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Bayer CropScience

EPA Correspondence No. 10-02E \ o^'TST

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February 12, 2010 Research Triangle Park, NC 27709

Tel: 919 549-2000

Document Processing Desk (PRD-EDSP)

Office of Pesticide Programs (7504P)

U.S. Environmental Protection Agency

One Potomac Yard (South Bldg.)

2777 South Crystal Drive

Arlington, Virginia 22202-4501

Re: 90-Day Response to Endocrine Disruptor Screening Program for Ethoprop

Order/DCI#: EDSP-041101-42

Chemical Common Name: Ethoprop

Chemical #: PC Code: 041101CAS#: 13194-48-4

Dear Sir or Madam:

We are submitting the 90-day response for ethoprop as required by the Endocrine Disruptor

Screening Program/Data Call-In that was received by Bayer CropScience on November 9, 2009.

We have enclosed a completed Initial Response Form for Individual Order Recipients (EPA

Form No. 6300-05). The documentation required to support our response (Option 2.IB and/or

2.2) is included in the report cited below:

MRID Number;

K. Rupprecht and M. Kern. (2010). 90-Day Response to EPA's Test Order for Endocrine

Screening on Ethoprop. Bayer CropScience, Research Triangle Park, NC. Order/DCI #:

EDSP-041101-42. Bayer Report No. G202148. February 12, 2010. 32 pages.

Please phone me at (919) 549-2870 or email me at larry.hodges@bayercropscience.com if you

have any questions regarding this submission.

Sincerely,

—^

Larry R. Hodges, Ph.D.

Registration Manager, Insecticides

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Bayer CropScience

Report No. G202148

Title:

90-DAY RESPONSE TO ERA'S TEST ORDER FOR

ENDOCRINE SCREENING ON ETHOPROP

Order/DCI #:

EDSP-041101-42

Guideline:

OPPTS 890 Guideline Series

Authors:

Kent Rupprecht

Matt Kern

Date:

February 12, 2010

Report No:

G202148

Bayer CropScience

P.O. Box12014 .. .

2 T.W. Alexander Drive * * *

Research Triangle Park, NC 27709

•••••• • ••

• • • • • • • • • • •

•••••• •••••<

Page 1 of 32
(»fay Bayer CropScience

" Report No. G202148

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)(1)(A)(B), or (C).

Company Agent: Larry Hodges

Bayer CropScience

Regulatory Manager

Signature/Date: February 12, 2010

Page 2 of 32
Kuyvr CropScience

Report No. G202148

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.

fib J2

'Kent Rupprecht

Toxicologist

Bayer CropScience

Date

Matt Kern

Ecotoxicologist

Bayer CropScience

Date

0 February 12, 2010

Larry R. Hodges

Registration Manager

Sponsor/Submitter

Date

Page 3 of 32
Bayer CropScience

Report No. G202148

90-DAY RESPONSE TO ERA'S TEST ORDER FOR

ENDOCRINE SCREENING ON ETHOPROP

On November 5, 2009, EPA issued a Test Order for endocrine screening on ethoprop. In this

Order, EPA provides the option to cite or submit existing data to satisfy part of 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 ethoprop 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 conducted according to

OPPTS Guidelines and Good Laboratory Practice (GLP) Standards. The whole organism apical

endpoints in these studies, such as reproduction parameters, organ weights and 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 ethoprop that are functionally equivalent

to endpoints assessed in EPA's Tier 1 endocrine screening battery are summarized in Tables

1a and 1b. 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 may be used for obtaining the data.

Estrogen System

Assays (estrogen receptor (ER) binding, ER transcriptional 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. A fish full life cycle

study on ethoprop with supporting results from two early life stage studies in fish is being cited

to address the requirement for a fish short-term reproduction screen. The other assays as

specifically described in EPA's OPPTS 890 Guideline Series have not been conducted with

ethoprop. However, adequate information exists to assess ethoprop's potential to interfere with

the estrogen system. As shown in Tables 1a and 1b, relevant data, which are functionally

equivalent to address the purpose of EPA's Tier 1 screening battery, are available from

guideline studies including lifetime feeding studies in rats and mice, chronic dog studies,

developmental toxicity studies, and a two-generation rat reproduction study. All of these latter

studies were conducted under GLP have been reviewed by EPA, and are classified as

acceptable.

Fish Full Life Cycle Study:

The fish short-term reproduction assay screens for disturbances in the hypothalamic-pituitarygonadal (HPG) axis including (anti-) estrogenic, (anti-)androgenic, aromatase inhibition, steroid

modulation effects. The assay examines abnormalities associated with survival, reproductive

behavior, secondary sex characteristics, histopathology, and fecundity (i.e., number of spawns,

number of eggs/spawn, fertility, and development of offspring) of fish exposed to test chemicals

(USEPA, 2009a). The study begins with reproductively mature fathead minnows observed to be

successful spawners over at least a 14 day period. These "proven breeders" are then exposed

to the test chemical for a period of 21 days. The principle of the fish short-term reproduction

screen is to measure the reproductive performance of a group of fathead minnows as the

primary indicator for endocrine disruption (USEPA, 2009b). Existing data for this "primary

Page 4 of 32
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Report No. G202148

indicator" for endocrine disruption is elaborated on below. Additional measurement of

morphological, histopathological, and biochemical endpoints are included to identify potential

toxicological and endocrine mechanisms for the test chemical (USEPA, 2009b).

The purpose of the Tier I battery is to make decisions if Tier 2 tests are necessary based on

available data. As stated from the guideline above, reproduction performance is the primary

indicator to screen for possible endocrine activity. For ethoprop, a significant database already

exists regarding its toxicity to fish well beyond a screening level evaluation. Specifically, early

life stage (ELS) tests for fathead minnow and sheepshead minnow have been completed with

ethoprop (Surprenant, 1987 and Sousa, 1997). These ELS studies ran 33-35 days with effect

on eggs and larval fish evaluated. Further, a very comprehensive fish life cycle test with

sheepshead minnow has been completed with ethoprop which included a 112 day exposure

encompassing multiple fish life stages (Dionne, 2004). This exposure period exceeds the 21

day exposure to adults in the proposed reproductive screen guideline (USEPA, 2009b) and

provides a more extreme assessment of potential effects in fish. A number of endpoints

included in the existing ethoprop database for fish are listed below. A comparison of endpoints

required in the fish screening assay and those existing for ethoprop are also presented in Table

2.

• Survival of fish to exposures of ethoprop to multiple fish life stage in three separate

studies with fathead minnow and sheepshead minnow.

• Growth (weight and length) from exposures to multiple fish life states in three separate

studies with fathead minnow and sheepshead minnow.

• Impacts on early life stage development and reproduction from early life stage and full

life cycle studies with fathead minnow and sheepshead minnow. The 112 day fish life

cycle study with sheepshead minnow was carried out starting with eggs grown to

sexually mature fish. The study continued with the exposure of FI eggs which

developed in to larvae over an additional 4 week period.

• Several biomarker endpoints are included in the fish short-term reproduction screen

(Table 2). When significant reproductive effects are noted, they may inform as to a line

of inquiry regarding a potential mode of action.

Fundamentally, the biomarker endpoints in the screen are captured in these "higher tiered"

exposures as translated in measurements of survival, growth and reproduction. Results from

existing chronic exposures of ethoprop showed no indication of reproductive effects. For the

fathead minnow early life stage study, no effects on embryos up to the highest test

concentration tested (420 ppb) occurred (Surprenant, 1987). Length and weight effects

occurred at 54 ppb and survivorship effects were observed at 96 ppb. In the sheepshead

minnow early life stage study, no effect on any endpoint was observed up to highest test

concentration of 46 ppb (Sousa, 1997). For the sheepshead minnow fish full life cycle study, no

reproductive effects occurred at any test concentration (high level 15 ppb) with the only slight

effect occurring on F^ weights at 3.7 ppb (Dionne, 2004).

For ethoprop, several fish studies encompassing sensitive life stages were conducted and no

effects on fish reproduction were detected. These studies were conducted under GLP and were

accepted by the USEPA for the registration of ethoprop under established guidelines (USEPA,

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Report No. G202148

1985, 1986, 1996a, 1996b). At a minimum, this "other scientifically relevant information" (OSRI)

should be considered adequate to meet the needs of data request for a fish short-term

reproductive screen and therefore the need to conduct this assay should be waived. Not fully

utilizing the existing fish reproductive data for ethoprop and requiring a more rudimentary tier 1

screen would cause undue expenditures of time, money and animals.

Other Scientifically Relevant Information:

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

battery are shown in Tables 1a and 1b. In a two-generation rat study (Neeper-Bradley, 1991)

conducted according to the 83-4 Guideline, FO adults were exposed to ethoprop in the diet for

10 weeks prior to mating and then throughout mating, gestation and lactation periods. At

weaning, on Lactation Day 21, twenty-eight (28) F1A weanlings/sex/group were selected as

parents of the F2 generation. During the first post-weaning week, significant mortality was

observed in F1A pups at the high dose (300 ppm) and sufficient numbers of F1A pups at this

dose were not expected to be available for mating to produce the F2 generation. Since the high

dose exceeded the maximum tolerated dose for pups, the level for FO parental animals was

decreased by one half (150 ppm) 3 weeks prior to the second mating period. High dose FO

parental animals were maintained on the 150 ppm test diets through terminal sacrifice.

Approximately four (4) weeks after the weaning of the last F1A litters, the FO parents were

paired again for three (3) weeks to produce the F1B generation. Test diet administration was

continued through mating, gestation, parturition and lactation of the second litters. Indirect

exposure for the F1A and F1B offspring covers the in utero and lactation periods with direct

exposure starting around postnatal day (PND) 11 or 12 when pups begin to consume treated

diet. For the F1B pups selected to produce the next generation, exposure continues from PND

21 for 10 weeks premating throughout mating, gestation, and lactation. Thus, the exposure

duration for the F1 generation exceeds that required by the pubertal assay and therefore

provides a more severe assessment of a compound's potential to affect endocrine-related

endpoints.

When tested up to 150/300 ppm in the diet in a two-generation rat study, ethoprop had no effect

on mating, fertility, pregnancy, or gestational indices of FO or F1 females. Gestational length in

days, were similar across all groups. Mating indices for FO and F1 males were also similar

across all groups. At necropsy, absolute and relative thyroid weights were unaffected for FO

and F1 animals. No histopathological changes were observed in any reproductive organs

(vagina, uterus, ovaries, seminal vesicles, epididymides, prostate, testes,) examined from FO

and F1 animals. Mean number of live pups per litter on PND 0, and sex ratios were statistically

similar across all treatment groups for F1 and F2 litters.

In a developmental neurotoxicity rat study (Sheets, 2004) ethoprop was administered via the

diet from gestation day (GD) 6 through lactation day (LD) 21 to mated female Wistar rats at

nominal concentrations of 0, 3.0, 30 and 180 ppm. Ethoprop had no effect on fertility, viability or

lactation indices of females. Gestational length in days, were similar across all groups. Mean

number of live pups per litter on PND 0, and sex ratios were statistically similar across all

treatment groups. Additionally, vaginal patency and preputial separation in offspring were not

affected by treatment at any dietary level.

In a chronic mouse study (Inoue, 1984), no changes in the ovaries, testes and adrenals weights

or treatment related histopathological findings in the ovaries, uterus (corpus and cervix),

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Report No. G202148

mammary gland, prostate, testes, epididymes, adrenal, pituitary and thyroid with parathyroid

were noted. In a chronic rat study (Williams, 1992), animals administered 400 ppm of the test

material in the diet (high dose) tended to have lower terminal body weights, compared with

those of controls. This difference was not large enough to be statistically significant, except for

males sacrificed after 56 weeks (recovery sacrifice). However, these lower body weights were

sufficient to cause lower absolute organ weights, organ-to-body weight percentages, and organto-brain weight ratios for some organs at interim, recovery and terminal sacrifices. These

differences were most noticeable in kidney weights, but also included right adrenal weights in

males. No changes in ovary, testes, and thyroid with parathyroid weights were noted. All weight

changes not associated with lower body weights were attributed to normal biological variation.

Macroscopically, there were no observations directly related to the test material, regardless of

the animal's fate. Microscopically, the non-neoplastic and neoplastic changes observed during

the study are common to the strain of rat at the ages examined. Females given 400 ppm and

sacrificed at the end of the study had a higher incidence of endometrial stromal polyps, but this

difference was not statistically significant.

In the chronic dog study (Brown, 1986), no changes in organ weights or histopathological

findings were noted.

In a developmental toxicity study (Rodwell, 1989a), oral administration of ethoprop to pregnant

rats induced dose-dependent maternal toxicity at levels of 9 and 18 mg/kg/day. Maternal

survival was not affected by the administration of the test article. Toxicity was expressed by

clinical signs and reduced body weight gain and food intake. Cesarean section was performed

at GD20 and the resulting gravid uterine weight and fetal parameters, including the number of

corpora lutea, implantation sites, pre-implantation sites, viable fetuses, early or late resorptions,

fetal body weight, and sex ratio, were comparable between the control and ethoprop groups

with the exception of the mean number of early resorptions which was significantly decreased in

the mid dose group (9 mg/kg/day) relative to the control or other treated groups. As a similar

finding was not observed at the high dose, this decrease was considered to be of random

occurrence.

In a developmental toxicity study (Rodwell, 1989b) oral administration of ethoprop to pregnant

rabbits did not affect maternal survival. There were no treatment-related clinical signs observed

in the ethoprop groups. Maternal body weight gain and food intake were similar in the control

and treated groups. Cesarean section was performed at GD29 and the resulting gravid uterine

weight and fetal parameters, including the number of corpora lutea, implantation sites, preimplantation sites, viable fetuses, early or late resorptions, fetal body weight, and sex ratio, were

comparable between the control and ethoprop groups with the exception of the mean number of

viable fetuses, which was significantly decreased in the mid dose group (1.25 mg/kg/day)

relative to the control or other treated groups. As a similar finding was not observed at the high

dose, this decrease was considered to be of random occurrence.

Results of estrogen receptor activity in in vitro reporter gene assays with ethoprop (Kojima,

.2004), tested from 10"8 to 10"5 M did not identify ethoprop as having estrogenic nor antiestrogenic activity using transfected Chinese Hamster Ovary-K1 cells. Due to the lack of details

reported by Kojima et a/., in particular the lack of information on cytotoxicity as well as a lack of

actual data reported for ethoprop, this publication does not substantially meet the Klimisch

criteria (Klimisch, 1997) and should be considered as unreliable.

Page 7 of 32
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Report No. G202148

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. A fish full life cycle study on ethoprop with

supporting results from two early life stage studies in fish is being cited to address the

requirement for a fish short-term reproduction study. These studies versus the fish short-term

reproduction screen are discussed above under the estrogen system. The other assays as

specifically described in EPA's OPPTS 890 Guideline Series have not been conducted with

ethoprop. However, adequate information exists to assess ethoprop's potential to interfere with

the androgen system. As shown in Tables 1a and 1b, relevant data, which are functionally

equivalent to address the purpose of EPA's Tier 1 screening battery, are available from

guideline studies including lifetime feeding studies in rats and mice, chronic dog studies,

developmental toxicity studies, and a two-generation rat reproduction study. All of these latter

studies were conducted, under GLP, have been reviewed by EPA, and are classified as

acceptable.

Other Scientifically Relevant Information:

Endpoints from guideline studies that are relevant in the assessment of a compound's potential

to cause androgenic or anti-androgenic activity are shown in Tables 1a and 1b. The relevant

endpoints shown in Tables 1a and 1b from a two-generation rat study (Neeper-Bradley, 1991),

developmental neurotoxicity rat study (Sheets, 2004), chronic mouse study (Inoue, 1984),

chronic rat study (Williams, 1992), chronic dog study (Brown, 1986), rat teratology study

(Rodwell, 1989a) and rabbit teratology study (Rodwell, 1989a) are presented in the "Other

Scientifically Relevant Information" of Vne Estrogen System section.

In the two-generation rat study these endpoints include reproductive indices in FO and F1

parent, litter parameters (F1 and F2), pup sex ratio and histopathology of seminal vesicles,

epididymides, prostate, testes (FO and F1 parental <$). The pup sex ratio and preputial

separation are discussed in the developmental neurotoxicity rat study. In the chronic dog, rat

and mouse studies, testes weights and histopathology of male sex organs are presented. The

fetal sex ratios in the rat and rabbit teratology studies are discussed.

Results of androgen receptor activity in in vitro reporter gene assays with ethoprop (Kojima,

2004), tested from 10~8 to 10~5 M did not identify ethoprop as having androgenic nor antiandrogenic activity using transfected Chinese Hamster Ovary-K1 cells. Due to the lack of

details reported by Kojima et a/., in particular the lack of information on cytotoxicity as well as a

lack of actual data reported for ethoprop, this publication does not substantially meet the

Klimisch criteria (Klimisch, 1997) and should be considered as unreliable.

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 ethoprop, adequate information exists to assess ethoprop1 potential to

interfere with the hypothalamic-pituitary-thyroidal (HPT) axis. As shown in Tables 1a and 1b,

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relevant data, which are functionally equivalent to the purpose of EPA's Tier 1 screening

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

chronic dog studies, a two-generation rat reproduction study, a developmental neurotoxicity

(DNT) study, and developmental toxicity studies. All of these studies were conducted under

GLP, have been reviewed by EPA, and are classified as acceptable. Findings relevant for an

assessment of potential effects on the thyroid system are described below.

When tested up to 150/300 ppm in the diet in a two-generation rat study (Neeper-Bradley,

1991), ethoprop had no effect on absolute and relative thyroid weights for FO and F1 parental

animals. Further, no histopathological changes were observed in the thyroid or pituitary

examined from FO and F1 animals. Mean number of live pups per litter on PND 0 was

statistically similar across all treatment groups for F1 and F2 litters. During the first postweaning week, significant mortality was observed in F1A pups at the high dose (300 ppm) and

sufficient numbers of F1A pups at this dose were not expected to be available for mating to

produce the F2 generation. Since the high dose exceeded the maximum tolerated dose for

pups, the level for FO parental animals was decreased by one half (150 ppm) 3 weeks prior to

the second mating period. High dose FO parental animals were maintained on the 150 ppm test

diets through terminal sacrifice. Approximately four (4) weeks after the weaning of the last F1A

litters, the FO parents were paired again for three (3) weeks to produce the F1B generation.

Mean F1B pup body weights per litter (total, male and female) were equivalent across dose

groups to LD 14. After which body weights were decreased in female and male F1B pups at 150

ppm. F1B pup survival indices were unaffected by treatment. F2 pup body weights were

equivalent across dose groups from birth through LD 4. Pup body weight gains per litter were

significantly reduced at 150 ppm from LD 4-28. A reduction in F2 pup weight gain was also

observed at 30 ppm for LD 4-7. Increased weight gain for LD 14-21 at 30 ppm most likely

represented a compensatory increase following a previous weight loss or stabilization of litter

weights as the pups began to self feed. From LD 7 to 14, a number (3%) of pups from the 150

ppm dose group died. Consequently, the 14-day F2 pup survival index and the lactational index

were reduced. Pup survival indices for LD 0, 4, 7, 21 and 28 were equivalent across groups.

Effects on pup growth and survival are due to general systemic toxicity of ethoprop.

In a chronic mouse study (Inoue, 1984), no treatment related histopathological findings in the

liver, pituitary and thyroid with parathyroid were noted. In the chronic dog study (Brown, 1986),

no changes in organ weights or histopathological findings were noted in the pituitary and

thyroid. Histopathology of the liver did indicate treatment-related hepatotoxicity at the high dose.

It is probable that the inconsistent elevation of GPT and alkaline phosphatase, reductions in

total plasma cholesterol, protein and albumin levels reflected persistent, moderate liver injury,

once these constituents are synthesized in the liver. These changes are therefore considered to

be secondary to the primary hepatic injury.

Three long-term rat dietary studies with ethoprop were performed.

In an acceptable guideline chronic rat study (Williams, 1992), Crl:CD®(SD)BR VAF/plus® rats

were fed with diet containing ethoprop at 0, 1.0 ppm, 60 ppm, 400 (reduced from 600 ppm

during week 3) for 104 weeks. Each group contained 70 animals/sex for the carcinogenicity

phase (sacrifice scheduled at week 104) and 10 animals for the chronic phase (sacrifice

scheduled at week 52). The control and top-dose group contained 10 extra animals for a

reversibly phase, put under normal diet for 1 month after week 52 (sacrifice at week 57).

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Statistical analysis demonstrated that there was no difference for thyroid tumor incidences

between treated and control groups. The apparent higher rate of thyroid tumors in male rats

treated with 400 ppm was due to the higher survival of this group. Additionally, historical control

data demonstrate that thyroid tumor incidences observed in this study are not unexpected and

within a normal range of values. This supports strongly the absence of treatment-related effect

for this observation.

In two chronic rat studies (Barnett, 1983; Spicer, 1987), considered by EPA as supplemental,

ethoprop was administered to Fisher 344 rats for two years. There was a marginal increase of

thyroid tumors in these two studies at the highest level tested, however there was no observed

dose response. The Williams study conducted with a high dose two to four times the high dose

used in these two studies demonstrated no increase in thyroid tumors when adjusted for

survival. Therefore, the thyroid tumor incidence observed in the ethoprop studies should not be

considered as treatment related.

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, 2009a). 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 2009c). 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. As outlined above, a number of studies have been conducted to investigate the

potential effects of ethoprop on thyroid systems of vertebrates. These studies were also done

with conserved models so an additional evaluation with an additional conserved species is

unnecessary to evaluation the thyroid activity potential in vertebrates. The substantial existing

data from studies in three species, rats, mice, and dogs, including a two-generation rat

reproduction study with thyroid weights and histopathology, should be deemed adequate for a

screening level thyroid evaluation. Therefore, the conduct of an AMA is unnecessary and would

result in the expenditure of resources and unnecessary sacrifice of animals.

CONCLUSIONS

There is no published scientific literature that indicates that ethoprop has any endocrine activity.

The whole organism apical endpoints, such as reproduction parameters, organ weights and

histopathology and fetal and offspring parameters reflect the culmination of any effects on the

biological endpoints being assessed in EPA's Tier 1 endocrine screening battery. Bayer

CropScience (BCS) believes that existing data on ethoprop are adequate to assess the potential

for this compound to interact with estrogen, androgen and thyroid systems and further testing is

not warranted. In addition, the toxicity endpoints used for ethoprop in human health risk

assessments are all based on cholinesterase inhibition which is protective of all other systemic

toxicities.

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^ Report No. G202148

REFERENCES

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

MRID No. 00138636. Barnett, J.; Jenkins, L; Parent, R.; et al. (1983) Evaluation of the Chronic

Toxicity arid Oncogenic Potential of Ethoprop in Fischer 344 Rats: GSRI Project No. 413-858-

41. Final rept. /(Unpublished study received Feb 8, 1984 under 359-694; prepared by Gulf

South Research Institute, submitted by Rhone-Poulenc, Inc., Monmouth Junction, NJ;

CDL252358-A; 252359). 1986 p. EPA classification of supplemental.

MRID No. 00160179. Brown, D. (1986) Ethoprophos: 52 Week Oral (Capsule Administration)

Toxicity Study in the Beagle: Rept. No. 4923-198/16. Unpublished study prepared by Hazleton

Laboratories Europe Ltd. 248 p. EPA classification of acceptable/guideline.

MRID No. 40291801. Spicer, E. (1987) Lifetime Dietary Toxicity and Oncogenicity Study in

Rats: IRDC Study No. 347-029. Unpublished study prepared by International Research &

Development Corp. 2589 p. EPA classification of supplemental.

MRID No. 40356301. Inoue, H. (1984) Chronic Feeding and Oncogenicity Studies in Mice with

Ethoprop: Rept. No. 497. Unpublished study prepared by Biosafety Research Center (AN-PYO

Center). 2490 p. EPA classification of acceptable/guideline.

MRID No. 406501-02. Surprenant, D. C. (1987) The Toxicity of Ethoprop Technical to Fathead

Minnow (Pimephales promelas) Embryos and Larvae. Springborn Smithers Laboratories,

Wareham, MA, USA. Laboratory Report Number BW-87-6-2408, December 3, 1987.

Unpublished. EPA classification of acceptable/guideline.

MRID No. 41304402. Rodwell, D. (1989a) Teratology Study in Rats with Ethoprop: Final Report:

Lab Project Number: 3147.39. Unpublished study prepared by Springborn Life Sciences, Inc.

241 p. EPA classification of acceptable/guideline.

MRID No. 41304403. Rodwell, D. (1989b) Teratology Study in Rabbits with Ethoprop: Final

Report: Lab Project Number: 3147.41. Unpublished study prepared by Springborn Life

Sciences, Inc. 250 p. EPA classification of acceptable/guideline.

MRID No 41921201. Neeper-Bradley, T. (1991) Two-Generation Reproduction Study of

Ethoprop Technical Administered in the Diet to CD (Sprague-Dawley) Rats: Lab Project

Number: 53-598. Unpublished study prepared by Bushy Run Research Center (Union Carbide).

913 p. EPA classification of acceptable/guideline.

MRID No. 42530201. Williams, K. (1992) 104-Week Combined Chronic Toxicity and

Carcinogenicity Study with Ethoprop in Rats: Lab Project Number: HLA 6224-151. Unpublished

study prepared by Hazleton Labs America, Inc. 3720 p. EPA classification of

acceptable/guideline.

MRID No 43326001. Rhone-Poulenc Ag Co (1994) Chronic Feeding and Oncogenicity Studies

in Mice with Ethoprop: Supplement: Lab Project Number: 497: 0094/025/002. Unpublished

study. 1712 p. EPA classification of acceptable/guideline.

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MRID No. 444721-01. Sousa, J. V. (1997) Ethoprop Technical - Early Life-Stage Toxicity Test

with Sheepshead Minnow (Cyprinodon variegatus). Springborn Smithers Laboratories,

Wareham, MA, USA. Laboratory Report Number 97-10-7127, December 12, 1997.

Unpublished. EPA classification of acceptable/guideline.

MRID No. 46315401. Dionne, E. (2004) Ethoprop - Chronic Toxicity to the Sheepshead

Minnow (Cyprinodon variegatus) During a Full Life-Cycle Exposure. Springborn Smithers

Laboratories, Wareham, MA, USA. Laboratory Report Number 13798.6154, June 29, 2004.

Unpublished. EPA classification of acceptable/guideline.

MRID No 46364801. Sheets, L; Fickbohm, B. (2004) A Developmental Neurotoxicity Screening

Study with Technical Ethoprophos in Wistar Rats. Project Number: B004723, 201113,

03/D72/PQ. Unpublished study prepared by Bayer Corp. 1103 p. EPA classification of

acceptable/guideline.

The following guidelines and review paper were used for reference:

OECD, 2006. Draft Detailed Review Paper on Thyroid Disruption Assays. OECD Environment,

Health and Safety Publication Series on Testing and Assessment. No. not assigned. Paris,

France.

USEPA, 1985. Office of Pesticide Programs. Standard Evaluation Procedure for Fish Early Life

Stage Toxicity Tests. EPA-540/9-86-138. U.S. Environmental Protection Agency, Washington

D.C.

USEPA, 1986. Office of Pesticide Programs. Standard Evaluation Procedure for Fish LifeCycle Toxicity Tests. EPA-540/9-86-137. U.S. Environmental Protection Agency, Washington

D.C.

USEPA, 1996a. Office of Prevention, Pesticides and Toxic Substances. Test Guideline,

850.1400: Fish Early-Life Stage Toxicity Test. "Public Draft". EPA 712-C-96-121. April 1996.

U.S. Environmental Protection Agency. Washington, D.C.

USEPA, 1996b. Office of Prevention, Pesticides and Toxic Substances. Test Guideline,

850.1500: Fish Life Cycle Toxicity. "Public Partial Draft". EPA 712-C-96-122. April 1996. U.S.

Environmental Protection Agency. Washington, D.C.

USEPA, 2009a. Test Order/DCI #: EDSP-041101-42 for Ethoprop. Date Issued: 11/05/2009.

USEPA, 2009b. Office of Prevention, Pesticides and Toxic Substances. Test Guideline,

890.1350: Fish Short-Term Reproduction Assay. EPA 740-C-09-007. October 2009. U.S.

Environmental Protection Agency. Washington, D.C.

USEPA, 2009c. Office of Prevention, Pesticides and Toxic Substances. Test Guideline,

890.1100: Amphibian Metamorphosis (Frog). EPA 740-C-09-002. October 2009. U.S.

Environmental Protection Agency. Washington, D.C.

Published literature:

Page 12 of 32
gayer

 OopScience

Report No. G202148

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.

25:1-5

Kojima, H., Katsura, E., Takeuchi, S., Niiyama, K., and Kobayashi, K. (2004). Screening for

estrogen and androgen receptor activities in 200 pesticides by in vitro reporter gene assays

using Chinese Hamster Ovary cells. Environ. Health Perspect. 112: 524-531.

Page 13 of 32
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Bayer CropScience

Report No. G202148

Table 2 Fish Short-Term Reproduction Assay End points Compared to Existing

Endpoints Collected for Ethoprop from Fish Chronic Exposures.

Fish Short-term

Reproduction Assay

Study Duration: 21 Days

Life Stage: Mature Adults

Endpoints Required

Reproductive Behavior and

SCO appearance

Survival

Growth

Adult length

Adult weight

Fertilization success

Fecundity

Biomarkers3

SSC measurements

Vitellogenin

Gonadal Somatic Index

Gonadal histopathology

Plasma sex steroids

(optional)

Ethoprop Fish Early Life

Stage Assay (2)

MRID No. 406501 -02 and

444721-01

Study Duration: 33-35 Days

Life Stage; egg to larvae

Endpoints Included

General Behavior

Survival

Growth

larvae length

larvae wet weight and/or

larvae dry weight

Viability and hatching success

Ethoprop Fish Full Life Cycle

Assay

MRID No. 46315401

Study Duration: 112 Days

Life Stage: All (egg to

reproductive adult to eggs

developed for 4 weeks)

Endpoints Included

General Behavior, F0

reproductive behavior and SCC

appearance

F0 28-day survival

F0 55-day survival

F0 112-day survival

F-i 28-day survival

Growth

Fo 28-day length

F0 28-day wet weight

F0 55-day male length

Fo 55-day female length

Fo 1 12-day male length

Fo 1 12-day female length

F0 1 12-day male wet weight

F0 1 12-day female wet weight

Ft 28-day length

FI 28-day wet weight

F0 Hatching success

F! Hatching success

F0 Fecundity

FT Time-to-hatch

a

 Biomarkers are used to suggest a possible mode of action. Since reproductive endpoints were

not affected in life cycle testing this information is not needed.

Page 18 of 32
Bayer CropScience

Report No. G202148

Appendix 1

Title Pages for Previously Submitted Studies Referenced Within This Document

Page 19 of 32
Bayer OopSd'ence

Report No. G202148

MRID No. 00138636

R00934 4

GULF SOUTH RESEARCH INSTITUTE

ATCHAFALAYA BASIN LABORATORIES

Aam Cod> 318 3SS-MII AMI Of/it* Bo* lift Ntw Ittrtt. Lov/tlvu fOSSO

January 20, 1983

Volume I

6SRI Project No. 413-858-41

EVALUATION OF THE CHRONIC TOXICITY

AND ONCOGENIC POTENTIAL OF ETHOPROP

IN FISCHER 344 RATS

FIHAl REPORT

Prepared tor:

Rhone-Poulenc, lac.

Agrocheaical Division

P.O. Box 125

Monnouth Junction, New Jersey 08852

Prepared by:

Gulf South Research Institute

P.O. Box 1177

New Iberia, louisiana 70560

w &*-*#-2

>s William Barnett, Jr., Phfl^

Toxicologist-Final Report

Lawrence J. Jed

Manager, Department of Toxicology

Richard A. Parent, Ph.

Director, Life Science Division

^~, j, ,_ ^

h.D., D.A.B.T.

Page 20 of 32
Bayer CropScience

Report No. G202148

MRID No. 00160179

HAZLEtOfM

LABORATORIES EUROPE LTD CONFIDENTIAL

R008975

ETHOPROPHOS: 52 WEEK ORAL

(CAPSULE ADMINISTRATION) TOXICITY

STUDY IN THE BEAGLE

Report for: Rtione-Poulenc Agrochlmle,

14-20 Rue Pierre Baizet,

69009 Lyon,

FRANCE.

Prepared by: 0. Brown, B.Sc., D.Phil.,

Principal Toxicologist

Report No:

Date:

Hazleton Laboratories Europe Ltd.,

Otley Road,

Harrogate,

North Yorkshire,

ENGLAND,

HG3 1PY.

4923-198/16

April 1986

Page 21 of 32
Bayer CropScience

Report No. G202148

MRID No. 40291801

CO 1 1 1 90•

International Research

and Development Corporation

MATTAWAN. MICHIGAN, U.5>. «WI TUEPHONt 16)61 MB-] 1)6

Amendmane

to Che

Final Report

(Data Submitted: April 30, 1985)

Sponsor: Rhone-Foilleac Agrochiaie

Test Article: Cthoprop Technical

Subject: Lifetime Dietary Toxic it; and Oncogenicity Study in

Rati

Date of Submission: June 5, 1985

347-029

"credence through research"

Page 22 of 32
Bayer CropScience

Report No. G202148

MRID No. 40356301

AN-PYO CEKTEJt

BEPOKT He. 497

(1984 )

R00921 6

Chronic Feeding and Oneogenieity Studiet

in Mice vith Ethoprpp

(Expctiaeat Ho. 94)

Decesiber 29, 1984

Blotafery Seicarch Center,

Foedc, Drugs and Pecticidec

{AK-PTO Center)

582-2, A»h«nA, Ebiechlndeo,

Fvikude-cho, lv«te-gun,

Sbiiuokc-ken, J«pan.

Page 23 of 32
B

A

Bayer CropScience

Report No. G202148

MRID No. 406501-02

Page 1 of 91

ETHOPROP TECHNICAL - EARLY LIFE-STAGE

TOXICITY TEST WITH SHEEPSHEAD MINNOW

(Cyprinodon varlegatus)

Guideline Reference Number: 72-4

Submitted to:

Rhdne-Poulenc Ag Company

2 T.W. Alexander Drive

Research Triangle Park, NC 27709

SLI Report #97-10-7127

SLI Study #10566.0497.6419.520

Study Director: Joseph V. Sousa

Springbom Laboratories, Inc.

790 Main Street

Wareham, Massachusetts 02571-1075

12 December 1997

FINAL REPORT

Page 24 of 32
(B*»e

j Bayer CropScience

^^ Report No. G202148

MRID No. 41304402

Springbom Laboratories. Inc.

M*miMllMi Toxicology DMcton

S53 North Broadway • SpencavBte. Ohio 45687 • (419) 647-4196 • Wax 4436041 • Facsimile 419-647-6560

TERATOLOGY STUDY IN RATS WITH ETHOPROP R 0 0 9 2 2 7

FINAL REPORT

EPA Data Requirement

Guideline 83-3

Author

Dean E. Rod veil, M.S.

Study Completed on

November 13, 1989

Performing Laboratory

Springbom Life Sciences, Inc. (SLS)

Toxicology and Human Safety Division

553 North Broadvay

Spencerville, OH 45887

SLS Study Mo.

3147.39

Submitted to:

Rhone-Poulenc Ag Company

P. 0. Box 12014

Research Triangle Park, NC 27709

Page 1 of 241

Page 25 of 32
N Bayer CropScience

Report No. G202148

MRID No. 41304403

R00922 8

TERATOLOGY STUDY IN RABBITS VITH ETHOPROP

FINAL REPORT

EPA Data Requirement

Guideline 83-3

Author

Dean E. Rodvell, H.S.

Study Completed on

November 15, 1989

Performing Laboratory

Springborn Life Sciences, Inc. (SLS)

Toxicology and Human Safety Division

553 North Broadway

Spencerville, OH 45887

SLS Study No.

3147.41

Submitted to:

Rhone-Poulenc Ag Company

P. 0. Box 12014

Research Triangle Park, NC 27709

Page 1 of 250

Page 26 of 32
Bayer CropScience

Report No. G202148

MRIDNo 41921201

VeluiMlof2 t--

Of '7-^-

DocutMnt2of2

BUSHY RUN RESEARCH CENTER

6702 Ntoton Bead, EKJKJII. Pwm»»h«nla 16832*902 lataphorw (412) 73U2OO

Thleoopl*r(412)73»48M

Spon«or

Jan Blacker, Ph.D., DABI |p\ Un n U Q* 3 t U

» O »Q7

Shone-Pouleac Ag Conpuiy

2 T. H. Alexander Drive

Bfloearch Triangle Park, HC 27709

Stn^v

Tvo-Ccnexation Reproduction Study of Bthoprop Technical

Administered in the Diet to CM (8pra»ue-Dawley) Bat*

Guideline 63-4

Substance

Bthoprop

Author

Tereca L. Keeper-Bradley, Ph.D.

Study Completion Date

June 6. 1991

Performing laboratory

Bushy Run Research Center

6702 Mellon Boad

Export, PA 15632-8902

Laboratory Prelect ID

53-598

Page 1 of 913

Union Carbide Chemlrali and PlMtics Company Inc.

Exallencs Throutfi Quality

Page 27 of 32
Bayer CropScience

Report No. G202148

MRID No. 42530201

WISCONSI N rOS T OF'IC f BO X JJ4I

UADICOM. Wlf COM1IN t]7» 7S«t

R00981 2

Sponsor:

Rh&ne-Poulenc Ag Company

Research Triangle Park, North Carolina

FINAL REPORT

Study Title:

104-Week Combined Chronic Toxlclty and Carcinogenic1ty

Study with Ethoprop in Rats

Data Requirement:

Guideline 83-5

Author:

Kevin 0. Williams, PhD

Study Completion Date:

September 10, 1992

Performing Laboratory:

Hazleton Laboratories America, Inc.

3301 Kinsman Boulevard

Madison, Wisconsin 53704

laboratory Project Identification:

HLA 6224-151

Volume I of X

Page 1 of 3720

Page 28 of 32
Bayer CropScience

Report No. G202148

MRID No 43326001

R0098U

AN-PYO CENTER

REPORT No. 497

(1984)

Chronic Feeding and Oncogenicity Studies

in Mice with Ethoproo

SUPPLEMENTARY SUBMISSION TO EPA ACCESSION No. 40356301

Supplementary Submission Date: 29 July 1994

(Experiment No. 94)

December 29,1984

Biosafety Research Center,

Foods, Drugs and Pesticides

(AN-PYO Center)

582-2, Arahama, Shioshinden

Fukude-cho, Iwata-gun,

Shizuoka-ken, Japan.

Page 1 of 1712

Page 29 of 32
Bayer CropScience

Report No. G202148

MRID No. 444721-01

B00445 2

#BW-87-6-2408

Page 1 of 41

THE TOXICITY OP ETHOPROP TECHNICAL

TO FATHEAD MINNOW (Pimephales

proroelas) EMBRYOS AND LARVAE

Guideline Reference Number: 72-4

RHONE POULENC, AG COMPANY

T.W. ALEXANDER DRIVE

P. O. BOX 12014

RESEARCH TRIANGLE PARR, NORTH CAROLINA 27709

SLS REPORT i: BW-87-6-2408

SLS STUDY |: 10566.0986.6105.120

STUDY DIRECTOR: Donald C. Surprenant

Springborn Life Sciences, Inc.

790 Main Street

Wareham, Massachusetts 02571

Revised Final Report

December 3, 1987

Page 30 of 32
B

A

Bayer CropScience

Report No. G202148

MRID No. 46315401

Bayer CropScience EBERX011

B004674

STUDY TITLE

Ethoprop - Chronic Toxicity to the Sheepshead Minnow (Cyprinodon

variegatus) During a Full Life-Cycle Exposure

DATA REQUIREMENT

FIFRA Guideline Number 72-5

AUTHOR

Emily Dionne

STUDY COMPLETION DATE

29 June 2004

PERFORMING LABORATORY

Springbom Smithers Laboratories

790 Main Street

Wareham, Massachusetts 02571-1075

SPONSOR

Bayer CropScience

17745 S. Metcalf Avenue

Stilwell, Kansas 66085

LABORATORY PROJECT ID

Springbom Smithers Study No. 13798.6154

Sponsor Protocol/Project No. YM852801

Bayer Study No. EBERX011

Page 1 of 114

Page 31 of 32
p44 Bayer CropScience

VaX

 Report No. G202148

MRID No 46364801

Report Number

201113

B004723

A Developmental Neurotoxletty Screening Study with

Teehnleal Grade Ethoprophoa In Wtetar Rate

Data Requirement

U.S. EPA, OPPTS 870.630)

HaaBh Canada PMRA DACO No. 4.5.12

Author*

Lany P. Sheets, PlUXand Barry Rckbohm, DVM, Ph.D.

Study Completion Date

September 10,2004

Tert Facility

Bayer CropSdenoe IP

17745 South Metoalf Avenue

SMtweH. Kansas 680854104

Study Number

03-D72-PQ

Page 1 of 1103

Page 32 of 32