Bayer CropScience

Report No. G202155

Title:

90-DAY RESPONSE TO ERA'S TEST ORDER FOR

ENDOCRINE SCREENING ON CYFLUTHRIN

(Order DCI# EDSP-128831-74)

Guideline:

OPPTS 890 Guideline Series

Authors:

Dana E. Sargent, MS

Michael Dobbs, PhD

Date:

February 26, 2010

Submitter:

Bayer Crop Science

P.O. Box12014

Research Triangle Park, NC 27709

Report ID:

G202155

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Report No. G202155

STATEMENT OF NO 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).

These data are the property of Bayer CropScience, and as such, are considered to be confidential for all

purposes other than compliance with FIFRA § 10. Submission of these data in compliance with FIFRA

does not constitute a waiver of any right to confidentiality which may exist under any other statute or in

any other country.

The above statement supersedes all other statements of confidentiality that may occur elsewhere in this

report.

Company Agent: Sherry Movassaghi

Bayer CropScience

Regulatory Manager

Signature/Date: 2/26/20_

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Report No. G202155

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.

Dana E. Sargent, MS

Toxicologist

Bayer CropScience

25 February 2010

Date

Michael Dobbs, PhD

Ecotoxicologist

Bayer CropScience

Date

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Report No. G202155

90-DAY RESPONSE TO ERA'S TEST ORDER FOR

ENDOCRINE SCREENING ON CYFLUTHRIN

On November 19, 2009, EPA issued a Test Order for endocrine screening on cyfluthrin (Order DCI#

EDSP-128831-74). 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 cyfluthrin 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, 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 cyfluthrin, that

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

summarized in Table 1a & b. 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.

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 at. (1997) has been

utilized to evaluate the quality of work reported in the literature. This approach is recognized and used by

regulatory authorities in many countries including EPA in the High Production Volume Program under

TSCA. Further, work in the literature has been compared to the relevant assay described in the OPPTS

890 Guideline Series to identify major differences between the assay included in EPA's validation

program for Tier 1 screening and the one reported in the literature.

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 cyfluthrin 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 cyfluthrin. However,

adequate information exists to assess cyfluthrin's potential to interact with the estrogen system. As

shown in Table 1a & b, relevant data are available from guideline studies including lifetime feeding

studies in rats and mice, subchronic and chronic dog studies, developmental toxicity studies, a

developmental neurotoxicity study in rat and a two-generation rat reproduction study. All of these latter

studies were conducted according to OPPTS Guidelines, under GLP, have been reviewed by EPA, and

are classified as acceptable.

Fish Full Life Cycle Study:

A fish short-term reproduction assay is included in the EDSP Tier 1 battery. This assay screens for

disturbances in the hypothalamic-pituitary-gonadal (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) offish

exposed to test chemicals (USEPA Order/DCI #EDSP-128831-74). 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

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Report No. G202155

short-term reproduction screen is to measure the reproductive performance of a group of fathead

minnows as the primary indicator for endocrine disruption (EPA 2009 890.1350).

In the case of cyfluthrin, potential effects on fish reproduction have already been extensively studied. A

full life cycle study was conducted on the fathead minnow (Pimephales promelas) starting with recently

fertilized eggs (< 24 hrs old), and continuing for 301 days post hatch until the Ft fish were 60 days old

(Rodes, et a/, 1990; MRID 41450401). This study was classified as 'core', meeting the guideline

requirement 72-4(a) for a freshwater fish life cycle study. A comparison of the endpoints measured in this

study and the end points measured in the Tier 1 fish short term reproduction assay is given in Table 2.

Survival was the most sensitive parameter in this study, with the parental generation showing a marked

reduction of survival during the first half of the study at the highest level tested (0.29 ppb). Survival and

hatchability of the F1 generation were also reduced at the highest test concentration. Hatchability of the

FO generation was not significantly impacted at any treatment level. No impact on growth of the FO or F1

generations was observed at levels below which survival effects were significant. With respect to

reproductive performance five parameters were examined: number of spawns, number of eggs,

eggs/spawn, reproductive days, and eggs/pair/reproductive day, along with hatchability. No treatment

related reproductive effects were seen at doses which did not also cause significant impairment of

survival.

As previously noted to the agency (BCS letter of Feb 2008 in response to FR notice draft list of

candidates for screening; see Appendix 2), there is little evidence that cyfluthrin directly influences

estrogen, androgen and thyroid systems. In ecotoxicological tests survival or growth effects were

typically as sensitive, or more so, than reproductive endpoints based on the fathead reproduction study

discussed above, as well as daphnid and mysid reproduction studies. At a minimum, this "other

scientifically relevant information" (OSRI) should be considered adequate to meet the needs of the 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 cyfluthrin 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 in the assessment of a compound's potential to cause

estrogenic or anti-estrogenic activity are shown in Tables 1a & b. In a two-generation rat study

(Eigenberg, 1996; MRID 4437101) conducted according to OPP 83-4 Guideline, P adults were exposed

to Cyfluthrin in the diet for 10 weeks prior to mating and then throughout mating, gestation, and lactation

periods. Indirect exposure for the F1 offspring covers the in utero and lactation periods with direct

exposure starting around post-natal (PND) 11 or 12 when pups begin to consume treated diet and from

PND 21, continues for 10 weeks premating throughout mating, gestation, and lactation periods for pups

selected to become F1 parents. 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 400 ppm in the diet in the two-generation rat study, cyfluthrin had no effect on mating,

fertility, pregnancy, or gestational indices of PO or F1 females. Estrous cycle length, gestational length in

days, and stage of estrus at necropsy were similar across all groups. Precoital interval was equivalent

across all groups. Mating indices for P and F1 males were also similar across all groups. There was a

statistically significant decrease in absolute ovarian weight in the high-dose group P females, and

statistically significant decrease in absolute testicular weight in the high-dose group F1 males. Neither

effect was thought to be compound-related as there were no corresponding decreases in the relative

weights, the changes were not seen across generations, and no histopathological changes were

observed in any reproductive organs examined (testes, ovaries, cervix, epididymis, pituitary, prostate,

seminal vesicles/coagulating gland, uterus, and vagina) from P and F1 animals.

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In addition, the number of implantation sites per dam, post-implantation loss per litter, mean number of

live pups per litter on PNDO, and sex ratios were similar across all treatment groups for F1 and F2 litters.

No anomalies of external genitalia were noted for F1 or F2 pups. In a developmental neurotoxicity study

with beta-cyfluthrin (Sheets, 2003; MRID 46054101), acquisition of vaginal patency and preputial

separation in F1 offspring was unaffected up to 200 ppm, even in the presence of up to 10% decreases in

body weight and body weight gain.

In a rat developmental toxicity study (Astroff, 1996; MRID 44116501) with beta-cyfluthrin there were no

effects on the number of corpora lutea, implantation sites, litter size, live fetuses, resorptions, preimplantation loss or sex ratio. There was slight increase in percent post-implantation loss, as well as a

decrease in fetal weights and a slight increase in skeletal variants indicative of growth retardation at the

highest dose of 40 mg/kg/day. These effects were associated with significant maternal toxicity, which

resulted in mortality for 3 dams in this dose group. In a rabbit developmental toxicity study (Becker, 1992;

MRID 42675401) with cyfluthrin there were no treatment-related effects on the number of live litters, fetal

weights, implantations, external, visceral or skeletal malformations and variations. Post-implantation loss

(expressed as a percentage of the number of implantation sites) was significantly increased at 60 and

180 mg/kg/day. However, both the study author and the EPA review concluded that this was a biological

response that occurs in does with high numbers of implantation sites. (EPA, HED, Toxicology Chapter for

Cyfluthrin/Beta-Cyfluthrin; dated July 18, 2002; TXR# 005081; DP Barcaode D283924)

There is a number of developmental toxicity studies conducted in rat via the inhalation route of exposure

(Renhof, 1988; MRID 40780401; Holzum, 1994; MRID 43393401). While there were indications of

delayed fetal development at the highest doses, mechanistic studies showed these effects to be

secondary to impairment of maternal ventilation (bradypnea and hypothermia) resulting in hypoxia and

respiratory acidosis. There was no significant decrease in number of implantation sites, number of

females with viable fetuses, or number of resorptions. There was a slight decrease in corpa lutea and

number of fetuses, but only at the highest dose, which was again considered secondary to significant

maternal toxicity. Therefore, based on the data available, there are no endocrine-related endpoints of

concern identified in the developmental toxicity studies.

In a chronic mouse study (Wahle, 1998; MRID 44589701), when CD-I mice were administered cyfluthrin

technical in the diet for 18 months, absolute and relative ovary weight was decreased at the highest dose

tested (HOT) of 1600 ppm (equivalent to 309.7 mg/kg/day in females) at the terminal sacrifice. However,

these effects were noted in the presence of significant body weight (-19%) and body weight gain

decreases, and without a trend in dose response or corresponding changes in histopathology. Therefore,

the effect on ovary weight was considered secondary to body weight effects. In an earlier chronic mouse

study (Suberg, 1983; MRID 00137304), cyfluthrin (49.7- 51.0% purity as a premix concentrate in

Wessalon S) was administered in the diet for 23 months to SPF mice. No treatment-related organ weight

or histopathological effects were noted in this study up to and including doses of 194.5/259.9 mg/kg/day

for males and females, respectively. In a chronic rat study (Wahle, 1997; MRID 44459301), there was an

increase in tumor incidence of mammary gland adenocarcinomas at terminal sacrifice in the high dose

females (450 ppm) when compared to controls (1/50 (2%), 0/50 (0%), 0/50 (0%), 4/50 (8%)). The EPA

Cancer Assessment and Review Committee (CARC) determine the following" "Dosing was considered

adequate based on decrease in body weight, compared to controls, as a critical endpoint in this study.

The increase in incidence of mammary gland adenocarcinomas is not considered to be toxicologically

significant because none of the increases in mammary tumors were statistically significant and, with the

exception of one fibroadenoma observed on day 668 when the animal died, all the hyperplasia and

mammary tumors were observed at terminal sacrifice. Neither the incidences of hyperplasia nor

fibroadenomas appeared to be dose-related. Historical control data are as follows: 1/50 adenomas and

1/50 adenocarcinomas in one study and 0/50 for both in a second study from the same laboratory;

3.8% (mean) and 2-15% (range) for carcinomas in the Hazleton laboratories; 1.5% (mean) and 0-

4.3% (range) for carcinomas in the Charles River (1990) laboratories and 1.5% (mean) and 0-4%

(range) for the National Toxicology Program (1985). A 1983 study (MRID 00137303) on cyfluthrin using

Wistarrats was negative at doses up to 25.5 mglkglday and cyfluthrin is not mutagenic in multiple assays.

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Therefore, based on the reviews of these studies, there were no endocrine-related effects as a result of

chronic exposure to cyfluthrin.

In subchronic and chronic dog studies (von Kuetz, 1986; MRID 41244109 and Jones, 1997; MRID

44435401, respectively), no changes in organ weights or histopathological findings were noted. In

addition, T3 and T4 levels were evaluated in the chronic dog, showing no effects on thyroid hormone

levels, organ weight or histopathology up to and including the high dose of 15 mg/kg/day.

Results of an ER transactivational assay with cyfluthrin have been reported in the literature. Kojima et al.

(2004) investigated the potential for 200 pesticides, including cyfluthrin, to bind to the alpha and beta ER

using transfected Chinese Hamster Ovary-K1 cells. Cyfluthrin was tested at concentrations ranging from

10"8to 10~5 M, and the REC2o (concentration of chemical that results in 20% of the agonist activity of 10"

10M E2) value and relative estrogenic activity at 10"5M concentration (RLA) were measured. According to

the results of this study, cyfluthrin showed weak positive estrogenic activity with a REC2o at 5.9x10"6 M

and a RLA of 45%. The authors tested fewer than the eight concentrations (only two or three

concentrations tested) required by the OPPTS 890.1250 Guideline and curve fitting does not appear to

have been performed. Thus, these results cannot be interpreted using the data interpretation criteria

provided in the OPPTS 890.1250 Guideline. In addition, due to the lack of details reported for the assays

performed by Kojima et al., in particular the lack of information on cytotoxicity and solubility, these

publications do not substantially meet the Klimisch criteria and should be considered as unreliable.

Scientific information indicates than an estrogenic or anti-estrogenic compound would produce

disturbances in mating, estrous cyclicity and alterations in the weight and histopathology of specific

reproductive organs (e.g. uterus, ovaries, testes, epididymes). Based on the cyfluthrin data presented

above, while the in vitro results from a single assay suggest limited potential, the more definitive in vivo

data for cyfluthrin shows no clear evidence of estrogenic or anti-estrogenic activity. Therefore,

requirement of the estrogen-based assays should be waived.

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 cyfluthrin is being cited to address the

requirement for a fish short-term reproduction screen. The fish full life cycle study versus the short-term

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

described in EPA's OPPTS 890 Guideline Series have not been conducted with cyfluthrin. However,

adequate information exists to assess cyfluthrin's potential to interfere with the androgen system. As

shown in Tables 1a&b, relevant data are available from guideline studies including lifetime feeding

studies in rats and mice, subchronic and chronic dog studies, developmental toxicity studies, a

developmental neurotoxicity study in rats and a two-generation rat reproduction study. All of these latter

studies were conducted according to regulatory test guidelines, under GLP, have been reviewed by EPA,

and are classified as acceptable.

Other Scientifically Relevant Information:

A compound that interferes with the androgen system would be expected to result in changes in sexual

development, estrous cyclicity, fertility and other reproductive endpoints, as well as weight and

histopathological changes to reproductive and sexual accessory organs. Endpoints from guideline

studies that are relevant in the assessment of a compound's potential to cause androgenic or antiandrogenic activity are shown in Tables 1a & b.

As discussed in the estrogen systems section above, a two-generation rat study (Eigenberg, 1996; MRID

4437101) was conducted according to OPP 83-4 Guideline for cyfluthrin. The exposure duration for the

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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 400 ppm

in the diet, Cyfluthrin had no effect on mating, fertility, pregnancy, or gestational indices of PO or F1

females. Estrous cycle length, gestational length in days, and stage of estrus at necropsy were similar

across all groups. Precoital interval was equivalent across all groups. Mating indices for P and F1 males

were also similar across all groups. There was a statistically significant decrease in absolute ovarian

weight in the high-dose group P females, and statistically significant decrease in absolute testicular

weight in the high-dose group F1 males. Neither was thought to be compound-related as there were no

corresponding decreases in the relative weights, nor were there similar changes in both generations. No

histopathological changes were observed in any reproductive organs examined (testes, ovaries, cervix,

epididymis, pituitary, prostate, seminal vesicles/coagulating gland, uterus, and vagina) from P and F1

animals. In addition, the number of implantation sites per dam, post-implantation loss per litter, mean

number of live pups per litter on PNDO, and sex ratios were similar across all treatment groups for F1 and

F2 litters. No anomalies of external genitalia were noted for F1 or F2 pups. In a developmental

neurotoxicity study with beta-cyfluthrin (Sheets, 2003; MRID 46054101), acquisition of vaginal patency

and preputial separation in F1 offspring was unaffected up to 200 ppm, even in the presence of up to 10%

decreases in body weight and body weight gain.

In a rat developmental toxicity study (Astroff, 1996; MRID 44116501) with beta-cyfluthrin there were no

effects on the number of corpora lutea, implantation sites, litter size, live fetuses, resorptions, preimplantation loss or sex ratio. There was slight increase in percent post-implantation loss, as well as a

decrease in fetal weights and a slight increase in skeletal variants indicative of growth retardation at the

highest dose of 40 mg/kg/day. These effects were associated with significant maternal toxicity, based on

mortality for 3 dams in this dose group. In a rabbit developmental toxicity study (Becker, 1992; MRID

42675401) with cyfluthrin there were no treatment-related effects on the number of live litters, fetal

weights, implantations, external, visceral or skeletal malformations and variations. Post-implantation loss

(expressed as a percentage of the number of implantation sites) was significantly increased at 60 and

180 mg/kg/day. However, both the study author and the EPA review concluded that this was a biological

response that occurs in does with high numbers of implantation sites (see detailed explanation in

estrogen section above; (EPA, HED, Toxicology Chapter for Cyfluthrin/Beta-Cyfluthrin, dated July 18,

2002; TXR# 005081; DP Barcaode D283924)). There is a number of developmental toxicity studies

conducted in rat via the inhalation route of exposure (Renhof, 1988; MRID 40780401; Holzum, 1994;

MRID 43393401). While there were indications of delayed fetal development at the highest doses,

mechanistic studies showed these effects to be secondary to impairment of maternal ventilation

(bradypnea and hypothermia) resulting in hypoxia and respiratory acidosis. There was no significant

decrease in number of implantation sites, number of females with viable fetuses, or number of

resorptions. There was a slight decrease in corpa lutea and number of fetuses, but only at the highest

dose, which was considered secondary to significant maternal toxicity. Therefore, based on the data

available, there are no androgen/antiandrogen-related endpoints of concern identified in the

developmental toxicity studies.

In multiple chronic mouse and rat studies (Wahle, 1998; MRID 44589701; Suberg, 1983; MRID

00137304; Wahle, 1997; MRID 44459301; Suberg, 1983: MRID 00137303), each using different strains

of animals, no treatment-related organ weight or histopathological effects were noted, which would be

associated with androgen or anti-androgen disruption. In subchronic and chronic dog studies (von Kuetz,

1986; MRID 41244109 and Jones, 1997; MRID 44435401, respectively), no changes in organ weights or

histopathological findings were noted.

Results of AR transactivational assay and Hershberger assay with cyfluthrin and beta-cyfluthrin have

been reported in the literature (Zhang et a/.,2008). In the transactivation assay, using MDA-kb2 cells,

Zang ef a/, concluded that cyfluthrin and beta-cyfluthrin, tested from 10~8 to 10~5 M, demonstrated antiandrogenic activity by blocking DHT-induced transcriptional activity in a dose-dependent manner at

concentrations of 1.0x10"7 to 1.0x10"5M. However, no summary of the actual measured results was

provided in the paper. In the same paper, Zang ef a/, conducted a Hershberger assay with cyfluthrin and

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beta-cyfluthrin. Only the antiandrogenic part of the Hershberger assay was conducted. As described in

the paper, 4 week old male Sprague-Dawley rats were castrated and allowed to recover for two weeks.

Nine groups (n=6) were assigned as follows: group 1 was sham-operated (this group was not described

further in the paper: group 2 was vehicle control (5 mL/kg peanut oil); groups 3-5 received oral doses of 6,

18, or 54 mg/kg/day cyfluthrin, respectively; and groups 6-8 received oral doses of 4, 12 or 36 mg/kg/day

of beta-cyfluthrin, respectively; group 9 was the positive control and received 50 mg/kg/day flutamide. All

groups except the sham-operated received testosterone proprionate (TP) subcutaneously (0.5 mg/kg)

before test chemical was administered. All groups were dosed by oral gavage for seven days. Rats were

weighed before each dosing. All animals were sacrificed following the last dose administration (time of

sacrifice not provided). In this study, the positive control for androgenic activity, testosterone propionate

(0.5 mg/kg/day sc.), produced no significant change in mean body weight gains, terminal body weight,

general organ weight (liver, spleen, kidney or adrenals) or sex accessory tissue weights (seminal

vesicles, ventral prostate, dorsolateral prostate, LABC, cowper's glands and glans penis) when compared

to the sham-operated control animals. The positive control for anti-androgenic activity, flutamide,

administered at 50 mg/kg/day produced no significant decrease in overall mean body weight or in liver,

kidney, adrenals or spleen weights. Flutamide did cause a significant decrease in sex accessory tissue

weights compared to the sham-operated and positive control for androgenic activity.

Mean sex accessory tissue weights were significantly decreased by cyfluthrin at the mid and high doses

(18 and 54 mg/kg/day, respectively) and by beta-cyfluthrin at the high dose of 36 mg/kg/day, compared to

animals receiving testosterone propionate + vehicle. Therefore, Zhang et al., concluded that both

cyfluthrin and beta-cyfluthrin showed evidence of anti-androgenic activity. This study was not conducted

in accordance with the current EPA OPPTS 890.1400 Guideline, and the deviations are noted below.

o Androgenic activity not assessed

o TP - 0.5 mg/kg/d versus 0.2 or 0.4 mg/kg/d

o Flutamide - 50 mg/kg/d versus 3 mg/kg/d

o Dose administration for 7 days versus 10 days

o Animals castrated earlier than recommended (4 weeks versus 6 weeks)

o Time of sacrifice not specified

o Sham operated - role of this group not defined in the study

In addition, weights of the sex accessory organs were not increased in animals receiving testosterone

propionate which supports that animals were castrated too young. The failures of the androgenic positive

control to produce an effect, along with castration of animals too early in development, constitute

significant deficiencies and thus, the results of the study should be considered as unreliable.

In addition, results of a hAR transactivational assay with cyfluthrin have been reported in the literature.

Kojima et al. (2004), investigated the potential for 200 pesticides, including cyfluthrin, to bind to the AR

using transfected Chinese Hamster Ovary-K1 cells. To test for antagonistic activity 10"10M DHT was

added to the cell cultures along with cyfluthrin at concentrations ranging from 10~8 to 10~5 M, and the RIC2o

(concentration of chemical that shows 20% inhibition of the androgenic activity of 10~10M DHT) value and

RLA (relative luciferase activity at 10"5 M compared to 100% of activity at 10 DHT) were measured.

According to the results of this study, cyfluthrin showed weak antiandrogenic activity with a REC2o at

8.4x10"6 M and a RLA of 74%. Deficiencies noted in this paper include testing fewer than the eight

concentrations (only two or three concentrations tested) required by the OPPTS 890.1250 Guideline and

curve fitting does not appear to have been performed. Thus, these results cannot be interpreted using

the data interpretation criteria provided in the OPPTS 890.1250 Guideline. In addition, due to the lack of

details reported for the assays performed by Kojima ef al., in particular the lack of information on

cytotoxicity and solubility, these publications do not substantially meet the Klimisch criteria and should be

considered as unreliable.

Scientific information indicates than an androgenic or anti-androgenic compound would produce

disturbances in mating, estrous cyclicity, reproductive indices, sexual maturation and alterations in the

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weight and histopathology of specific reproductive and sex accessory organs (e.g. uterus, ovaries, testes,

epididymes, seminal vesicles, and prostate). Based on the cyfluthrin data presented above, while the in

vitro results may suggest some potential for anti-androgenic effects, the more definitive in vivo data for

cyfluthrin shows no clear evidence of androgenic or anti-androgenic activity. However, in order to provide

a more robust weight of evidence, and to address the significant deficiencies noted in the Zhang et al.,

Bayer will conduct a guideline Hershberger assay with cyfluthrin. Based on the strength of the available

data for cyfluthrin, all other requirements of the androgen-based assays should be waived.

Steroid Synthesis

The endpoints discussed above for the estrogen and androgen systems are also relevant for assessment

of a compound's potential to interfere with steroidogenesis or inhibit aromatase. These endpoints are

shown in Tables la & b, and those considered as functionally equivalent to address the purpose of the

aromatase and steroidogenesis assays are indicated. 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. In addition to effects on

sexual maturation, fertility, reproduction, and reproductive organ weights and histopathology, compounds

that interfere with steroid synthesis have also been shown to affect the adrenal glands, reduce the

incidence of mammary tumors and alter cholesterol levels. As described in detail in the previous

sections, developmental, reproductive, and developmental neurotoxicity studies with cyfluthrin or betacyfluthrin have not shown any indication of effects on sexual maturation, fertility, reproductive indices, nor

treatment-related organ weight or histopathological changes in reproductive and sex accessory organs.

In subchronic and chronic studies with beta-cyfluthrin and/or cyfluthrin there were no treatment-related

histopathological changes in reproductive organs, adrenal glands or in cholesterol levels that would be

associated with interference with steroidogenesis or aromatase. Based on the available data, Bayer

requests that the steroidogenesis and aromatase assays be waived for cyfluthrin.

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 cyfluthrin,

adequate information exists to assess cyfluthrin's potential to interfere with the hypothalamic-pituitarythyroidal (HPT) axis. As shown in Tables 1a & b, relevant data are available from guideline studies

including lifetime feeding studies in rats and mice, subchronic and chronic dog studies, a two-generation

rat reproduction study, a developmental neurotoxicity (DNT) study, and developmental toxicity studies.

All of these studies were conducted according to regulatory test guidelines 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.

Other Scientifically Relevant Information:

There were no thyroid organ weights or histopathological effects noted in any subchronic or chronic

rodent studies (Suberg 1988, MRID 41244108; Pauluhn 1989, MRID 417830001; Pauluhn and Renhof

1983; MRID 40239301, 40082901, 00157793), nor in a subchronic dog study (von Kuetz, 1986; MRID

41244109). In a one year feeding study in dogs, mild degeneration and c-cell hyperplasia was noted in

males and females at the highest dose. However, the incidence and severity were within concurrent and

historical control range and were not considered treatment-related (Jones, 1997; MRID 44435401). In

addition, no effects on thyroid hormones measured in the chronic dog study (total triiodothyronine (T3);

total thyroxine (T4); and T3 Uptake (indirect TBG)) were noted at any interval (samples were analyzed at

3, 6, 9 and 12 months).

Page 10 of 38
Bayer CropScience

Report No. G202155

Other downstream effects which might be indicative of interference of the thyroid system include changes

in endpoints such as acoustic startle, passive avoidance and water maze measurements (learning and

memory), motor activity and brain morphometrics in the DNT study (Sheets, 2003; MRID 46054101). In

this study, dams were treated with beta-cyfluthrin by the dietary route from gestation day 0 through

lactation day 21 at doses of 2.4,11.0 and 17.8 mg/kg/day. Body weights and body weight gain was

decreased in pups at the high dose starting at lactation day 4 through post-weaning. Absolute brain

weight for female pups at terminal sacrifice was decreased 6%, but there was no effect on relative weight,

no effects in male pups and no morphological changes were seen in either sex. Male pups showed a

30% decrease in mean peak amplitude in the acoustic startle on PND 22. However, this effect was not

seen at any other time point nor in females at any time point, therefore, it was not considered

lexicologically significant. In addition, no effects were noted in the functional observation battery or any of

the learning and memory or sexual development endpoints. Based on the information provided, there is

no evidence to suggest that cyfluthrin/beta-cyfluthrin interferes with the hypothalamic-pituitary-thyroidal

axis. Therefore, Bayer requests that the rat pubertals and amphibian metamorphosis assays be waived.

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. 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. As outlined above, a number of studies have been conducted to

investigate the potential effects of cyfluthrin 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 with rats and mice, chronic dog studies, a two-generation rat reproduction study, a developmental

neurotoxicity (DNT) study, and developmental toxicity studies 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.

Conclusion

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

for this compound to interact with estrogen, androgen and thyroid systems and, with exception of a

guideline quality Hershberger Assay, further testing is not warranted. Although some results in the

literature suggest weak ER and AR binding and weak anti-androgenic activity, these findings are not

supported by the in vivo Guideline studies. The most sensitive toxicity endpoint for Cyfluthrin is

neurotoxicity. Current human health risk assessments are based on this endpoint and are protective of

other systemic effects.

Page 11 of 38
Bayer CropScience

Report No. G202155

REFERENCES

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

MRID 00137303 Suberg, H.; Loeser, E.; Blass; et al. (1983) FCR 1272 (Cyfluthrin, the Active Ingredient

of Baythroid) Chronic Toxicity Study on Rats (2-Year Feeding Experiment): 11949; 86032. (Unpublished

study received Feb 13, 1984 under 3125-351; prepared by Bayer AG, W. Ger., submitted by Mobay

Chemical Corp., Kansas City, MO; CDL072365-C)

MRID 00137304 Suberg, H.; Loeser, E.; Blass; et al. (1983) FCR 1272 (Common Name: Cyfluthrin)-

Chronic Toxicological Study on Mice (Feeding Study over 23 Months): Report No. 12035; 86107.

(Unpublished study received Feb 13, 1984 under 3125-351; prepared by Bayer AG, W. Ger, submitted

by Mobay Chemical Corp., Kansas City, MO; CDL: 072366-A)

MRID 00157793 Pauluhn, J. (1984) Study for Subchronic Inhalation Toxicity to the Rat for 13 Weeks:

FCR 1272 (Cyfluthrin): Rept. No. 12436. Unpublished Mobay study no. 86443 prepared by Bayer AG

Institute of Toxicology and Hanover Medical University. 170 p.

MRID 40082901 Pauluhn, J. (1987) Study of the Subchronic Inhalation Toxicity in Accordance with OECD

Guidline No. 413: FCR 1272: Cyfluthrin: Addendum to Bayer Report No. 12436, Dated Feb. 1, 1984:

Study No. T9015085. Unpublished Mobay Report No. 86443 prepared by Bayer AG. 157 p.

MRID 40239301 Pauluhn, J. (1983) Study of the Subchronic Inhalation Toxicity in Accordance with OECD

Guideline No. 413: Baythroid: Supplemental Submission: Second Addendum to Bayer No. 12436.

Unpublished study prepared by Bayer AG. 24 p.

MRID 40780401 Renhof, M.; Pauluhn, J. (1988) FCR 1272: Common Name Cyfluthrin: Study for

Embryotoxic Effects on Rats after Inhalation: Report No. 16391: Report No. 97403. Unpublished study

prepared by Bayer Ag. 169 p.

MRID 40968501 Pauluhn, J. (1988) Addendum to FCR 1272: Cyfluthrin: Study for Embryotoxic Effects on

Rats after Inhalation: Report No. 97403; 16391-A. Unpublished study prepared by Bayer Ag. 12 p.

MRID 41450401 Rhodes, J.E.; McAllister, W.A.; Leak, T.; Stuerman, L. (1990) Full Life-Cycle Toxicity of

14C-Cyfluthrin (Baythroid; to the Fathead Minnow (Pimephales promelas) underflow-through conditions.

Report No. 100097; 33821. Unpublished study prepared by ABC Labs. 905 p.

MRID 42332001 Renhof, M.; Pauluhn, J. (1988) FCR 1272 (Common Name Cyfluthrin): Study for

Embryotoxic Effects on Rats after Inhalation (Supp. to MRID 40780401): Lab Project Number: 97403:

16391. Unpublished study prepared by Bayer Ag, Wuppertal. 5 p.

MRID 42675401 Becker, H.; Biedermann, K. (1992) Embryotoxicity Study (Including Teratogenicity) with

FCR 1272 (Baythroid) in the Rabbit: Lab Project Number: 309914: 103980. Unpublished study prepared

by RCC, Research & Consulting Co., Ltd. 303 p.

MRID 43393401 Holzum, B.; Schmidt, U.; Pauluhn, J.; et al. (1994) FCR 1275: Explanatory Report on

Results and Mechanistic Studies for Embryotoxic Effects in Rats after Inhalation: Lab Project Number:

06369:23219:22581. Unpublished study prepared by Bayer Ag. 1374 p.

MRID 44371401 Eigenberg, D.; Elcock, L. (1996) A Two-Generation Reproduction Study in Rats Using

Technical Grade Cyfluthrin Administered Via the Diet: Lab Project Number: 93-672-UZ: 107408: 93-672-

UZ1. Unpublished study prepared by Bayer Corp. 973 p.

Page 12 of 38
Bayer CropScience

Report No. G202155

MRID 44371402 Eigenberg, D. (1997) A Supplementary Two-Generation Dietary Reproduction Study in

Rats Using Technical Grade Cyfluthrin: Lab Project Number: 94-672-CK: 107474: 94-672-CK1.

Unpublished study prepared by Bayer Corp. 771 p.

MRID 44459301 Wahle, B.; Christenson, W. (1997) Technical Grade Cyfluthrin: A Combined Chronic

Toxicity/Oncogenicity Testing Study in the Rat: Lab Project Number: 107769: 8384: 94-272-BK.

Unpublished study prepared by Bayer Corp. 4187 p. Relates to L0000267.

MRID 44589701 Wahle, B.; Christenson, W. (1998) Technical Grade Cyfluthrin: An Oncogenicity Testing

Study in the Mouse: Lab Project Number: 108041: 95-271-DR. Unpublished study prepared by Bayer

Corporation. 2141 p.

MRID 45189201 Jones, R.; Hastings, T. (2000) Technical Grade Cyfluthrin (FCR 1272): A Chronic

Toxicity Feeding Study in the Beagle Dog: Lab Project Number: 94-276-ZR: 8365: 108007. Unpublished

study prepared by Bayer Corporation. 14 p.

MRID 45228101 Wahle, B.; Christenson, W. (2000) Technical Grade Cyfluthrin: An Oncogenicity Testing

Study in the Mouse: Supplemental Submission to Bayer Report No. 108041: MRID No. 44589701: Lab

Project Number: 95-271-DR: 108041-1: 8492. Unpublished study prepared by Bayer Corp. 29 p.

Published literature:

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.

Klimisch HJ, Andreae E and Tillmann U (1997). A systematic approach for evaluating the quality of

experimental and ecotoxicological data. Reg.Tox. and Pharm. 25:1-5

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, 2009. 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.

Zhang J., Zhu W., Zheng Y., Yang J., and Zhu X. (2008). The antiandrogenic activity of pyrethroid

pesticides Cyfluthrin and beta-cyfluthrin. Reproductive Toxicology. 25: 491-496.

Page 13 of 38
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Bayer CropScience

Report No. G202155

Table 2: Fish Short-term reproduction assay endpoints compared to existing endpoints

collected for cyfluthrin from fish chronic exposure.

Fish Short-term Reproduction Assay

Study Duration: 21 Days

Life Stage: Mature Adults

Endpoints Included

Reproductive Behavior and SCC

appearance

Survival

Growth

Adult length

Adult weight

Fertilization success

Fecundity

Biomarkers3

SSC measurements

Vitellogenin

Gonadal Somatic Index

Gonadal histopathology

Plasma sex steroids (optional)

Cyfluthrin Fish Full Life Cycle Assay

Study Duration: 301+ Days

Life Stage: All (egg to reproductive adult to

eggs to 60 day old juveniles

Endpoints Included

Fo reproductive behavior

F061 day survival

F0 120 day survival

F0 153 day survival

F0301 day survivalF, 60-day survival

Growth

F0 30-day length

F061-day length

F0 90-day length

F0 120-day length

F0 90-day wet weight

F0 120-day wet weight

F! 60-day length

F! 60-day wet weight

F0 Hatching success

F! Hatching success

Fo Fecundity

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

not more sensitive then survival in life cycle testing this information is not needed.

Page 18 of 38
Bayer CropScience

Report No. G202155

APPENDIX A

TITLE PAGES WITH MRID NUMBERS OF REPORTS SUBMITTED

PREVIOUSLY TO EPA

Page 19 of 38
Bayer CropScience

Report No. G202155

MRID 41244108

BAYER AG

FACHBEREICH TOXIKOLOGIE

Friedrich-Ebert-Str. 217-333

Bayer Report Mo.: 16807

June 21. 1988

5600 Wuppertal 1 |B|iuep|ju

Federal Republic of Germany

FCR 4545

SUBCHRONIC TOXICOLOGICAL STUDY ON RATS

(ADMINISTRATION WITH FEED FOR 13 WEEKS)

by

Dr. H. Suberg

Histopathology:

C. H. Wood

(Histological Services Ltd., England)

Study No.: T 8023085

End of Study: November 1986

As long as the results contained in this report have not been published, they

may be used only with the consent of BAYER AG. This report or any part thereof

nay not be reproduced by any means. I

Page 20 of 38
Bayer CropScience

Report No. G202155

MRID41267801

BAYER AG

FACHBEREICH TOXIKOLOGIE

Bayer Report No.: 16180

November t,

Wuppertal

Federal Republic of Germany

FCH 4545

STOOT OF SPBCHROMIC ORAL TOUCHY TO DOCS

(13-Week Feeding Study)

by

Dr. E. von Keutz

Institute of Toxicology/Pharmaceuticals

Friedrich-Ebert-Straese 217-333

D-5600 Wuppertal 1

Federal Republic of Germany

Hiatopathology Report by A. J. Newman

Histological Services Ltd.

Bromyard Road

Ledbury

Herefordshire

HR8 1LG

England

Study No.: T8 022 121

As long as the results contained In this report have not been published,

they may be used only with the consent of BAYER AG. This report or any

part thereof may not be reproduced by any means.

Page 21 of 38
Bayer CropScience

Report No. G202155

MRID 417830001

BAYER AG Report No.: 18146

Department of Toxicology Date report: 28.6.1989

Friedrich-Ebert-Str. 217-333

D-5600 Wuppertal 1

FCR 4545 (c.n.: Betacyfluthrin, proposed)

SUBACUTE INHALATION TOXICITY STUDY

IN THE RAT ACCORDING TO OECD GUIDELINE NO. 412

by

Dr. J. Pauluhn

Study no: T3027446

Total pages: 946

Until they are published, the findings contained in this

report may only be used with the approval of BAYER AG.

Further reproduction of all or part of this report is not

permissible.

18146 /MO -01 -014497

Page 22 of 38
Bayer CropScience

Report No. G202155

MRID 00157793 (1984); 40082901 (1987); 40239301 (1983)

BAYER AG July 30, 1987

Fachbereich Toxikologie Wuppertal-Elberfeld

Federal Republic of Germany

Bayer Report No.: 15469 A

FCR 1272

(Cannon Name: Cyfluthrin, the Active Ingredient of

 RBAYTHROID)

STUDY OF THE SUBCHRONIC INHALATION TOXIC1TY

IN ACCORDANCE WITH OECD GUIDELINE NO: 413

Addendum to Bayer Report No. 12436, dated February 1, 1984

by

Dr. J. Pauluhn

Study Completion Date

July 8, 1983

Study No.: T9015085

As long as the results of the research contained in this report have not been

published, they may be used only with the consent of BAYER AG. This report or

any part thereof may not be reproduced by any means.

page 1 of 182

Page 23 of 38
Bayer CropScience

Report No. G202155

MRID 00137303

BAYER AG July 19, 1983

INSTITUT FUER TOXIKOLOGIE Wuppertal

Federal Republic of Germany

Bayer Report No.: 11949

pea1

(CYFLUTHRIN, THE ACTIVE INGREDIENT OF BAY7HROIDTM)

CHRONIC TOXICITY STUDY OM RATS

(2-Year Feeding Experiment)

by

Dr. H. Suberg

and

Or. E. Looser

Appended: Histopathology Report

by

Or. G. Pappritz

Experimental Pathology Services AG

As long as the results of the research contained in this report have

not been published, they may be used only with the consent of BAYER AG.

This report or any part thereof may not be reproduced by any means.

11949/MO-01-003141

Page 24 of 38
B

(BAYER)

JL.

Bayer CropScience

Report No. G202155

MRID 44459301

Toxfcoloay

Sludy liy&u

•M272-BK

Study Title

Technical Grade Cyfluthrin:

A Combined Clironic Toxicily/Oncogenicity Testing Study in the Rai

Data Requirement

FIFRA Guideline No. 83-5 Combined Chronic Toxicity/Oncogcnicity Studies

OECD Guideline No. 453 Combined Chronic Toxicity/Oncogeiiicity Studies

TSCA Guideline No. 798.3320 Combined Chronic Toxicily/Oncogenicily Studies

MAFF Guideline 59 NohSan No. 4200 Combined Chronic Toxicity/Oncogeiiicity Studies

IJiijrei I'oiiHiriuiiJn

Apiculture Division

Report Number

107769

1 FILE

| 838 4

MRID 00137304

Authors

U.S. Wahle and

W.R. Christenson

Study Completion Date

December 12, 1997

Sponsor

Bayer Corporation

Agriculture Division

Box 4913, Hawthorn Road

Kansas City, MO 64120-(X) 13

Performing Laboratory

Bayer Corporation

Agriculture Division

Toxicology

17745 South Metcalf

Stilwell, KS 66085-9104

Laboratory Project Study ID

94-272-BK

Page 1 of4187

MOB83B4 J MO-00-011122

Page 25 of 38
Bayer CropScience

Report No. G202155

BATBR AG

 Wuppertal-Blberfeld, den 24.8.83

IHSTITOTE OF TOXICOLOGY

Report no. : I2o35

FOR 1272

(eonon name eyfluthrin)

Chronic toxieological study on alee

(Feeding study over 2J aontns)

Dr. E. Suberg

and

Dr. E. Losar

HistopatholoK? report by Bxparimantal Pathology

Servlees AG (Pathologist Dr. H. Vesten) in the

appendix

Until they are published, the findings contained, in this

report «ay only be used with the approval of BAXER AG.

Further reproduction of all or part of this report is not

permissible.

Page 26 of 38
Bayer CropScience

Report No. G202155

MRID 44589701 (1998); 45228101 (2000, suppl)

TotJcolocy

Scudy ID NJI

95-J7I.DR

Study Title

Technical Grade Cyfluthrin:

An Oncogcnicity Testing Study in the Mouse

Data Requirement

F1FRA Guideline No. 83-2 Oncogenicily Study

OECD Guideline No. 451 Carcinogenicity Study

EEC/Directive 87/302/EEC: Carcinogenicity Test

MAFF Guideline: Oncogenicity Test

Bayer Corporation

Agriculture Clivjiioa

Report Number

108041

RLE

849 2

Authors

B.S. Wahle, M.S.

Phone: 913-433-5249

E-mail: brad.wahle.b@bayer.com

W.R. Christenson, Ph.D.

Phone: 913-433-5225

E-mail: russ.christenson.b@bayer.com

Study Completion Date

May 28. 1998

Sponsor

Bayer Corporation

Agriculture Division

Box 4913, Hawthorn Road

Kansas City, MO 64120-0013

Performing Laboratory

Bayer Corporation

Agriculture Division

Toxicology

17745 South Metcalf

Slilwcll, KS 66085-9104

BC8432/MO-00-01E837

Laboratory Project Study ID

95-271-DR

Page 1 of2141

Page 27 of 38
Bayer CropScience

Report No. G202155

MRID 44435401 (1997); 45189201 (2000, suppl)

Technical Grade Cyfluthrin (FCR 1272):

A Chronic Toxicity Feeding Study in the Beagle Dog

RLE

836 5

Data Requirement

40 CFR Part 158

US-EPA-FIFRA, Section 158.340. Guideline 83-1

Report Authors

R. D. Jones and T. F. Hastings

Study Completion Date

November 10,1997

Test Facility

Bayer (Corporation

(formerly Miles Inc.)

Agriculture Division

Toxicology

17745 South Metcalf

Stilwell, Kansas 66085-9104

Study Number

Study Number 94-276-ZR

page 1 of 1151

MOB8365/MO-00-011119

Page 28 of 38
Bayer CropScience

Report No. G202155

MRID44H6501

A Developmental Toxldty Study with

FOR 4545 Technical In the Wlstar Rat

Data Requirement

40 CFR Part 158

US-EPA-FIFRA, Section 158.135, Guideline B3-3

Author

A. Barry Astroff

Study Completion Data

September 4,1996

Test Facility

Bayer Corporation

Agriculture Division

Toxicology

17745 South MeteaH

Stilwen, Kansas 66085-9104

Study Number

95-612-EW

"BC79£§/'MO-01-01101S

Agriculture DMston

Report Number

107453

RLE

798 9

10(411

Page 29 of 38
Bayer CropScience

Report No. G202155

MRID 42675401

Bericht Nr.: R 5770

R C C

RESEARC H & CONSULTIN G COMPAN Y LT D

PROJECT 309914

EMBRYOTOXICITY STUDY (INCLUDING TERAT06EKICITY) WITH

FCR 1272

IN THE RABBIT

REPORT: PART I

UTHORS

ERFORHED BY

EPORT COMPLETED ON

H. Becker , K. Bledermann

1) RCC, Research and Consulting Conpany Ltd

P.O. Box, CH 4452 Itlngen / Switzerland

2) RCC UMWELTCHEMIE AC, P.O. Box,

CH 4452 Itlngen / Switzerland

DECEMBER 3, 1992

- Page l of 302 -

P.O. Box CH 4452 Itlngen / Switzerland

Phone 061 / 975 11 11 Telex 966 136 RCC CH

Telefax 061 971 52 84

Page 30 of 38
Bayer CropScience

Report No. G202155

MRID: 40780401; 40968501; 42332001

BAYER AG

FACHBEREICH TOXIKOLOGIE

(TOXICOLOGY DIVISION)

Wuppertal, 1.2.1988

Report no. 16391

FCR 1272

Common name cyfluthrin

Study for embryotoxic effects on rats after inhalation

by

Dr. M. Renhof

and

Dr. J. Pauluhn

Study number: T0020125/T3021686

Total pages: 163

Until they are published, the findings contained in this report

may only be used with the approval of BAYER AG. Further reproduction of all or part of this report is not permissible.

16391/MO-01-003769

Page 31 of 38
Bayer CropScience

Report No. G202155

MRID 43393401

STUDY TITLES

FCR 1272

Explanatory Report on Results and Mechanistic Studies

for Embryotoxic Effects in Rats after Inhalation

First Amendment to Report No. 23219 of August 12, 1994

Authors: B. Holzum, U. Schmidt, J. Pauluhn, W. Bomann

DATA REQUIREMENT

US EPA-FIFRA GUIDELINE 83-3

AUTHOR

B. Holzum

STUDY COMPLETION DATE

First Amendment: March 28, 1996

PERFORMING LABORATORY

BAYE R A G

Institute of Toxicology, Friedrich-Ebert-Strasse 217-333

D-42096 Wuppertal

LABORATORY PROJECT ID

First Amendment: Report No. 23219 A

Page 1 of 9

23213A/MO-01 -003812

Page 32 of 38