, effects on offspring viability and growth were seen at 3000/2000 ppm in both the FO and

Fl generations. Although no treatment-related clinical observations were seen in adult animals of

either generation, offspring from the high-dose groups exhibited smallness of size, reduced mobility,

unkempt appearance, hunching, or tremors. Parental toxicity was evident by significantly lower

body weights and body weight changes for males and/or females from the 1000-, 3000- (FO) and

2,000/3,000-ppm (Fla) groups. All effects in offspring were observed only at the parentally toxic

doses of 2000/3000 ppm. At 3000 ppm, the number of live pups per litter was decreased on Day 0

among Fla litters, and on Days 0 and 4 among Fib litters. The viability index was decreased in Fla

litters, while the viability and lactation indices were both decreased among Fib litters. Pup body

weights were also decreased throughout lactation across all Fl litters at 3000 ppm.

For Fla dams at 2000 ppm, the duration of the first gestation was significantly shorter compared to

the control group. The number of live pups per litter was also decreased on Day 0 among F2a litters

and on Days 0 and 4 among F2b litters at 2000 ppm. The total number of pups delivered per litter

was decreased among all F2 litters in this dose group. In general, pup body weights were also

decreased throughout lactation across all Fl litters at 2000 ppm. The number of implantation sites
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per dam, post-implantation loss per litter, and pup sex ratios were similar across all treatment

groups for both litters within each generation. No anomalies of external genitalia were noted for Fl

or F2 pups. There were no gross or histopathological changes observed in any reproductive organs

examined (cervix, coagulating gland, prostate, epididymides, seminal vesicles, testes, uterus, or

vagina), pituitary, or liver for adult animals of either sex or generation.

In addition to the multigeneration study, a study was conducted to assess the potential effect of

iprodione on sex differentiation (Repetto-Larsay, 1997). When administered daily from gestation

day 6 to 19 at doses of 0,20,120, or 250 mg/kg/day, iprodione produced severe maternal toxicity at

250 mg/kg/day including mortality. Further evidence of maternal toxicity at 120 and 250 mg/kg/day

consisted of statistically significant reductions in body weight gain and corrected body weight

change, as well as macroscopically enlarged adrenals in 7/25 and 20/25 dams, respectively.

Cesarean sections performed on gestation day 20 showed that iprodione had no effect on group

means and litter averages for corpora lutea, implantations, litter size, live fetuses, and early and late

resorptions at any dose level tested. Mean fetal weights were statistically lower at 250 mg/kg/day

for both sexes. No morphologically abnormal differentiation in external and internal genitalia was

found in any iprodione-exposed fetus. The external sex of fetuses was identical to the sex

determined at internal examination, and the sex ratio was within normal values for all treated

groups. In female fetuses, a slight increase in the anogenital index (i.e. anogenital distance/fetal

body weight) only was observed at 250 mg/kg/day, a dose of iprodione which resulted in significant

maternal toxicity. Results for male fetuses are discussed under the section on the androgen system

below.

Developmental toxicity studies in rats (Tesh et al., 1986) and rabbits (Rodwell, 1985) were

conducted according to guidelines 83-3(a) and 83-3(b) with daily dosing of dams/does from

gestation day 6 to 16 and from gestation day 6 to 18, respectively. In rats, treatment with iprodione

up to 200 mg/kg/day did not affect the number of implantations, live young, resorptions, pre- and

post-implantation losses, and mean placental weights. At 200 mg/kg/day in rats, there was an

increased incidence of space between the body wall and organs, indicating slight fetal immaturity,

but fetal evaluations showed no evidence of any adverse morphogenic change in response to

treatment with iprodione. In the rabbit developmental study, the number of viable fetuses was

slightly decreased, while post-implantation loss was slightly increased at the high dose of 200

mg/kg/day; these effects were due to two females that had total litter resorption. The high dose of

200 mg/kg/day also resulted in significant mean maternal body weight loss throughout the entire

treatment period and an increased rate of abortions, indicating that the decrease in the number of

viable fetuses and the slight increase in post-implantation loss were due to significant maternal

toxicity at this dose. The mean number of implantation sites, corpora lutea, fetal body weight, and

fetal sex ratios were not affected at any dose of iprodione. Furthermore, no treatment-related

external anomalies or malformations were observed in fetuses.

Subchronic toxicity studies were conducted in mice (Fryer et al., 1990a) and rats (Fryer et al., 1990b)

according to guideline 82-1. Effects on ovaries and uterus were observed in both studies but only at

levels that either exceeded the limit dose of 1000 mg/kg/day (mice) or exceeded a maximum

tolerated dose (rats). In mice, decreased mean absolute uterine weights and uterine atrophy were
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observed at 6000 ppm (approximately 1303 mg/kg body weight/day) and 12000 ppm

(approximately 2608 mg/kg body weight/day). Ovarian weights were also decreased at 12000 ppm

and an increased incidence of absence of corpora lutea was observed at 6000 and 12000 ppm.

These findings were seen only at doses exceeding the limit dose of 1000 mg/kg/day and were not

seen at either 1500 or 3000 ppm. Increased mean adrenal weights were seen at 1500 ppm and

higher, but were without a clear dose-response relationship. In rats, administration of iprodione via

the diet for 13 weeks resulted in reduced mean absolute ovarian weights at 2000 and 3000 ppm and

uterine weight at 3000 ppm. Macroscopically, pale adrenals and uterine thinness were noted in all

females at 3000 ppm and in several animals at 2000 ppm. Microscopically, enlargement of the cells

of the zona glomerulosa in the adrenals, uterine atrophy, and a reduced number of corpora lutea

were seen at 2000 and 3000 ppm. All of these effects, however, occurred in conjunction with

significant decreases in overall bodyweight gain seen in females throughout the course of the study

(overall gain 30% lower at 2000 ppm and 60% lower at 3000 ppm), indicating that these changes

may be secondary to systemic toxicity at doses which exceeded the maximum tolerated dose.

Chronic toxicity studies were conducted in dogs (Broadmeadow, 1984; Kangas, 1991) according to

guideline 83-l(b). After 52 weeks of treatment at 3600 ppm, an increase in absolute and relative

adrenal weights and fat vacuolation in the zona fasciculata and pallid zona fasciculata and zona

glomerulosa were observed. These findings in the adrenals were not observed at 600 ppm and

lower. Pituitary, ovary, and uterus weights were unaffected by treatment. Further, no treatmentrelated microscopic changes were seen in the pituitary, ovaries, uterus, or mammary gland.

In mice, females administered 4000 ppm (approximately 793 mg/kg body weight/day) for 99 weeks

exhibited lower absolute and relative uterine and ovarian weights, but these changes were

correlated to significantly lower terminal body weight (Chambers et al., 1993). The high dose of

4000 ppm iprodione resulted in lower mean body weight gains among females during weeks 18-45

of treatment. Adrenal weight was not affected by treatment, but hypertrophy of the cells of the

zona fasciculata was seen in females at 4000 ppm at interim sacrifice only. At the terminal sacrifice,

an increased incidence of ovarian luteomas and leutinization and absence of corpora lutea were

more frequently seen at 4000 ppm. No lexicologically significant findings were observed

microscopically in the uterus (including cervix), vagina, pituitary, and mammary gland. In a two-year

feeding study in rats, no treatment-related effects were observed on endocrine-related tissues

(ovary, uterus, cervix, vagina, adrenals, mammary gland, and pituitary) in females receiving dietary

levels up to 1600 ppm (Chambers eta/., 1992).

Other Scientifically-Relevant Information - in vitro studies:

A study by Andersen et al. (2002) reports data from experiments using MCF-7 cells to assess

potential effects of pesticides on the estrogen system. Although iprodione was listed as being

tested in these assays, only the cytotoxicity results were reported. Due to the lack of experimental

details, dose-response assessment, and lack of information on the results for iprodione, this study

does not meet the criteria as described by Klimisch et al. (1997) and should be considered as

unreliable.
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In conclusion, ovaries, uterus, and adrenals have been identified as target organs following exposure

to iprodione. In subchronic studies, effects on ovaries and uterus were observed only at doses

which either exceeded a limit dose of 1000 mg/kg/day or exceeded a maximum tolerated dose. In a

long-term study in mice, effects in the ovaries, including an increase in luteomas, were observed at

the highest level tested. Effects in adrenals were also observed at high dose levels in rats, mice and

dogs. Mechanistic studies in male rats indicate that iprodione interferes with the biosynthesis of

steroid hormones, which could also account for many of the changes observed in females.

Androgen System

Assays (androgen receptor (AR) binding, Hershberger, pubertal male, and fish short-term

reproduction) have been included in the EDSP Tier 1 battery to assess the potential of a chemical to

affect the androgen signaling pathway. Endpoints from guideline studies that are relevant to assess

a compound's potential for androgenic or anti-androgenic activity are listed in Tables la and Ib. As

iprodione induced Leydig cell tumors in male rats after lifetime exposure, several studies have been

conducted to examine underlying mechanisms related to endocrine systems. Further, AR,

Hershberger and male pubertal assays with iprodione have been published in the literature. The

information available from both unpublished studies and the literature is discussed below and is

sufficient for EPA to assess the potential effects of iprodione on the androgen system.

AR Binding Assay:

The AR binding assay is intended to determine the ability of a chemical to compete with [3H] ligand

for binding in rat ventral prostate tissue homogenate. The study design of the AR binding assay

conducted by Fail et al. (1994) utilized ventral prostate from intact CD Sprague Dawley rats rather

than castrated rats as recommended in OPPTS Guideline 890.1150. As positive controls gave the

expected results, this deviation did not affect the integrity of the study or the ability to evaluate the

potential for iprodione to bind to the AR. The relative binding assay was performed by adding

increasing concentrations of competitor, either the synthetic androgen R1881 (positive control),

dihydrotestosterone (DHT), testosterone, flutamide, hydroxyflutamide, iprodione, or seven

iprodione metabolites, to a fixed concentration of

 3H-R1881 (2.5 nM instead of 1 nM recommended

by the test guideline). The assay evaluated seven concentrations of iprodione, ranging from 1 u,M to

1 mM tested in duplicate, and demonstrated that iprodione caused little, if any, displacement of

 3HR1881. Scatchard plot analysis indicated that iprodione exhibited extremely low noncompetitive

binding. The principal androgens testosterone and DHT, the active metabolite of testosterone,

bound with relative binding affinities of 35% and 100%, respectively, and demonstrate the lab's

ability to detect positive compounds.

In addition, potential AR binding with iprodione was evaluated in COS cells expressing the human AR

(hAR) in a competitive whole cell-binding assay (Blystone et al., 2009). In this study, iprodione was

assessed across ten concentrations (1 - 200 u,M in triplicate) for its ability to displace

 3H-R1881.

Similar to results seen by Fail etal. (1994), iprodione exhibited low potency in displacing

 3H-R1881,

binding to the AR with an IC50 = 86.0 u.M.
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The ability of iprodione to bind the hAR was further evaluated in competition experiments using a

constant amount of

 3H-R1881, DHT and testosterone as ligands for the AR, and eight test

compounds that included iprodione and seven metabolites (de Groene, 1999). In this study,

androgen receptors were isolated from the human cell line T47D for use in the competitive binding

assay. Seven concentrations of iprodione, the metabolites RP32490 and RP36115, and DHT tested

in the binding assay covered six orders of magnitude, ranging from 10"11 -10"5 mol/l. For all other

test and reference compounds, concentrations tested ranged from 10"11 -10"4 mol/l. Results

indicated that unlabelled R1881 bound with an IC50 of 1.7 nmol/l, which was in the expected range.

DHT and testosterone displaced

 3H-R1881 with IC50 values of 187 nmol/l and 694 nmol/l,

respectively. One metabolite, RP25040, showed weak displacement of

 3H-R1881, but it was not

possible to calculate an IC50 value because only the highest concentrations of 10"4 and 10'5 mol/l

caused some displacement. All other test compounds, including iprodione, were not able to

compete with

 3H-R1881 for the AR (de Groene, 1999).

These competitive binding studies provide sufficient data to evaluate the ability of iprodione to bind

the AR and fulfill the requirement for a competitive AR binding study as part of the test order.

Displacement binding in three different test systems from three different laboratories indicates that

iprodione binds with very low affinity to the AR.

In addition, iprodione was assessed for agonist and antagonist activity in an AR-mediated

transcriptional activation assay in the stably transfected MMTV luciferase reporter MDA-kb2 cell line

(tested from 100 pM to 10 u,M by Blystone et at., 2007; tested from 1 to 300 uM by Blystone et al,

2009). At 300 u,M, iprodione caused cytotoxicity as measured by the MTT assay and appeared to

crystallize in the media. When tested alone, iprodione did not exhibit agonist activity as no increase

in luminescence was observed. Although the authors suggest that iprodione may act as an AR

antagonist based on an IC50 of 245.9 u.M for the decrease in DTH induction, this value is close to the

cytotoxic concentration of 300 u,M. These results support that iprodione has a very low affinity for

AR binding.

Hershberger assay:

As part of a series of experiments to assess the effect of iprodione on the androgen system, a

Hershberger assay was conducted to evaluate the effect of iprodione on androgen-sensitive tissue

weights in castrated male rats (Blystone et al., 2009). Only the anti-androgenic part of the

Hershberger assay has been conducted with iprodione in this study. However, the OPPTS 890.1400

Guideline states, "Experience indicates that xenobiotic androgens are rarer than xenobiotic antiandrogens," and there is no literature evidence suggesting androgenic activity of iprodione. In this

study, male Sprague-Dawley rats were castrated on PND 42. Beginning on PND 49, animals received

iprodione (0, 50,100, or 200 mg/kg body weight/day) by gavage and 100 ug testosterone

propionate (TP) sc. After 10-11 days of treatment, animals were necropsied for the following organ

weights: glans penis, ventral prostate, seminal vesicle, Cowper's gland, levator ani +

bulbocavernosus muscle (LABC), liver, adrenals, and kidneys. Iprodione significantly decreased

ventral prostate weight at 200 mg/kg/day and LABC at all doses; adrenal and liver weights were

significantly increased at 200 mg/kg/day and 100 and 200 mg/kg/day, respectively. This study also

evaluated serum testosterone and leutinizing hormone (LH) concentrations at the end of the
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treatment period. Iprodione did not affect serum levels of either hormone at any dose level. The

castration protocol, treatment parameters, and endpoint analysis used in this study are in

agreement with OPPTS 890.1400 test guidelines. However, a concurrent positive control (flutamide)

and a vehicle only control were not included in the study as recommended by the OPPTS guideline.

Although the lack of these controls decreases the level of confidence in the results for iprodione, the

observed findings are consistent with the overall toxicology profile for this compound. Based on this

and the absence of any evidence of androgenic activity in the iprodione database, the requirement

for the androgenic portion and the testing requirement for a Hershberger assay should be waived.

Pubertal assay:

The pubertal assay is designed to detect effects on pubertal development and thyroid function. A

male pubertal assay was conducted in which Sprague-Dawley weanling rats were dosed by gavage

with 0, 50,100, or 200 mg/kg body weight/day iprodione from post-natal day 23 - 51/52 (Blystone

et a/., 2007), the same duration period as suggested in the OPPTS 890.1500 test guidelines. In this

study, blood samples were taken for hormone measurements (testosterone, androstenedione, 17ahydroxyprogesterone, progesterone, aldosterone, corticosterone, and LH) and organ weights (liver,

paired kidney, paired adrenals, glans penis, ventral prostate, seminal vesicle, LABC, paired Cowper's

gland, paired testes, and paired epididymides) were evaluated. Iprodione significantly delayed

preputial separation (PPS) by 2 and 2.8 days at 100 and 200 mg/kg/day, respectively. At 200 mg/kg

body weight/day, seminal vesicle and epididymides weights were decreased, while adrenal weights

were increased. Serum testosterone (all dose levels), androstenedione (100 and 200 mg/kg body

weight/day), and 17a-hydroxyprogesterone (100 and 200 mg/kg body weight/day) were decreased,

whereas LH was unaffected. In general, the results of this study are consistent with other studies

suggesting that iprodione affects steroidogenesis (see section on steroidogenesis below). This study

is in close agreement with OPPTS 890.1500 test guidelines, and therefore suffices to provide the

required information on the potential for iprodione to interfere with male pubertal development.

Although the thyroid was not investigated in this study, results from adult animals indicate that the

thyroid is not a target organ for iprodione (see section below on the thyroid system).

Other Scientifically Relevant Information:

Endpoints from guideline studies that are relevant to the in vitro and in vivo assays in EPA's Tier 1

screening battery are shown in Table la and b.

All relevant reproductive effects in the two-generation reproduction study in rats (Henwood, 1991)

were discussed above; at concentrations up to 3000 ppm administered via the diet, there were no

histopathological effects specific to any male tissues, including epididymides, coagulating gland,

prostate, seminal vesicles, or testes. Relevant reproductive endpoints from developmental toxicity

studies in rats (Tesh era/., 1986) and rabbits (Rodwell, 1985) were also described above. In a sex

differentiation study in rats, at Cesarean sectioning on gestation day 20, anogenital distance was

decreased in male fetuses at the mid- (120 mg/kg/day) and high-dose (250 mg/kg/day) groups

compared to vehicle controls (Repetto-Larsay, 1996; MRID 44365001). However, these effects

occurred at dose levels that induced maternal toxicity during a critical period of development

(gestation days 16-20). Further, no differences in the anogenital index were observed at any dose
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level. Wolf et al. (1999) reported that iprodione administered at 100 mg/kg body weight/day from

gestation day 14 to lactation day 3 did not demasculinize or feminize male rat pups, further

supporting the lack of an anti-androgenic effect mediated by the AR on sexual differentiation.

In a subchronic mouse study at 6000 and 12000 ppm (equivalent to 1066 and 2130 mg/kg/day), an

increase in absolute adrenal weight was observed in males. Histopathological changes in adrenals

were noted only at 12000 ppm and consisted of enlarged cells and vacuolation of cells in the zona

glomerulosa and fasciculata (Fryer et al., 1990a). In a subchronic rat study (Fryer et al., 1990b), the

two highest levels tested of 2000 and 3000 ppm caused a significant reduction in weight gain in

males over the duration of the study (approximately 40% lower at 2000 ppm and 75% lower at 3000

ppm). Treatment-related microscopic changes were seen in the testes, prostate, and seminal

vesicles at 3000 ppm and consisted of increased incidences of interstitial cell hyperplasia, atrophy,

and reduced secretion, respectively. In the adrenal, fine vacuolation in the zona fasciculata and

enlarged cells in the zona glomerulosa were observed in males at 2000 and 3000 ppm and could be

secondary to overt toxicity or related to effects on steroidogenesis noted below.

In a chronic study in mice, absolute adrenal weight was increased in males after 52 weeks of

treatment at 4000 ppm but no effect was observed at study termination after 99 weeks and no

microscopic changes were noted at either the interim or final sacrifice (Chambers eta/., 1993).

Pituitary and testes (with epididymides) weights were unaffected by treatment. In the testes,

generalized vacuolation and hypertrophy of interstitial cells was evident at 4000 ppm at the interim

sacrifice and at 800 and 4000 ppm at the final sacrifice. In a chronic rat study, administration of

iprodione via the diet up to 1600 ppm (equivalent to 69 mg/kg/day in males) had no effect on

pituitary or adrenal weights at interim or final sacrifice intervals (Chambers et al. 1992). Absolute

and relative testes weight (with epididymides) was increased at final sacrifice at 1600 ppm and

corresponded to an increased incidence of testicular tumors. Histopathological examination of male

reproductive organs revealed interstitial cell hyperplasia, reduced numbers of spermatozoa in the

epididymides, and an increased incidence of decreased colloidal secretion in the seminal vesicles at

300 and 1600 ppm. Atrophy of seminiferous tubules, absence of spermatozoa in some cases, and

increased incidence of prostate atrophy were also observed at 1600 ppm. In addition, at 1600 ppm,

interstitial cell (Leydig cell) tumors were observed. Microscopic changes in adrenals from males

included increased incidences of enlarged cells in zona glomerulosa and vacuolation in the zona

fasciculata at 1600 ppm (interim and final sacrifices) and vacuolation of the zona reticularis at 300

(final sacrifice only) and 1600 ppm (interim and final sacrifices).

In dogs administered iprodione via the diet for 52 weeks, an increase in absolute and relative

adrenal weights was observed in males at 3600 ppm, the highest level tested (Broadmeadow et al,

1984). Microscopically at 3600 ppm in males, both the zona glomerulosa and the zona fasciculata

had an increased depth and the cells were large, with a pale cytoplasm. Significant decreases were

noted in absolute prostate weights at 600 ppm and absolute and relative prostate weights at 3600

ppm but no microscopic change was observed. Pituitary and testes weights were comparable to

control, and no treatment-related microscopic changes were observed in testes, epididymides,

seminal vesicles, or pituitary. In a later chronic (52-week) study conducted up to 600 ppm, no effect

was detected on prostate weight (Kangas, 1991).
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Studies conducted in rats to investigate the mechanism for the induction of Leydig cell tumors also

showed various effects on male reproductive organs. Hormone measurements made in these

studies are discussed below in the section on steroidogenesis. Significant increases in absolute and

relative (to body weight) adrenal weights, increases in relative testes weights, decreases in absolute

and relative total accessory sex organ (TASO; includes prostate and seminal vesicles) weight and

lower absolute total epididymides weights were evident after treatment at 3000 ppm (175 mg/kg

body weight/day) via the diet for 2, 7, or 14 days (Fail et al., 1996a; 1996b). An earlier study also

demonstrated that a high dose of iprodione (600 mg/kg body weight/day) administered by gavage

resulted in decreased size of the prostate, seminal vesicles, and TASO after 15 or 30 days of

treatment and decreased epididymides weights and increased adrenal weights after 30 days. BrDU

labeling revealed a significant dose-related increase in Leydig cell proliferation after 14 days of

iprodione treatment by gavage at 70, or 300 mg/kg/day (Kennel, 2002a).

The toxicology database indicates that the adrenals and male reproductive organs have been

identified as target organs in the androgen system following exposure to iprodione. In subchronic

studies, effects on the adrenals, testes, prostate, and seminal vesicles were observed only at doses

which either exceeded a limit dose of 1000 mg/kg/day (mouse) or were secondary to severe

decreases in body weight gain (rat). Long-term studies in mice and rats indicate effects in the

adrenals and testes, including an increase in Leydig cell tumors in rats observed at the highest level

tested. Effects in adrenals were also observed at high dose levels in dogs. Mechanistic studies in

male rats described below indicate that iprodione interferes with the biosynthesis of steroid

hormones.

Thyroid System

Assays (rat pubertals and amphibian metamorphosis) have been included in the EDSP Tier 1

screening battery to assess the potential of a chemical to interfere with thyroid function. Although

these assays as specifically described in EPA's OPPTS 890 Guideline Series have not been conducted

with iprodione, adequate information exists to assess iprodione's potential to interfere with the

hypothalamic-pituitary-thyroidal (HPT) axis. As described below, information on thyroid weight and

histology are available from guideline studies including lifetime feeding studies in rats and mice, and

a chronic dog study.

Other Scientifically Relevant Information:

No effect on thyroid weight was seen in subchronic toxicity studies in mice (Fryer et al., 1990a) or

rats (Fryer et al., 1990b). A 52-week study in dogs also showed no effect on thyroid weight or

histopathology (Broadmeadow, 1984). In long-term studies in mice and rats, absolute and relative

thyroid weights for both sexes were unaffected by treatment (Chambers eta/., 1993; 1992).

However, analysis of absolute thyroid weight using body weight as a covariate showed a slight

increase at the highest levels tested in male mice and male rats at study termination. In the absence

of histopathological findings, the slight increases in thyroid weight when adjusted for body weight

are not considered toxicologically significant. The significantly lower absolute thyroid weights

observed in female mice at the 53-week interim sacrifice were attributed to an unusually high
Bayer CropScience Report NO. usooss

Page 13_

control value and were not considered to be treatment-related. Although thyroid hormone data are

not available, the absence of histopathological changes in the thyroid following subchronic and

chronic exposure at maximally tolerated levels indicates that iprodione is not likely to affect thyroid

hormone levels. Therefore, the existing data are adequate to assess any potential impact of

iprodione on the thyroid system.

Amphibian Metamorphosis (Frog):

The Amphibian Metamorphosis Assay (AMA) involves the use of tadpoles to determine if chemicals

affect the hypothalamic-pituitary-thyroid (HPT) axis during metamorphosis and consequently results

in developmental effects (USEPA, 2010). The AMA represents a generalized vertebrate model to the

extent that it is based on the conserved structure and function of the HPT axis (USEPA, 2009). A

review of existing thyroid assays was reported by OECD in a detailed review paper (OECD, 2006).

This report points out the conserved nature of the HPT axis. Potential effects on the thyroid have

already been assessed in subchronic and chronic guideline studies with conserved models so an

additional evaluation with an additional conserved species is unnecessary to evaluate the thyroid

activity potential in vertebrates. The existing data from studies in three species (rats, mice, and

dogs) should be deemed adequate for a screening level thyroid evaluation. Therefore, the conduct

of an AMA is unnecessary, would result in the expenditure of resources and unnecessary sacrifice of

animals, and a waiver should be granted.

Steroid Synthesis

Chronic exposure of iprodione to rats resulted in the formation of Leydig cell tumors. In the interest

of identifying a mode of action to account for this tumorigenic response, several in vivo and in vitro

mechanistic studies were conducted with iprodione. Although the specific aromatase and

steroidogenesis assays required in the EDSP Tier 1 screens were not performed (OPPTS 890.1200

and OPPTS 890.1550, respectively), the results from the mechanistic studies provide pertinent

information and are adequate to assess potential effects of iprodione on steroid hormone synthesis.

In addition, the endpoints discussed above for the estrogen and androgen systems are also relevant

for assessment of a compound's potential to interfere with steroidogenesis. These endpoints are

shown in Table la and those considered as functionally equivalent to address the purpose of the

aromatase and steroidogenesis assays are indicated.

In vivo Mechanistic Studies:

Iprodione has been shown to cause a dose-dependent decrease in mean plasma testosterone levels

in rats administered a single dose of 70 or 300 mg/kg body weight from 0.5 - 6 hours post dosing

(Chuzel, 1998; Chuzel, 2001). The decreases in plasma testosterone returned to baseline

concentrations by 24 hours post dosing, presumably as a consequence of the compensatory

increase in plasma LH, which was significantly increased 2-4 hours after dosing. The doses of

iprodione tested in these studies were analagous to those at which benign Leydig cell tumors were

induced in the rat 2-year carcinogenicity study bioassay (70 mg/kg) (Chambers et at., 1992) and
(*A

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E

y Bayer CropScience Report NO. usooss

Page 14

those producing Leydig cell hyperplasia in a 90-day rat study (300 mg/kg) (Fryer et al, 1990b;

Gopinath and Ames, 1993). Moreover, the transient decrease in testosterone plasma levels is

consistent with changes in the concentration of iprodione achieved in the plasma and testes which

peaked 2-10 hours after a single dose of 70 mg/kg (Fisher, 1998).

Following repeated oral administration of iprodione for 14 days at 6, 70, or 300 mg/kg body

weight/day, significant decreases in plasma testosterone were seen at 70 mg/kg body weight/day

(peak effect time 2 hours) and 300 mg/kg body weight/day (peak effect time 4 hours) (Kennel,

2002b). Concurrent increases in LH were seen at all dose levels, with peak effect times of 1, 2, and 4

hours post dosing of 6, 70, and 300 mg/kg body weight/day, respectively. Other repeated dose

studies in the rat showed increases in LH and follicular stimulating hormone (FSH) levels following

14/15 days of iprodione treatment and alterations in the secretion pattern of LH and testosterone

following 30-days of treatment (Fail eta/., 1994; Fail eta/., 1996b).

In vitro Mechanistic Studies:

As mentioned above, no clear evidence of competitive binding to the AR was found for iprodione or

its major metabolites (RP 32490, RP 36114, RP 36118 and RP 36119) (Fail eta/., 1994). 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

concentrations of 1-10 ug/ml (Benhamed, 1995). Iprodione has also been shown to inhibit

testosterone secretion from rat testicular sections in vitro at similar media concentrations (1-100

ug/mL), and this inhibition was not dependent on human chorionic gonadotropin stimulation (Fail et

al., 1996a). These findings are supported by in vivo metabolism data demonstrating that a single 70

mg/kg dose results in concentrations of iprodione in the testes of 5.6 - 6.8 ug/g after 2 hours, which

is within the range of concentrations shown to inhibit testosterone secretion in vitro (Benhamed,

1995). The biochemical steps involved in iprodione-induced changes in steroidogenesis have also

been investigated. Porcine Leydig cell cultures were used to demonstrate that iprodione appears to

interfere with steroid synthesis by disrupting the active transport of cholesterol substrate into

mitochondria (Benhamed, 1996). Thus, iprodione-induced inhibition of testosterone secretion likely

results from an indirect inhibition of steroid synthesis.

Results of an aromatase assay have been reported in the peer-reviewed literature (Andersen et al.,

2002). Incubation of human placenta! microsomes with iprodione at a single concentration of 50

u.M resulted in a significant stimulation of aromatase activity, suggesting that iprodione stimulates

the conversion of androgen to estrogen in vitro. Although the study incorporated 4-androsten-4-ol3,17-dione (1 u.M) as a positive aromatase inhibitor, a positive control for stimulation of aromatase

activity was not included and the detection of compounds which stimulate aromatase was not part

of EPA's validation program for this assay. Further, testing only one concentration, instead of the

eight concentrations required by the OPPTS 890.1200 Guideline, makes interpretation of the results

difficult and provides no confidence in concluding that iprodione may stimulate activity. In addition,

the number of replicates tested was not specified and apparently only one run was performed,

instead of the three independent runs required by the OPPTS Guideline. Based on these limitations,

the aromatase assay reported by Andersen eta/., (2002) should be considered unreliable.
®Bayer CropScience Report NO. usooss j n

Page 15

The above in vivo and in vitro mechanistic studies provide evidence that iprodione interferes with

testosterone biosynthesis at concentrations that result in Leydig cell tumors in rats after chronic

exposure. Further, results of regulatory subchronic and chronic studies in rodents and dogs show

histopathological changes (discussed in the estrogen and androgen sections above) in adrenals,

testes, and ovaries, tissues which secrete steroid hormones. The effects observed at high doses in

the mouse ovaries (luteinization of interstitial cells) and in the adrenals of rodent and dogs

(hypertrophy and/or vacuolation of cells in the zona glomerulosa and/or zona fasiciculata) are also

likely to be related to an interference in steroidogenesis. Therefore, based on the existing

information, the requirement for specific aromatase and steroidogenesis assays for iprodione

should be waived.

Conclusion

BCS believes that existing data on iprodione are adequate to assess the potential for this compound

to interact with estrogen, androgen and thyroid systems and that further testing is not warranted.

BCS's existing database, combined with several peer-reviewed publications, provides substantial

coverage of the relevant endocrine endpoints noted in the toxicity testing guidelines of the OPPTS

890 Guideline Series. Moreover, extensive mechanistic testing, both in vivo and in vitro, has been

completed to investigate hormonal dysregulation and formation of Leydig cell tumors in male rats

after iprodione exposure. Currently, endocrine-related endpoints are the points of departure for

both acute (decreased anogenital distance in male rat fetuses) and (non-cancer) chronic

(histopathological lesions in the male rat reproductive system and effects on the adrenal glands in

both sexes) risk assessments. Based on the extensive endocrine testing already performed, BCS

believes that further endocrine testing with the Tier 1 assays is not warranted.
Bayer CropScience Report NO. usoos9

Page 16

References

The following study has not been submitted previously to EPA and are included with this response:

Fryer, S.E., Duckworth, J., Gibson, W.A., Gopinath, C, and Suttie, A. (1990a). Iprodione: Sub-acute

toxicity to mice by dietary administration for 13 weeks. Huntingdon Research Centre Ltd.,

Huntingdon, Cambridgeshire, England. C022886, November 23,1990. Unpublished.

The following studies have been submitted previously to EPA and are cited by MRID number:

MRID 00144391. Broadmeadow, A. (1984). Iprodione: 52-week toxicity study in dietary

administration to Beagle dogs. Life Science Research Ltd., Eye, Suffolk, England. C021579,

September 28,1984. Unpublished. EPA classification acceptable/guideline.

MRID 00162983. Henwood, S.M. (1991). Two-generation reproduction study with iprodione

technical in rats. Hazleton Laboratories America, Inc., Madison, Wl. HLA Identification No. HLA

6224-154. April 29,1991. Unpublished. EPA classification of acceptable/guideline.

MRID 00162984. Tesh, J.M., McAnulty, P.A., Deans, C.F., Wilby, O.K., and Tesh, S.A. (1986).

Iprodione (technical grade): Teratology study in the rat. Rhone-Poulenc Agrochimie, Lyon, France.

C023030, May 28,1986. Unpublished.

MRID 42211101. Kangas, L. (1991). A 52-week dietary toxicity study of iprodione in the Beagle dog.

Bio-Research Laboratories Ltd., Senneville, Quebec, Canada. Laboratory project identification no.

84296, C021573, December 20,1991. Unpublished. EPA classification of acceptable/non-guideline.

MRID 42637801. Chambers, P.R., Crook, D., Gibson, W.A., Gopinath, C, and Ames, S.A. (1992).

Iprodione: Potential tumorigenic and toxic effects in prolonged dietary administration to rats.

Rhone-Poulenc Agrochimie, Lyon, France. R014586, December 15,1992. Unpublished. EPA

classification of acceptable/guideline.

MRID 42825002. Chambers, P.R., Crook, D., Gibson, W.A., Read, R.M., and Gopinath, C. (1993).

Iprodione: Potential tumorigenic effects in prolonged dietary administration to mice. RhonePoulenc Agrochimie, Lyon, France. C021564, May 10,1993. Unpublished. EPA classification of

acceptable/guideline.

MRID 42960701. Fryer, S.E., Duckworth, J., Gibson, W.A., Gopinath, C, and Suttie, A. (1990b).

Iprodione: Subacute toxicity to rats by dietary administration for 13 weeks. Huntingdon Research

Centre, Huntingdon, Cambridgeshire, England. Study no. RNP 322/90767, C022531, November 21,

1990. Unpublished. EPA classification of acceptable/guideline.
Bayer CropScience Report NO. usooss

Page 17_

MRID 42960701. Gopinath, C, and Ames, S.A. (1993). Iprodione: Retrospective subacute toxicity to

rats by dietary administration for 13 weeks. Huntingdon Research Centre Ltd., Huntingdon,

Cambridgeshire, England. Study no. RNP 322/931320 (Supplement to RNP 322/90767), C022532,

Septembers, 1993. Unpublished. EPA classification of acceptable/non-guideline.

MRID 43535002. Fail, P.A., Anderson, S.A., and Pearce, S.W. (1994). Toxicity testing of a fungicide,

iprodione in adult male CD Sprague Dawley rats. Laboratory of Reproductive Endocrinology, Center

for Life Sciences and Toxicology, Research Triangle Institute, Research Triangle Park, NC. RTI

Identification No. 65C-5703, C024395. October 24,1994. Unpublished. EPA classification of

acceptable/non-guideline.

MRID 43830601. Benhamed, M. (1995). Effects of iprodione and its metabolites on testosterone

secretion in cultured Leydig cells. INSERM U 407, Sophia Antipolis Cedex, France. INSERM/U

407/95001, R014672. July 13,1995. Unpublished. EPA classification of acceptable/non-guideline.

MRID 44171901. Benhamed, M. (1996). Effects of iprodione and its metabolites RP 36112 and RP

36115 on testosterone secretion in cultured Leydig cells: Sites of action. INSERM U 407, Sophia

Antipolis Cedex, France. INSERM/U 407/96001, C024294. October 21,1996. Unpublished.

MRID 44171903. Fail, P.A., Anderson, S.A., and Pearce, S.W. (1996a). Toxicity testing of a fungicide,

iprodione: Endocrine toxicology studies of testes from adult male CD Sprague-Dawley rats exposed

to iprodione in vitro. Laboratory of Reproductive and Endocrine Toxicology, Research Triangle

Institute, Research Triangle Park, NC. RTI Identification No. 65C-6169; Rt95-IPDA; RTI-532, C024292,

November 26,1996. Unpublished. EPA classification of acceptable/non-guideline.

MRID 44171904. Fail, P.A., Anderson, S.A., and Pearce, S.W. (1996b). Toxicity testing of a fungicide,

iprodione: Endocrine toxicology studies of testes from adult male CD Sprague-Dawley rats exposed

to iprodione in vivo. Laboratory of Reproductive and Endocrine Toxicology, Research Triangle

Institute, Research Triangle Park, NC. RTI Identification No. 65C-6169; Rt95-IPDA; RTI-527, C024293,

November 26,1996. Unpublished. EPA classification of acceptable/non-guideline.

MRID 44365001. Repetto-Larsay, M. (1997). Iprodione: Toxicology study in pregnant rat by gavage

to examine sex differentiation. Rhone-Poulenc Agro CRSA, Cedex, France. Study no. SA96448,

C022658, June 9,1997. Unpublished. EPA classification of acceptable/non-guideline.

MRID 44729201. Chuzel, F. (1998). Iprodione: Hormonal measurements in adult male Sprague

Dawley rats following administration of iprodione by gavage. Rhone-Poulenc Agro CRSA, Cedex,

France. Study no. SA98283, B003656, October 14,1998. Unpublished. EPA classification of

acceptable/non-guideline.
Bayer CropScience Report NO. usooss

Page 18_

MRID 44750701. Fisher, P. (1998). Quantification of iprodione and metabolites in the plasma and

testes of the rat following a single oral administration of [14C]-iprodione. Rhone-Poulenc Agro CRSA,

Cedex, France. Study no. SA98326, B003653, November 30,1998. Unpublished. EPA classification

of acceptable/non-guideline.

MRID 45859601. Chuzel, F. (2001). Iprodione: Hormonal measurements in adult male SpragueDawley rats following a single administration of iprodione by gavage. Aventis CropScience, Sophia

Antipolis Cedex, France. Study no. SA01016, C019327, July 26, 2001. Unpublished. EPA

classification of acceptable/non-guideline.

MRID 45859602. Kennel, P. (2002a). Measurement of Leydig cell proliferation following a 14-day

treatment period with iprodione by gavage in the rat. Bayer CropScience, Sophia Antipolis Cedex,

France. Study no. SA01315, C025273, August 7, 2002. Unpublished. EPA classification of

acceptable/non-guideline.

MRID 45859603. Kennel, P. (2002b). Iprodione: Hormonal measurements following a 14-day

treatment period with iprodione by gavage in the rat. Bayer CropScience, Sophia Antipolis Cedex,

France. Study no. SA01287, C024675, July 12, 2002. Unpublished. EPA classification of

acceptable/non-guideline.

Other published literature:

Andersen, H.R., Vinggaard, A.M., Rasmussen, T.H., Gjermandsen, I.M., and Bonefeld-Jorgensen, E.C.

(2002). Effects of currently used pesticides in assays for estrogenicity, androgenicity, and aromatase

activity in vitro. Toxicol and App Pharmacol 179:1-12.

Blair, R.M., Fang, H., Branham, W.S., Hass, B.S., Dial, S.L., Moland, C.L, Tong, W., Shi, L, Perkins, R.,

and Sheehan, D.M. (2000). The estrogen receptor relative binding affinities of 188 natural and

xenochemicals: structural diversity of ligands. Toxicol. Sci. 54:138-153.

Blystone, C.R., Lambright, C.S., Cardon, M.C., Furr, J., Rider, C.V., Hartig, P.C., Wilson, V.S., and Gray,

Jr., I.E. (2009). Cumulative and antagonistic effects of a mixture of the antiandrogens vinclozolin

and iprodione in the pubertal male rat. Toxicol. Sci. Ill: 179-188.

Blystone, C.R., Lambright, C.S., Furr, J., Wilson, V.S., and Gray Jr., I.E. (2007). Iprodione delays male

rat pubertal development, reduces serum testosterone levels, and decreases ex vivo testicular

testosterone production. Toxicol. Lett. 174: 74-81.

Klimisch, H.-J., Andreae, M and Tillman, U. (1997) A Systematic Approach for Evaluating the

Quality of Experimental Toxicological and Ecotoxicological Data. Regulatory Tox. and Pharm.
Bayer CropScience Report NO. usooss

Page 19

25:1-5.

Wolf, C, Lambright, C., Mann, P., Price, M., Cooper, R.L, Ostby, J., and Gray Jr., LE. (1999).

Administration of potentially antiandrogenic pesticides (procymidone, linuron, iprodione,

chlozolinate, p,p'-DDE, and ketoconazole) and toxic substances (dibutyl- and diethylhexyl phthalate,

PC6 169, and ethane dimethane sulphonate) during sexual differentiation produces diverse profiles

of reproductive malformations in the male rat. Toxicol. Ind. Health 15: 94-118.

The following are also used for reference:

de Groene, E.M. (1999). Human androgen receptor binding assay with the fungicide iprodione and

7 mammalian metabolites. TNO Voeding, TNO Nutrition and Food Research Institute, Analytical

Sciences Division, Zeist, The Netherlands. TNO report V99.616, Project no. 50436. June 23,1999.

OECD (2006); Draft Detailed Review Paper on Thyroid Disruption Assays; OECD Environment, Health

and Safety Publication Series on Testing and Assessment (Number not assigned), Paris, France

USEPA (2010); Test Order/DCI#: EDSP-109801-174 for Iprodione; Issued Jan 7, 2010.

USEPA (2009); Office of Prevention, Pesticides and Toxic Substances; Test Guideline, 890.1100:

Amphibian Metamorphosis (Frog). EPA 740-C-09-002; U.S. Environmental Protection Agency,

Washington, D.C.
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>Reproductive indices, litter parameters

,

\

S

S

S

P

ro

cc.

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0.

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\

\

V

s

sc

to

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3

'c

111

c

to

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§

to

CL

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4-1

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u_

s

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^Internal sex parameters

\

S

^External genitalia anomalies

Q

CC.

••^— *

I/I

ro

-E

4^"

'u

1ro

4-*

01

CL

_O

01

0

rr>

ro

00 ^^

Ol Si

c °0

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,

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't/i Number of corpora lutea, implantation

implantation loss, resorptions, fetuses S

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<

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in rsi

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<u

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w

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C O ro .c s e- J= 0 ?fc ( - EO OJ 00i_<u J=t_O) Xu.CQ. O

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I Erf " lideline 82-1: Subchronic Feeding - Rat (MRID !

960701)

^ (N

t9 ^*

i

i^is

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vagina, and mammary gland)

9

1

SiS1

Organ wt (testis) and histopathology (testis, epididymis,

seminal vesicles, and prostate)

t

^^SS\Organ wts (adrenal and thyroid) and histopathology

(thyroid and adrenal)

9

lideline 82-1: Subchronic feeding - Mouse (Submittedth response)

3 ._

o 5

I

iSS

Organ wt (ovary) and histopathology (ovary, uterus,

vagina)

0

SS^NOrgan wts (adrenal and thyroid) and histopathology

(thyroid and adrenal)

0

lideline 83-3(b): Developmental Toxicity in Rabbits

RID 00155469) 5

(3 _

i1

V

I

V

Uterine, ovarian weights 0

i^^SSFetal Sex Determination 0i• ^SSLitter parameters; corpora lutea, implantation sites, pre- and post-implantation loss 0i•1 SExternal/visceral examination ^

• Ni\

lideline 83-l(b): Chronic Toxicity in Dogs (MRID

144391, 42211101)

Organ wts and histopathology: uterus (with oviducts and

cervix), ovaries, vagina (histopath only), mammary gland

(histopath only)

Organ wts and histopathology: seminal vesicles (with

=> o • •

(D O
cn

3

o

u.

«>

CD

O

C

CD

a

o

u

C 0 ro _c

!E o

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< oJ

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oi

5

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(U c

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^

1

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1 ids), epididymides (wit

'5 «

•*-• 4-»

"D (u

C 4-»

ro N

•a TO

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ni *«

•a ecoagulating contents), p ^

^

^

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s

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£

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^

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ity (MRI

D 00070963,

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!

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5 9

i

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\

i

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-o

uterus (corpus and

th only), mammary gla

. . ro

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ro ro D. c

0 '5b

1 If Organ wts a cervix), ovar (histopath o

"

,

^

i

S

•

-C

seminal vesicles (with

ids), epididymides (wit

>• 5^

2? •-

|||

ro "O ££

g" ro rf

+j w QJ

-a -gj o Organ wts a coagulating contents), p

*

•^

">

N

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T3

'oadrenal, pituitary, thyr

o

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.a

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g

ro

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O

"

icity/carcinogenicit

y

X

o

T3

0)

C

]n

E

S

4-»

ro

cc. *-*

in g

ro Ji

m(U (N ^J

.£ *

"oJ O

12 ££

5 ^.

t

i

>y

•

N

_£.uterus, cervix (histopai

varies, mammary glani

.. O

{!

ro £ Q. ro

§ 2

~c ~^r "c Organ wts a only), vagin; (histopath o

*

i

^

i

S

i

Wl"

OJ

(A

O

Q.

(/> «.

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 §

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Ol 'g

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testes

*

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S

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'oadrenal, pituitary, thyr

00

0

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"
Bayer CropScience Report No.

Page

US0059

27

Table 2: Functional Equivalence Matrix - Apical Endpoints in Existing Studies Relevant to

Amphibian Metamorphosis

Guideline (83-4): Two-Generation Rat

Reproduction (MRID 00162983)

• Fl and F2 pup survival and growth

Guideline 83-3(a): Developmental Toxicity in Rats

(MRID 00162984)

• Fetal survival and weight

Guideline 82-1: Subchronic Feeding - Rat (MRID

42960701)

• Organ wts and histopathology: adrenal, pituitary,

thyroid

Guideline 82-1: Subchronic Feeding - Mouse

(Submitted with Response)

• Organ wts and histopathology: adrenal,

pituitary, thyroid

Guideline 83-l(b): Chronic Toxicity in Dogs (MRID

00144391, 42211101)

• Organ wts and histopathology: adrenal, pituitary,

thyroid

Guideline 83.4: Mouse carcinogenicity (MRID

00070963, 42825002)

• Organ wts and histopathology: adrenal, pituitary,

thyroid

Guideline 83-5: Rat combined

toxicity/carcinogenicity

(MRID 42637801)

• Organ wts and histopathology: adrenal, pituitary,

thyroid

Amphibian Metamorphosis

S

S

s

s

s

s

s
Bayer CropScience Report NO. usoosg

Page 28

APPENDIX A

TITLE PAGES WITH MRID NUMBERS

OF REPORTS SUBMITTED PREVIOUSLY TO EPA
HM Bayer CropScience Report No.

Page

US0059

29

MRID 00144391

EPA classification of acceptable/guideline

CONFIDENTIAL 84/RHOOZZ/179

C02 1 579

IPRODIONE : 52-WEEK TOXICITY STUDY

IN DIETARY ADMINISTRATION TO BEAGLE DOGS

FINAL REPORT

To:

Rhone-Foulenc Agrochlmle,

Bolte Postale 9163.

69263 Lyon Cedex 09.

France.

From:

Life Science Research Ltd.

Eye,

Suffolk IP23 7PX

England.

Draft: 10 July 1984

Final: 28 September 1984
Bayer CropScience Report No.

Page

US0059

30

MRID 00162983

EPA classification of acceptable/guideline

HAZLETOIM

WISCONSI N 730 1 KfffSVA N BOu;. fVAB D

"OS.' Gcf.c t BO M 754 6

V»2'SO»: . WISCONSIN S370 7

Sponsor:

Rh8ne-Poulenc Ag Company

Research Triangle Park, North Carolina

C 021572

FINAL REPORT

Study Title:

Two-GeneralIon Reproduction Study with

Iprodione Technical in Rats

Data Requirement:

Guideline 83-4

Author:

Susan M. Henwood, MS

Study Completion Dale:

April 29, 1991

Performing Laboratojrv:

Hazleton Laboratories America, Inc.

3301 Kinsman Boulevard

Madison, Wisconsin 53704

Laboratory Project Identification:

HLA 6224-154

Page 1 of 1668

VOLUME 1 OF V

Fan COe-241-722 7 T e , o » 7 O 3 9 S 6 HAZRA L
Bayer CropScience Report No.

Page

US0059

31

MRID 00162984

EPA classification of acceptable/guideline

CONFIDENTIAL 85/RHA064/765

023030

IPRODIONE (TECHNICAL GRADE) : TERATOLOGY

STUDY IN THE RAT

To:

Rhone-Paul enc Agroch1m1e

Bolte Postale 9163

F-69263 Lyon Cedex 09

France

From:

J.M. Tesh

P.A. McAnulty

C.F. Deans

O.K. W1lby

S.A. Tesh

Life Science Research

Eye

Suffolk IP23 7PX

England

28 Hay 1986
Bayer CropScience Report No.

Page

US0059

32

MRID 42211101

EPA classification of acceptable/non-guideline

C 02157 3

BIO-RESEARCH LABORATORIES LTD.

STUDY TITLE

A 32 Week Dietary Toxicity Study

of Iprodione in the Beagle Dog

Volume I

SPONSOR

Rhdne-Poulenc Canada Inc.

2000 Argentia Road

Plaza 3. Suite 4OO

Mississauga, Ontario

LSN 1V9

DATA REQUIREMENT

No Applicable Guideline

AUTHOR

L. Kangas B.A.Sc.

Study Director

STUDY COMPLETED ON

December 2O. 1991

PERFORMING LABORATORY

Bio-Research Laboratories Ltd.

87 SenneviUe Road

Seitnevllle. Quebec H9X 3R3

LABORATORY PROJECT ID

84296

PAGE 1 OP 448 PAGES

MONTREAL

87 Srnnrvilie Rd.. Srnncvtttr. Qurbrc H9X int. Camilla

Trl: (3J4I 6JO-SJOO Trlrt: O3-82D8J Fax: <S14) 457-388)
Bayer CropScience Report No.

Page

US0059

33

MRID 42637801

EPA classification of acceptable/guideline

R014586

CONFIDENTIAL RNP 346/920808

IPRODIONE

POTENTIAL TUMORIGENIC AND TOXIC EFFECTS IN PROLONGED DIETARY

ADMINISTRATION TO RATS

VOLUME I OF X

Study completed:

Data requirements:

15 December 1992

EPA P1PRA, Subdivision F

paragraph 83-2

Addressee:

Rhdne Poulenc Agrochimie,

Departement de Toxicologie,

14-20 rue Pierre Baizet,

BP9I63,

69263 Lyon Cedex 09,

FRANCE.

gi Dietary Analysis by:

Rhdne Poulenc Agrochimie,

Departement d'Analyse des R&idus,

14-20 rue Pierre Baizet,

BP9I63.

69263 Lyon Cedex 09.

FRANCE.

ADME Bioanalyses,

Pare haute Technologic,

Sophia Antipolis,

694 Avenue du Docteur M Donat,

06250 Mougins,

FRANCE.

Report issued: 15 December 1992

Authors:

Paul R. Chambers,

David Crook,

William A. Gibson,

Chinikandath Gopinath,

Suzanne A. Ames.

Department of Rodent Toxicology.

Huntingdon Research Centre Ltd.,

P.O. Box 2,

Huntingdon,

Cambridgeshire.

PE186ES.

ENGLAND.

Page 1 of 2043
Bayer CropScience Report No.

Page

US0059

34

MRID 42825002

EPA classification of acceptable/guideline

C 02156 4

RNP 359/921240

IPRODIONE

POTENTIAL TUMORIGBNIC HPFUCIS IN

PROLONGED DIETARY ADMINISTRATION

TO MICE

VOLUME I

Study completed:

Data requirement:

10 May 1993

EPA FIFRA, Subdivision F

parsgnpb

dene Agrocbimie,

t de Toxicologie,

> Pierre Baizet,

i Cede* 09,

'analysis by:

e'Poulenc Agrochimie,

t d' Analyse des Residus,

>:Rue Pierre Baizet,

B3,

j:lyon Cedex 09.

Authors:

Paul R. Chambers.

David Crook,

William A. Gibson,

Rosemary M. Read,

Chirukandath Gopinath.

Department of Rodent Toxicology,

Huntingdon Research Centre Ltd.,

P.O. Box 2,

Huntingdon,

Cambridgeshire,

PE18 6ES,

ENGLAND.

r_ a ! Bioanalyses,

is Jtaute technologie,

lAntlpolls,

Ivemie du-Docteur M. Dooat,

f Mougins,

*CE.

Wrt issued: 10 May 1993.

Page 1 of 1918
Bayer CropScience Report No.

Page

US0059

35

MRID 42960701

EPA classification of acceptable/guideline

CONFIDENTIAL RNP 322/90767

C 02253 1

IPRODIONE

SUB-ACUTE TOXICITY TO RATS

BY DIETARY ADMINISTRATION

FOR 13 WEEKS

Study completed! 7 December 1989

Regulation*: Preliminary Study for EPA FIFRA 82-1

JHAFP 59 NohSan No. 4200

Addressee:

Rhone Poulenc Agrochinie,

Department de Toxicologie,

14-20 rue Pierre Baizet,

BP-9163.

69263 Lyon Cedex 09,

PRANCE.

Report issued 21 November 1990.

Authors:

Sarah E. Fryer.

Julia Duckworth,

Willie* A. Gibson.

Chirukandath Gopinath,

Andrew Suttie.

Huntingdon Research Centre Ltd.,

P.O. Box 2,

Huntingdon.

Cambridgeshire,

PE1B 6ES,

ENGLAND.

Page 1 of 194
£

A

t

E

5 Bayer CropScience

Report No.

Page

US0059

36

MRID 42960701

EPA classification of acceptable/guideline

CONFIDENTIAL RNP 322/931320

Supplement to RNP 322/90767

C 02253 2

IPRODIONE

RNP/322 RETROSPECTIVE

SUBACUTE TOXICmr TO RATS

BY DIETARY ADMINISTRATION

FOR 13 WEEKS

Sponsoring Company:

RhAne Poulenc Agrochimie,

Department de Toxicologle.

14 - 20 rue Pierre Balzet,

BP-9163,

69263 Lyon Cedex 09,

FRANCE.

Testing facility:

Huntingdon Research Centre Ltd.

P.O. Box 2,

Huntingdon,

Cambridgeshire.

PE186ES,

ENGLAND.

Report issued 3 September 1993

Page 1 of 16
Bayer CropScience Report No.

Page

US0059

37

MRID 43535002

EPA classification of acceptable/non-guideline

C02439 5

RESEARCH TRIANGLE INSTITUTE 5C4I

FINAL REPORT

TITLE:

Protocol 4/4t

Protocol 486:

AUTHORS:

PERFORMING LABORATORY:

SPONSOR:

SPONSOR REPRESENTATIVE:

STUDY INITIATION DATE:

EXPERIMENTAL DATES:

FINAL REPORT DATE:

RTI IDENTIFICATION NO.:

Toxitity Testing of a Fungicide, Iprodione, in Adult Male

CD*Sprague Dawley Rats

Toxldty Testing of a Fungicide, Iprodione (Part I):

Chemistry Binding and Dose-Range Finding in Adult

Male CD* Sprague Dawley Rats Exposed to Oral

Iprodione

Toxidty Testing of a Fungicide, [prodlone (Part llfc 30-

Day Endocrine Toxicology Screen in Adult Mate CD*

Sprague Dawley Rats Exposed to Oral Iprodione

PatridaA.FaiLPh.D.

Stephanie A. Anderson, BS.

Susan W. Pearce, B.S.

Laboratory of Reproductive Endocrinology

Center for Life Sciences and Toxicology •

Chemistry and Life Sciences

Research Triangle Institute

P.O. Box 12194

Research Triangle Park. NC 27709-2194

Rh&ne-Poulenc Ag Company

2T.W. Alexander Drive

Research Triangle Park, NC 27709

RemiG. Bare, Ph.D.

Rh6ne-Poulenc Ag Company

October 11.1993 (Protocol 474)

November 12,1993 (Protocol 486)

Protocol 474: 10/13/93 - 03/31 /94

Protocol 486: 11/15/93-03/31/94

October 24,1994

6SC-5703

ftopwry of Rhfine-Pbutano Apochir-.i

Strictly confidential:

thta document and its content arc . or

RStantioa purpose* only.

Any other use fi prohibited

without written emuent of

RhOne-Poulenc Agrochimie

3040 Ccrnwallis Road . Post Office Box 12194 . Research Triangle Park. North CaroSna 27709-2194 USA

•/:. Page 1 of 381
Bayer CropScience Report No.

Page

US0059

38

MRID 43830601

EPA classification of acceptable/non-guideline

INSTTTOT NATIONAL DE LA S ANTE ET DE LA RECHERCHE MEDICALE &0 O -f-j£

INSHRM Unit6 407

Unite de Recherches sur les Communications Cellulaires en Biologic de la Reproduction

Directeur : Dr Mohamed BEN AHMED D Q14.67 2

EFFECTS OF IPRODIONE AND ITS METABOLITES ON

TESTOSTERONE SECRETION IN CULTURED LEYDIG

CELLS

Author: Dr. M. Benahmed

Performing laboratory: INSERM U. 4O7; Communication

Cellulaire en Biologic de la Reproduction. Laboratoire de Biochimie,

Bat. 3 B, Centre Hospitalier Lyon-Sud, 69495, Pierre Benite, France.

Tel: (33) 78 86 16 07; Fax: (33) 78 86 33 44

I?

ii

i

Sponsor: Rhone-Poulenc Secteur Agro, 14-20, rue Pierre Baizet,

Lyon, 69263 France.

Experimental dates: 24 may 1994-23 January 1995

Final Report Date: JULY 13, 1995

Report Identification N*: INSERM/U407/95001

Laboratoire de Biochimie - Bailment 3 B

CENTRE HOSPITALIER LYON-SUD

69495 PIERRE-BENITE Cedex (FRANCE)

Tel: (33) 78 86 16 07- Fax: (33) 78 86 59 22
HH Bayer CropScience Report No.

Page

US0059

39

MRID 44171901

EPA classification of acceptable/non-guideline

C02429 4

EFFECTS OF IPRODIONE AND ITS METABOLITES RP 36112

AND RP 36115 ON TESTOSTERONE SECRETION IN

CULTURED LEYDIG CELLS: SITES OF ACTION.

Report identification N°: INSERM/U 407/96001

STUDY DIRECTOR: Dr. M. BENAHMED

Property of Rhone-Ponlenc Agrochunie

Strictly confidential!

this document Bad ita content are lor

registration purposes only.

Any oiticr use is prohibited

without written consent of

RhOno-Poulcnc Aerochimic

Experimental date: July 29. 1994 to July 18. 1996

Final Report Date: October 21. 1996

Performing laboratory INSERM U 407. Communication Cellulaire en Biologie de la

Reproduction. BSt 3B, Centre Hospitalier Lyon-Sud. 69 49S Pierre-Benite cedex. France.

Tel: (33) 78 86 16 O7 - Fax: (33) 78 86 59 22

Sponsor: Rhone-Poulenc Agrochimie- Centre de Recherche- 355, rue DostoVcvski- BP 153- FO6903 SOPHIA ANTIPOLJS Cedex

page 1/53
Bayer CropScience Report No.

Page

US0059

40

MRID 44171903

EPA classification of acceptable/non-guideline

FINAL REPORT

^02429 2

Sponsor;

RhOne-Poulenc Ag Company

2 T.W. Alexander Drive

P.O. Box 12014

Research Triangle Park, NC 27709

Study Title;

Toxicity Testing of a Fungicide, Iprodione: Endocrine Toxicology Studies of Testes

From Adult Male CD® Sprague Dawley Rats Exposed to Iprodione In Vitro

Data Requirement:

Not Applicable

Authors;

Patricia A. Fail Ph.D.

Stephanie A. Anderson, B.S.

Susan W. Fearce, B.S.

Study Comnlatlon Date:

November 26,1996

Performing Laboratory:

Laboratory of Reproductive and Endocrine Toxicology

Center for Life Sciences and Toxicology

Chemistry and Life Sciences

Research Triangle Institute

P.O. Box 12194

Research Triangle Park, NC 27709-2194

RTI Identification No.;

65C-6169; Rt95-IPDB; RTI-532

Volume I of I

Page 1 of 151

Property of Rh6ne-Poulcnc Agnv> •

Slrlcily conF.dcni • -.

this documeni nnd iis ......

registration purpn--,-

Any other US-L- is |-,i:-.J.

Without written r:s;ir-,, .
Bayer CropScience Report NO. usooss

Page 4£

MRID 44171904

EPA classification of acceptable/non-guideline

FINAL REPORT C 0 2 A 2 9 3

Sponsor:

Rhdne-Poulenc Ag Company

2 T.W. Alexander Drive

P.O. Box 12014

Research Triangle Park. NC 27709

Study Title:

Toxicity Testing of a Fungicide, Iprodione: Endocrine Toxicology Studies of Testes

From Adult Male CD® Sprague Dawley Rats Exposed to Iprodione In Vivo

Data Requirement:

Not Applicable

Authors:

Patricia A. Fail, Ph.D.

Stephanie A. Anderson, B.S.

Susan W. Pearce, B.S.

Study Completion Pate:

November 26,1996

Performing Laboratory;

Laboratory of Reproductive and Endocrine Toxicology

Center for Life Sciences and Toxicology

Chemistry and Life Sciences

Research Triangle Institute

P.O. Box 12194

Research Triangle Park, NC 27709-2194

RTI Identification No.:

65C-6169; Rt95-lPDA; RTI-527

Volume I of I

Page 1 of 137

Froperry of Rhane-Pouienc Agrocbimt"

Serially eonndenllal:

Oiis document and its content ore for

•:' ••. irf-tion purposes only.

•. IK.-J use is prohibited

w«f UBH conceal of

•oufc-ftc Agrochimio
Bayer CropScience Report No.

Page

US0059

42

MRID 44365001

EPA classification of acceptable/non-guideline

ft* RHONE-POULENC

RHONE-POULENC AOROCHIMIE

Centre de Recherche

355. rue Oosloievslu

BPIS3

FO6903 3OPHIA-AKITIPOUS C*de«

TEL. 92 94 34 OO - FAX 93 95 84 54

Property of Rhdne-Poulenc Agrochimic

Smelly confidential:

this document and Its content are for

registration purposes only.

Any other use U prohibited

without written consent of

Rhdne-Poulenc Agrochimle

C02265 8

IPRODIONE

TOXICOLOGY STUDY

IN PREGNANT RAT BY GAY AGE

TO EXAMINE SEX DIFFERENTIATION

DATA REQUIREMENT:

NOT APPLICABLE

REPORT OF STUDY SA 96448

STUDY DIRECTOR: M. REPETTO-LARSAY

PERFORMING LABORATORY:

Rhonc-Poulcnc Agrochimie

Centre de Recherche

355. rue Dostoievski

BP1S3

F-O6903 Sophia Antipolis Cedex

Rhdne-Poulenc Agrochimie

14-20. rue Pierre Baizet

BP9I63

F-09263 Lyon Cedex 09

STUDY COMPLETED ON: JUNE 09.1997

PAGE l OF 204
(*A

i

EI

y Bayer CropScience Report No.

Page

US0059

43

MRID 44729201

EPA classification of acceptable/non-guideline

dP RHONE-POULENC

RHONE-POULENC AGRO

B.R 153

aSS, RUE DOSTOigVSKI

F - 08903 SOPHIA AMTIPOUS Cedex

rtU 04 02 94 34 OO • FAX 04 93 05 84 54

DOCMAPN°<03379

VOLUME 2 Of 2

B00365 6

IPRODIONE

HORMONAL MEASUREMENTS IN ADULT

MALE SPRAGUE DAWLEY RATS

FOLLOWING ADMINISTRATION OF

IPRODIONE BY GAVAGE

DATA REQUIREMENT

NO APPLICABLE DATA REQUIREMENT

REPORT OF STUDY SA 98283

STUDY DIRECTOR: F. CHUZEL

PERFORMINO LABORATORY:

Rbfinc-Foulenc Agro

Centre de Recherche

355, rue DostoVevski

BPI53

P-06903 Sophia Antipolis Cedex

Rhdne-Poulenc Agro

14-20. rue Pierre Baizet

BP9163

P 69263 Lyon Cedex 0»

STUDY COMPLETED ON: OCTOBER 14,1998

PAGE l OF 93

A"6"E-POULENC AGROO4IKME SOCI^TE kMOMVUF M) CAPITAi CC i.*3i.ftift ooo f
HH Bayer CropScience

 ReP°rt No

-

 US0059

^^ Page 44

MRID 44750701

EPA classification of acceptable/non-guideline

(if RHONE-POULENC

RHdNE-POULENC AGRO

a^DOSTOfcvsK, STUDY TITLE B C 0 3 6 5 3

F • 06903 SOPHIA ANTIPOUS CeHox

T£U 04 92 94 34 00 • FAX 04 93 65 64 54

IPRODIONE

Quantification of Iprodione and metabolites in the plasma and testes of the rat

following a single oral administration of [uC]-]prodione.

DATA REQUIREMENT

Not Applicable

AUTHOR

PHILIP FISHER

STUDY COMPLETED ON

30* November 1998

PERFORMING LABORATORY:

Rh&ne-Poulenc Agro Rh6ne-Poulenc Agro

Centre de Recherche 14-20 rue Pierre Baizet,

355 rue Dostoievski BP 9163,

BP. 153 69263 Lyon cedex

F-06903 Sophia Antipolis France.

LABORATORY PROJECT IDENTIFICATION

STUDY SA 98326

Page 1 of 52
Bayer CropScience Report NO. usooss

Page 45

MRID 45859601

EPA classification of acceptable/non-guideline

C 01932 7

Aventis CropScience

DocMap N°60S307

1 PRODI ONE

HORMONAL MEASUREMENTS IN ADULT

MALE SPRAGUE DAWLEY RATS

FOLLOWING A SINGLE

ADMINISTRATION OF 1 PRODI ONE

BY GAVAGE

DATA REQUIREMENT

NO APPLICABLE DATA REQUIREMENT

REPORT OF STUDY SA 01016

STUDY DIRECTOR: F. Cnuzsi.

PERfQgMINCi LAnORATQR V: SPONSOR:

Aventis CropScience Avcnlis CropScience

355, rue Dostoi'evskt 14-20, rue Pierre Baizcl

BP 153 BP9163

F-06903 Sophia Anlipolis Cede* F-69263 Lyon Cedex 09

STUDY COMPLETED ON: JULY 26,2001

PAGE 1 OF 78

Avcniis CropScience SA - 355 rue Dostolevski • BP 153 • F-O69O3 Sophia Amipolis Cedex • www.avenlis.com

Telephone +J3 (O) 4 92 *» 34 OO • Fax +33 (0) 4 93 95 84 S4

Avoub CrapSctenee SodUt AnooynK on caplul de 2 144 1J7 JOO F

Siege Sociil : 59 BWnue Rent Cnsin • CP 106. F-«92«6 Lyon CeOct 09 • RC Lyo« B 969 «U 3O»
Bayer CropScience Report No.

Page

US0059

46

MRID 45859602

EPA classification of acceptable/non-guideline

Bayer CropScience C 02527 3

DOCMAP N°605623

D7ROD1ONE

MEASUREMENT OF LEYD1G CELL PROLIFERATION

FOLLOWING A 14-DAY TREATMENT PERIOD

WITH IPROD10NE BY GAVAGE IN THE RAT

REPORT OF STUDY SA 01315

STUDY DIRECTOR: P. KENNEL

PERFORMiNfi

Bayer CropScience

355, rue DostoTevski

BPJ53

F-06903 Sophia Anlipolis Cedex

SPONSOR:

Bayer AG

Bayer CropScience

Alfred Nobel Str. SO

40789 Monheim

Germany

STUDY COMPLETED ON: AUGUST 07,2002

PAGE 1 OF 201
HN Bayer CropScience Report No.

Page

US0059

47

MRID 45859603

EPA classification of acceptable/non-guideline

Bayer Crop Science C 02467 5

1PRODIONE

HORMONAL MEASUREMENTS

FOLLOWING

A 14-DA Y TREATMENT PERIOD

WITH 1PROD1ONE BY GAVAGE

IN THE RAT

NO APPLICABLE DATA REQUIREMENT

REPORT OF STUDY SA 01287

STUDY DIRECTOR: P. KENNEL.

DOCMAPN°«S«»

PEKFORMING L,ABDRftTr>RYBayer CropScience

355. rue Dosioievski

BP153

F-069D3 Sophia Anlipnlis Cedcx

Bayer AC

Bayer CropScience

Alfred Nobel Sir. SO

40789 Monheim

Germany

STUDY COMPLETED ON: JULY 12,2002

PAGE l OF 137