BIOPESTICIDES REGISTRATION ACTION DOCUMENT



## MON 89034 x TC1507 x MON 88017 x DAS-59122-7 (SmartStax®)

B.t. Corn Seed Blend

U.S. Environmental Protection Agency (EPA) Office of Pesticide Programs Biopesticides and Pollution Prevention Division (BPPD)

April 8, 2011MON 89034 x TC1507 x MON 88017 x DAS-59122-7 ( SmartStax®) B.t. Corn Seed Blend Page 2 of 39 Biopesticides Registration Action Document



### TABLE OF CONTENTS

I. BACKGROUND ............................................................................ 3

II. SCIENCE ASSESSMENT ................................................................ 4

III. REGULATORY RATIONALE......................................................... 25

IV. TERMS AND CONDITIONS............................................................ 27MON 89034 x TC1507 x MON 88017 x DAS-59122-7 ( SmartStax®) B.t. Corn Seed Blend Page 3 of 39 Biopesticides Registration Action Document

I. BACKGROUND

Active Ingredients:

Bacillus thuringiensis Cry 1A.l05 protein and the geneti c material necessary (vector PV-ZMIR245) for its production in corn event MON 89034

Bacillus thuringiensis Cry2Ab2 protein and the genetic material necessary (vector PV-ZMIR245) for its producti on in corn event MON 89034

Bacillus thuringiensis Cry1F protein and the genetic material necessary (vector PHP8999) for its production in corn event TCI507

Bacillus thuringiensis Cry3Bbl protein and the genetic materi al necessary (vec tor PV-ZMIR39) for its production in com event MON 88017

Bacillus thuringiensis Cry34Ab1 protein and the genetic mate rial necessary (vector PHP17662) for its production in corn event DAS-59122-7

Bacillus thuringiensis Cry35Ab1 protein and the genetic materi al necessary (vector PHP I7662) for its production in corn event DAS-59122-7

Trade & Other Names:

MON 89034 x TC1507 x MON 88017 x DAS-59122-7 RIB Complete Insect Protected,

Herbicide-Tolerant Corn

MON 89034 x TC1507 x MON 88017 x DAS-59122-7 In sect Protected, Herbicide-Tolerant Corn with Interspersed Refuge

Genuity® SmartStax® RIB Complete

Refuge AdvancedTM Powered by SmartStax®

OPP Chemical Codes: 006490, 006481, 006502, 006515, 006514

Type of Pesticide: Plant-Incorporated Protectants (PIPs)

Basic Manufacturers: Monsanto Company 800 North Lindbergh Blvd St. Louis, MO 63167

Mycogen Seeds c/o Dow AgroSciences LLC

9330 Zionsville Road Indianapolis, Indiana 46268-1054MON 89034 x TC1507 x MON 88017 x DAS-59122-7 ( SmartStax®) B.t. Corn Seed Blend Page 4 of 39 Biopesticides Registration Action Document

Target Pest(s): European corn borer (ECB) Southwestern corn borer (SWCB) Southern cornstalk borer (SCSB) Corn earworm (CEW) Fall armyworm (FAW)

Stalk borer

Lesser corn stalk borer Sugarcane borer (SCB) Western bean cutworm (WBC)

Black cutworm Western com rootworm (WCRW) Northern corn rootworm (NCRW) Mexican corn rootworm (MCRW)

Product Profile:

EPA conditionally registered M ON 89034 x TC1507 x MON 88017 x DAS-59122-7 in July 2009. MON 89034 x TC1507 x MON 88017 x DAS-59122-7 is a bioengineered corn PIP product containing two (2) Bt PIPs active against corn rootworm (CRW) and three (3) Bt PIPs active against various corn borer pests. MON 89034 x TC1507 x MON 88017 x DAS-59122-7 currently requires a combined 5% refuge for corn rootworm a nd lepidopteran pests where the corn earworm is not a significant pest and a 20 % combined refuge in cotton growing regions where the corn earworm is a significant pest.

MON 89034 x TC1507 x MON 88017 x DAS-59122-7 seed blend products combine 95% MON
89034 x TC1507 x MON 88017 x DAS-59122-7 corn with 5% refuge non-Bt corn. No external block refuge is required wher e the corn earworm is not a significant pest. A 20% refuge is required in cotton growing regions where th e corn earworm is a significant pest.

II. SCIENCE ASSESSMENT

A. INSECT RESISTANCE MANAGEMENT

Summary

1) Corn Rootworm

BPPD has reviewed Monsanto’s and Dow AgroSc iences’ submissions for a 5% SmartStax seed mixture including biological and efficacy data as well as simula tion modeling. In addition, BPPD conducted independent modeling analyses of the applicants’ proposal using a model (deterministic and probabilistic) developed by EPA/ORD. After careful review of the applicants’ modeling and the analyses conducte d by ORD, BPPD concluded that for corn rootworm (CRW),

a 5% seed mixture and 5% struct ured refuge have comparable dur abilities. Despite identifying a

number of uncertainties with the CRW assessment, the FIFRA SAP (2011) verified BPPD’s

conclusion that a 5% MON 89034 x TC1507 x M ON 88017 x DAS-59122-7 seed blend should have comparable durability to a 5% block refuge.

2) Lepidoptera (European Corn Bore r and Southwestern Corn Borer)

Based on a review of the Science Advisory Panel (SAP) report (SAP 2011) and revised modeling submitted by Monsanto/Dow, BPPD conc ludes that a 5% seed blend for MON 89034 xMON 89034 x TC1507 x MON 88017 x DAS-59122-7 ( SmartStax®) B.t. Corn Seed Blend Page 5 of 39 Biopesticides Registration Action Document

TC1507 x MON 88017 x DAS-59122-7 corn will likely be less durable (perhaps significantly so) than a comparable (5%) block refuge for the product. BPPD notes, however, that a MON 89034

x TC1507 x MON 88017 x DAS-59122-7 5% seed blend should be more durable than a 20% block refuge for a single toxin Bt corn product or a comparable (5%) seed blend for a two toxin pyramid. Larval movement, potential survival (and selection) of heterozygote genotypes, and loss of refuge effectiveness duri ng the growing season ar e the primary factors that are likely to reduce durability in seed blends.

To improve BPPD's ability to assess the ri sks of resistance for a MON 89034 x TC1507 x MON 88017 x DAS-59122-7 seed blend, the foll owing topics and uncertainties must be

addressed:

 Revised modeling incorporating the structur al elements recommended by the SAP (i.e., explicit larval movement, switch from a fre quency-based model to one including densitydependent larval mortality, epistatic mechanis ms for resistance in target pests) with separate analyses for SWCB and ECB. N on-uniform oviposition should be modeled for both ECB and SWCB, especially (but not only) for the second generation of adults which will more likely lay eggs on Bt rather th an on damaged (or crowded out) non-Bt refuge plants in seed blends.

 Biological research on adult movement (relat ed to mating and movement from refuges), larval movement, larval feeding (i.e., sele ctive feeding within co rn ears or on pollen), survival of heterozygote genotypes on MON 89034 x TC1507 x MON 88017 x DAS59122-7 (markers may need to be determined for heterozygotes), and the potential for epistatic mechanisms of resistance (particularly with older instars).

Problem Formulation

BPPD’s risk assessment focused on assessing the risk of resistance developing to a 5% MON

89034 x TC1507 x MON 88017 x DAS-59122-7 seed mi xture in three main target pests: European corn borer, Southwestern corn borer, and corn rootworm. The registrants proposed the continued use of the existing 5% structur ed refuge requirement for MON 89034 x TC1507 x MON 88017 x DAS-59122-7 in most parts of the Co tton Belt so as to not further contribute to

the risk of resistance evolution in corn earwo rm (CEW). Although it is known that CEW migrate northward during the growing season to corn-g rowing regions (i.e., the U.S. Corn Belt and Canada), CEW typically are not capable of overwintering in these regions. Rather, CEW are known to overwinter in the South, often in cotton fields. Some reverse migration from the Corn Belt to the Cotton Belt was observed by Gould et al. 2002, which sparked interest and the need to quantify the impact of south-north and north-s outh migration on the adaptation rates in CEW. Computer simulations by the Agricultural Biotechnology Stewardship Technical Committee (ABSTC) showed no significant inte raction between the percent of the late summer adult CEW population in the south that is made up of immigran ts and the date at which migrants return and no effect of return migration on the resistance gene frequency.

In the case of fall armyworm (FAW), a sec ondary target pest of MON 89034 x TC1507 x MON 88017 x DAS-59122-7 in the continental US, the sp ecies distribution is currently limited to areas of southern Florida and southern Texas; hence FAW are not currently a corn pest in the regions proposed for the adoption of a 5% MON 89034 x TC1507 x MON 88017 x DAS-59122- 7 seed mixture. Should future climate change elicit a range expansi on for FAW and expand itsMON 89034 x TC1507 x MON 88017 x DAS-59122-7 ( SmartStax®) B.t. Corn Seed Blend Page 6 of 39 Biopesticides Registration Action Document

overwintering capacity into the Co rn Belt, then a revised risk a ssessment will be needed for this target pest and the proposed 5% MON 89034 x TC1507 x MON 88017 x DAS-59122-7 seed

mixture.

A. Seed Mixture vs. Structured Refuge

Seed mixtures incorporating Bt and non Bt crop seeds have been a topic of discussion for almost

two decades. While such an Insect Resistance Management (IRM) strategy has obvious benefits ( i.e., no grower compliance component, facilitating th e planting of Bt and refuge fields), it has been proposed that under some circumstances this approach could lead to more rapid evolution of resistance in some target pests.

Scientific Advisory Panels (1998 and 2000) discour aged the Agency from the use of Bt seed mixtures to control lepidopter a target pests because substant ial larval movement could be expected between Bt and non-Bt plants leading to more rapid selection of resistance. Conversely,

the 2009 SAP concluded that a 20% seed blend stra tegy for Bt corn with low- or medium-dose effects on corn rootworm (Coleoptera: Chryso melidae) was supported by the insect’s limited larval movement. But the SAP specifically note d that this recomme ndation should not set a precedent for other Bt crops targeting other pests (SAP 2009).

Theoretical work by Mallet and Porter (1992) show ed that insect resistance was accelerated in seed mixtures compared to Bt stands where 10% of the population was no t exposed to selection, when the probability of larval movement ranged from intermediate to high ( ≥ 0.2), intensity of selection was great, and dominance of the resistance gene was low. They also reported that when insects selectively chose their food source (avoi dance of toxic substances), then effective dominance was increased, and seed mixtures could delay resistan ce evolution but that predicted outcomes depended also on other circumstances.

Using Mallet and Porter’s model, Tabashnik (19 94) reported that 10% Bt seed mixtures were more durable than pure Bt stands and that bloc k refuges of 10% were at least as durable (and more) as 10% seed mixtures when inheritance of resistance was recessive, partly recessive, or additive. As the percentage of refuge increase d from 0-50%, Tabashnik fu rther reported that a block refuge strategy performed equally well or better than seed mixtures. Seed mixtures in conjunction with refuges were the most durable of all deployment st rategies evaluated.

Onstad and Gould (1998) recommen ded 20% block refuges adjacent to the Bt fields over seed blend strategies because of un certainties surrounding expression of high-dose against the target pest. Their modeling results predicted that bloc k refuges would be more durable than seed

mixtures aimed at contro lling lepidopteran pests.

In a 2-yr field study with a seed mixture expr essing Cry1Ab and non-Bt co rn, Davis and Onstad (2000) obtained larval dispersal data, which were used to parameterize their simulation model

and assess the effect on the durabil ity of seed mixtures. Davis and Onstad observed that survival (after recovery) was lower for larvae that successfully dispersed from Bt to non-Bt plants compared to larvae that dispersed from non-Bt to non-Bt plants; this should favor heterozygote genotypes and make inheritance of resistance le ss recessive (Mallet and Porter 1992). In addition, increased mortality of susceptible larvae moving off refuge plants onto Bt plants would

result in a reduced effective re fuge. They reported that neonate dispersal away from Bt plants was greater than dispersal observed from non-Bt pl ants and noted that extensive use of seedMON 89034 x TC1507 x MON 88017 x DAS-59122-7 ( SmartStax®) B.t. Corn Seed Blend Page 7 of 39 Biopesticides Registration Action Document

mixtures could select for populations with impr oved dispersal capabilities . The empirical data was used to parameterize the simulation model (Onstad and Gould, 1998), and it was determined that while seed mixtures delay evolution of resi stance in ECB they are less effective at doing so than IRM strategies using a 20% block refuge.

Carierre et al. (2004) concluded that the differences in Bt trait durability predicted by block refuges and seed mixtures in Mallet and Porter (1992) and Taba shnik (1994) were caused by a reduction in refuge insects in seed mixtures that had moved from non-Bt pl ants to Bt plants and could be overcome if the percent of non-Bt plants in seed mixtur es was increased (compared to blocks).

B. Uncertainties

BPPD’s assessment (BPPD 2010) of Monsanto and DowAgroScience’s proposal identified a number of uncertainties regardi ng the biology of the target pest s and potential impacts on a seed blend strategy.

1. BPPD recognizes that to determine whether a 5% seed mixture ( both lepidoptera and coleopteran controlling agents) is a superior, equivalent, or inferior strategy to the currently approved 5% block refuge for MON 89034 x TC1507 x MON 88017 x DAS59122-7, a number of uncertainties and questions need to be considered.

2. There is evidence that some fraction of the adult ECB population may take part in longdistance dispersal (references described above) and that this behavior is a normal part of ECB life-history. Evidence s uggests that these insects are able to cover more than 12 km in one flight attempt. Results by Dorhout et al (2008) suggest that a fraction of 1-d old females appear to engage in obligate mi gratory flights. Mark-recapture studies in aggregation sites have failed to collect more than 1% of the released individuals. To determine whether a structured refuge some distance away from the Bt field or an integrated refuge via seed blend is the better IRM option for ECB, information with respect to the proporti on of the population engaging in obligate migratory behavior and timing of mating with respect to dispersal is crucial.

3. The proportion of the female ECB populati on that would have to engage in preovipositional long distance di spersal before durability of a 5% MON 89034 x TC1507 x

MON 88017 x DAS-59122-7 s eed mixture became compromised and whether that proportion would be a reasonabl e assumption is uncertain.

4. When susceptible ECB larvae move from Bt pl ants to non-Bt plants and their survival is lowered compared to susceptible larvae that have not previously been exposed to Bt (Onstad & Gould 1998), then a se ed mixture can be expected to decrease the effective refuge. Likewise, if susceptib le larvae leave non-Bt plants, arrive on Bt plants, and are subsequently killed, then seed mixtures can be expected to redu ce the refuge population to less than what can be expected to emer ge from a block refuge. In either case, literature supports that such conditions woul d increase the risk of resistance evolution in the target pests. An assessment is needed of whether the reduction in effective refuge

is substantial and could reduce the ov erall durability of the Bt product.MON 89034 x TC1507 x MON 88017 x DAS-59122-7 ( SmartStax®) B.t. Corn Seed Blend Page 8 of 39 Biopesticides Registration Action Document

5. Based on the timing of mating for SWCB (within 24-48h) and the pre-copulatory flight behavior over natal fields by males, it has been suggested that random mating occurs in the field for this target pest. Results by Qureshi et al. (2006), however , suggest that SWCB are also capable of dispersing great er distances. Based on the limited studies available in the public literature, it appear s that mating could primarily take place in natal fields but that greate r dispersal may also occur af ter the mating phase. Whether mating occurs before or after dispersal or whether only a fraction of females disperse during the pre-mating phase is important in formation and can impact the recommended IRM approach.

6. There may be regions in the continental U.S. where the Cotton Belt and Corn Belt overlap and where corn earworm is known to overwinter. Such potential areas must be identified because they could contribute to increased selection in corn earworm (CEW - aka cotton bollworm, CBW), which is a main target pest of both cotton and corn.

7. A reduction in male CRW in Bt mixtures wa s discussed by the SAP (2009) with respect to 5% Cry34/35 Bt corn mixtures. The SA P (2009) concluded that a reduction in the number of males could negativel y affect refuge effectiveness. This concern also applies for the pyramided Bt corn mixture ta rgeting CRW and should be addressed.

8. Different types of events and behaviors have been documented to affect WCRW adults’ dispersal spatially and temporally in the US Corn Belt. Despite this additional evidence for long distance dispersal, some data gaps st ill exist and should be addressed so that dispersal can be best incorporated into si mulation models. For example, Spencer (2009) reported that individuals of the variant WCRW type disper sed more than 200 m/day; however, the proportion of individuals in a population undertaking this sort of long distance movement is unknown. Likewise, uncer tainties associated with proportion of populations dispersing during cold front events (wind speeds of > 1.5 m/s) and frequencies of such events make it challeng ing to include this m ode of dispersal.

9. It is unclear what proportion of female CRW populations would have to engage in preovipositional long distance disp ersal before durability of a 5% SS seed mixture could potentially be compromised.

10. It is unclear how non-compliance will affect th e durability of a 5% block refuge relative

to a 5% seed blend and whether such non- compliance assumptions are reasonable for

the US.

Corn Rootworm Assessment

BPPD reviewed Monsanto’s and Dow AgroSciences’ submissions for a 5% MON 89034 x

TC1507 x MON 88017 x DAS-59122-7 seed mixture including biolog ical and efficacy data as well as simulation modeling (BPPD 2010). In ad dition, BPPD conducted independent modeling analyses of the applicants’ proposal using a mode l (deterministic and probabilistic) developed by EPA/ORD. After careful review of the appl icants’ modeling and the analyses conducted by ORD, BPPD concludes that or corn rootworm (CRW), a 5% seed mixture and 5% structured refuge have comparable durabilities;

Monsanto Company and Dow AgroSciences separately submitted efficacy, adult emergence, andMON 89034 x TC1507 x MON 88017 x DAS-59122-7 ( SmartStax®) B.t. Corn Seed Blend Page 9 of 39 Biopesticides Registration Action Document

larval movement data, which served to support some of their assumptions made in their simulation models. The modeling analyses focu sed on the time to resistance or ‘rate of adaptation’ for European corn borer, Southwestern corn borer, and corn rootworm from the use

of a 5% MON 89034 x TC1507 x MON 88017 x DAS-59122 -7 seed mixture (95% Bt and 5% non-Bt seed). Dow’s model predicted similar incr eases in corn rootworm resistance allele frequencies for both ref uge strategies, while

EPA/ORD’s simulation analyses were conducte d separately for CRW and ECB/SWCB using a two-locus deterministic and probabilistic model

, which is an extension of the model used in Caprio and Glaser (2010a). The analysis was conducted by running 1000 simulations, each time re-sampling a group of uncertain parameters using a PERT- Beta distribution (setting a minimum, most likely, and maximum value for each parameter of concern). For each pest, the model output generated a probability distribution fo r durability (time to resistance) based on the

1000 simulations that were conducted. To anal yze these distributions , BPPD established durability estimates for various levels of risk (i .e., the likelihood that a resistance event would occur within a particular timeframe ). For example, a 5% level of ri sk would mean that in 95% of the simulations, resistance evolved in greater time than the durability estimate predicted. Conversely, in the other 5% of the simulations resistance developed with in the predicted time

frame.

In the CRW model simulations (see Table 1), the m ean time to resistance was 82 years for a 5% seed blend and 53 years for a 5% structured refuge. As described above, a probability

distribution was also created from the simulations for the estimated time to resistance with a seed blend and structured refuge. With a 5% leve l of risk, the durabil ity of MON 89034 x TC1507 x

MON 88017 x DAS-59122-7 seed fo r CRW was 33 years, while the block refuge was 22 years. This means that in only 5% of the 1000 simu lations conducted, resistance evolved within 33 years (seed blend) and 22 y ears (structured refuge).

Table 1. Durability estimates by EPA/ORD and Dow for 5% SmartStax seed mixt ure and 5% structured refuge targeting Corn rootworm

1 For benchmark and worst-case assumptions

2 Dow’s model predicted similar durability for SmartStax under both refuge scenario s but no actual values were provided.

FIFRA Scientific Advisory Panel

The Agency held a Scientific Advisory Panel meeting on December 8-9, 2010 to addressBPPD’s risk assessment of 5% MON 89034 x TC1507 x MON 88017 x DAS-59122-7, a multitoxin double pyramid targeting above ground (Lepi doptera) and below ground (Coleoptera) pests of maize. In the Agency’s risk assessme nt, BPPD evaluated M onsanto’s modeling for Lepidoptera pests and Dow’s modeling for corn r ootworm; additionally, BPPD collaborated with EPA/ORD in an independent modeling effort to evaluate the applican ts’ proposal (BPPD 2010). The SAP provided its written repor t to the Agency on March 3, 2011. Refuge Scenario Dow CRW Model ORD CRW model

Increase in Resistance Allele Frequency 1 5% Level of Risk Average Years

5% Seed Blend Similar rates of increase 2 for the 20 years modeled 33 years 81.9 years 5% Structured Refuge 22 years 52.9 yearsMON 89034 x TC1507 x MON 88017 x DAS-59122-7 ( SmartStax®) B.t. Corn Seed Blend Page 10 of 39 Biopesticides Registration Action Document

Lepidopteran Assessment (ECB, SWCB, CEW)

The SAP expressed concern about the risk of re sistance by the European corn borer (ECB) and southwestern corn borer (SWCB) in a 5% MON 89034 x TC1507 x MON 88017 x DAS-59122- 7 seed blend compared to a 5% structured refuge (approved by the Agency in 2009). Their

overall conclusion was that a 5% M ON 89034 x TC1507 x MON 88017 x DAS-59122-7 strategy would be substantially less durab le than a 5% MON 89034 x TC1507 x MON 88017 x DAS-59122-7 (SSX) structured re fuge and that there was “insu fficient scientific basis for supporting the SSX RIB as an effective IRM st rategy” for ECB and SWCB. The following is a summary of the SAP’s main concerns about M onsanto’s assumptions and parameter values chosen in their model for European corn borer and southwestern corn borer:

A. Structural equations to model larval moveme nt were not included in the model, and the approximations used by the applicant were stru ctured to minimize the effect of larval

movement on the rate of resistance evol ution. The durability of 5% SSX RIB was overestimated by modeling larval movement im plicitly and by not considering different larval-movement hypotheses (NBI, NBP, BNI, and BNP). Larval movement in Bt/non-Bt seed mixtures may lead to greater heterozygo te survival, which in turn would speed up

resistance evolution.

B. No cross-resistance was incorporated into the model between Cry1F and Cry1A.105 and Cry2Ab when the applicants’ data (Schlenz et al. 2008) indica ted some level of epistasis

and cross-resistance between Cr y1F and the other two toxins.

C. Other forms of epistasis (expression of a gene is suppressed by a gene at another locus) were not considered; rather the applicant assumed that survival of genotypes was multiplicative for all three lo ci (least conservative assu mption because heterozygote survival was, therefore, low). Other forms of epistasis should have been explored for ECB and SWCB such as, for example (but not only), “developmentally restricted expression of low levels of Cry-protease where older larvae survive Bt exposure when moving from non-Bt onto Bt”. Additionally, resi stance at all loci could be determined by the most rapidly evolving locus, which could drag other resistant loci along and, thereby,

increase the rate of resistance evolution.

D. Non-uniform oviposition of 2 nd generation ECB and SWCB in seed blends should favor Bt plants because adult females could distinguish between damaged (non-Bt) and protected (Bt) plants. This selective oviposition behavior based on unsuitable non-Bt host plants will reduce the effective refuge in a seed blend compared to a structured refuge.

For 1 st generation ECB and SWCB, non-uniform oviposition is also a probability, especially when the refuge plants incurred root damage from corn rootworm (CRW) and subsequently experience crowding out by fast er growing (CRW protected) Bt plants.

E. Strong density-dependence occurs in SWCB, a nd this aspect was not incorporated into the applicant’s model to estimate resistan ce evolution. “Soft selection” might be operating in this species in contrast to vi ability selection; “larvae that win out in cannibalistic encounters in the pr esence of Bt are likely to be those that have a slight fitness advantage from being more resistant to Bt”.MON 89034 x TC1507 x MON 88017 x DAS-59122-7 ( SmartStax®) B.t. Corn Seed Blend Page 11 of 39 Biopesticides Registration Action Document

F. The Panel recommended that emphasis in modeling assessments of stacked cultivars should be placed on durability for the pest th at shows the greatest potential rate of resistance evolution. The Panel suspected that this may be SWCB for MON 89034 x

TC1507 x MON 88017 x DAS-59122-7

G. For corn earworm and SSX RIB, the panel conc luded that there were serious risks to both cotton and corn due to pollination concerns of corn ears in a seed blend environment. The panel was unable to quantify the role of sel ection on the rate of re sistance evolution in

CEW associated with a SSX RIB in the Corn Belt and migration between the northern corn growing and southern cott on growing regions at the time.

The panel suggested that the current industry and EPA models be revised (or new models created) to address the factors that led to overestimates of dur ability. In particular, the panel recommended that new modeling focus on improving the parameters for survival of genotypes (especially heterozygotes) in a pyramided toxin e nvironment. Further, the panel indicated that modeling on a regional scale may be suitable to investigate the effect s of region-wide pest population suppression from a seed blend deployment.

The panel recommended additional research regard ing dispersal/movement of adults, effects of plant-to-plant movement on larvae, survival of different genotypes on Bt toxins (particularly heterozygotes), and effects of kernel pollin ation effects on corn earworm (CEW) refuge.

The panel suggested that seed bl ends could be implemented with a phase-in approach in which the seed blend percentage was lowered as data were developed (i.e., resistance monitoring and population density). No specific blend percenta ge numbers were recommended by the panel for this approach. It was also s uggested that the resistance manage ment plan have a well-defined trigger for remedial action (in the event that resistance develops).

Corn Rootworm Assessment

For corn rootworm, the SAP concluded that seed blend and block durability for SSX would be comparable.

BPPD Review of Monsanto/Dow’s Submissi on Responding to the SAP Report

Monsanto and Dow AgroSciences addressed the SAP’s concerns and submitted a written response to BPPD. As part of th is response, Monsanto and Dow AgroSciences conducted revised modeling to evaluate the proposed seed blend (MRID No. 484234-01).

The applicants agreed with the SAP’s conclusion that a 5% SSX RIB woul d be less durable than a 5% SSX with a structured refuge, they notedhowever that when realistic levels of noncompliance were incorporated, this difference in durability was reduced. BPPD concurs with this statement and notes that the SAP did not ap pear to address compliance in their model.

After reviewing the Monsanto/Dow submission, (B PPD 2011) BPPD concludes that a seed blend expressing (such as MON 89034 x TC1507 x MON 88017 x DAS-59122-7 ) three high-efficacy toxins (against mobile lepidoptera pests) with low potential for cross-resi stance and low risk for other epistatic effects should generally be more durable than a seed blend expressing two highefficacy toxins with low or no epistatic effects. For MON 89034 x TC1507 x MON 88017 xMON 89034 x TC1507 x MON 88017 x DAS-59122-7 ( SmartStax®) B.t. Corn Seed Blend Page 12 of 39 Biopesticides Registration Action Document

DAS-59122-7, however, the relative difference in durability between a seed blend and a block refuge of equivalent size cannot be quantif ied until Monsanto and Dow address the SAP’s modeling recommendations (i.e., exp licit larval movement, epistasis, non-uniform oviposition in seed blends, and density-depende nt effects) and other concerns described in this review.

BPPD noted that Dow compared the pyramided seed blend strategy solely to the single PIP with a 20% block refuge and showed that (under their mode ling construct) the pyramided product was more durable than the single PIP. As stated by the SAP, a comparison between a pyramid and a 20% single trait structured refuge should always show that the pyramid is more durable. The relative comparison, however, is important between single PIP , pyramided PIP (SSX RIB ), and the pyramided PIP with a structured refuge . Monsanto included a co mparison between the three IRM strategies and reported that a 5% SSX seed blend would be more durable than a single gene product with a 20% refuge and SSX with a 5% structured refuge with 50% grower noncompliance but somewhat less durable than SSX with a 5% structured refuge and 100% compliance. BPPD concludes that a comparison be tween the seed blend an d a structured refuge

with realistic numbers of non-compliance (i.e. 20%-30%, based on surveys conducted by the Agricultural Biotechnology Stewardship Techni cal Committee) would have improved their analysis. In addition, Monsanto could have us ed a probability appr oach to modeling noncompliance with the mean as 20% and worst-case and best-case choice for min and max values. The durability of block refuges should be higher with less non-compliance.

BPPD agrees with the applicants that some of the dose profile s chosen in the SAP’s modeling analysis of SSX RIB were lower than what the applicants’ empirical data and published literature supported. It is likely that highe r dose values would improve overall durability for both blocks

and blends.

BPPD’s review of the specific concerns raised by the SAP (and Monsanto/Dow’s response) is

detailed below:

A. LARVAL MOVEMENT:

Explicit larval movement:

BPPD concludes that Monsanto and Dow did not directly address the SAP’s recommendation to include explicit larval movement into their model. Instead, Dow and Monsanto provided the Agency with supplemental modeling in their respons e to the SAP report that (as in the previous modeling) used a spatially implicit model to estimate SSX RIB durability. Hence, both applicants have likely overestimated th e durability of a MON 89034 x TC1507 x MON 88017 x

DAS-59122-7 seed blend as was done in the initial modeling (see BPPD 2010 and SAP 2011).

Larval movement hypotheses:

The SAP also recommended that the applican ts incorporate different larval movement hypotheses into their model. BPPD found that the applicants did not address this recommendation either, presumably because th eir field data did not support high larval movement and survival or maybe because of lim itations with their current model structure.

BPPD notes, however, that in th eir preliminary efficacy study (one season, two locations; MRID 479437-01 (Appendix 3)) Monsanto and Dow reported th at there was some degree of damage inMON 89034 x TC1507 x MON 88017 x DAS-59122-7 ( SmartStax®) B.t. Corn Seed Blend Page 13 of 39 Biopesticides Registration Action Document

pure stand MON 89034 x TC1507 x MON 8801 7 x DAS-59122-7 and MON89034 x TC1507 plots and some SWCB larvae were found (unclear how many), although significan tly less than

what was observed in 90% and 95% seed ble nd plots with MON89034 x TC1507. Hence, to add additional conservatism to their analysis, BPPD recommends that Monsanto follow the SAPs advice and incorporate different larval movement hypotheses into their model for SSX RIB.

B. EPISTASIS

Cross-resistance: The applicants addressed epistasis by incorporating various degrees of crossresistance into their new modeling submission using Dow’s deterministic, spatially implicit model. The applicants were able to demonstrat e that durability of SSX RIB declined greatly initially and then somewhat slower as the degree of cross-resistan ce increased. With an assumption of 5% cross-resistance the estima ted durability decreased from >> 1000 generations (RAF was 0.008 at 1000 gen) to 387. BPPD notes that this is a drastic drop in durability. Although the applicants appear to argue that the potential for cro ss-resistance is non-existent or minimal, BPPD concludes that based on the SA P’s recommendations, a small degree of crossresistance should be included in the simulati ons to create a more conservative model.

Other forms of epistasis: The applicants argued that epistasis via a Cry-protease mechanism and altered expression of receptor ge nes were unlikely to be of relevance because such mechanisms would provide little or no selec tive advantage to ECB feeding on the three high-dose Bt proteins

in MON 89034 x TC1507 x MON 88017 x DAS-59122- 7 . BPPD is not convinced of the applicants’ argument for not including other form s of epistasis such as, for example, a Cryprotease mechanism. The SAP stated that a Cry-protease could potentially “degrade multiple Cry toxins, reducing or eliminating thei r toxicity to the insects”. The SAP also stated that it is more likely that Cry-protease expres sion occurs in later instars of ECB and SWCB, which would

affect their fitness in a seed mixture when plant-to-plant movement occurred. If such a mechanism confers the ability to tolerate multiple Bt toxins and has genetic heritability, then it

should be a “selectable” trait in an environment with significant amounts of Bt corn (SSX). Hence, BPPD recommends that the applicants consider including such a mechanism for older

instars of ECB and SWCB in their model.

C. NON-UNIFORM OVIPOSITION

The applicants did not address the SAP’s recomm endation regarding non-uniform oviposition in seed blends. The Panel stated that: 1) in seed blends of SSX, refuge plants might incur root damage from CRW (and other tissue damage from ECB), which could stunt their growth and allow protected SSX plant to effectively crowd ou t refuge plants. First generation females would then be more likely to oviposit onto SSX plants in seed blends than non-Bt plants; and 2) in a seed blend environment, second generation fema les could discriminate between damaged (nonBt) and non-damaged (Bt protected) plants and could, therefore, be more likely to oviposit onto Bt plants than they would otherwise. Hence, BP PD recommends that the applicants incorporate a degree of non-uniform ovipositing behavior by bo th first and second generation females favoring Bt plants. This would reduce the seed blend dur ability due to a reduction in effective refuge compared to a structured refuge of comparable non-Bt proportion.

D. DENSITY-DEPENDENCE FOR SWCB

BPPD disagrees with Monsanto and Dow’s jus tification (lack of m ovement onto and SWCB larval presence on SSX) for not addressing densit y-dependence in their model. As stated inMON 89034 x TC1507 x MON 88017 x DAS-59122-7 ( SmartStax®) B.t. Corn Seed Blend Page 14 of 39 Biopesticides Registration Action Document

section 2.1 above, some SWCB larvae were found in pure stand SSX and MON 89034 x TC1507 plots and seed blend plots. Hence there is ev idence for larval estab lishment on and movement onto SSX plants. BPPD recommends that the ap plicants incorporate de nsity-dependence into their simulation models as was recommended by the SAP (2011)

E. IRM EMPHASIS ON SPECIES AT GREATES T RISK OF EVOLVING RESISTANCE

The SAP concluded that IRM stra tegies should be designed around the pest that shows the greatest potential rate of resistance evolution. Th e Panel suspected that this might be SWCB for MON 89034 x TC1507 x MON 88017 x DAS-59122-7 . Should the applicants conduct new modeling incorporating BPPD’s recommendations as outlined in this review, a separate analysis should be provided for ECB and SWCB (as was done in the original submission -- discussed in BPPD 2010).

Overall Lepidopteran Pest Conclusions

 Based on a review of the Science Advisory Panel (SAP) report (SAP 2011) and revised modeling submitted by Monsanto/Dow, BPPD c oncludes that a 5% seed blend for MON

89034 x TC1507 x MON 88017 x DAS-59122-7 co rn will likely be less durable (perhaps significantly so) than a comparable (5%) block refuge for the product. BPPD notes, however, that a MON 89034 x TC1507 x MON 88017 x DAS-591 22-7 5% seed

blend should be more durable than a 20% bloc k refuge for a single toxin Bt corn product or a comparable (5%) seed blend for a two toxin pyramid. Larval movement, potential survival (and selection) of heterozygote genotypes, and loss of refuge effectiveness during the growing season are the primary factors that are likely to reduce durability in

seed blends.

 BPPD has major reservations regarding the modeling approaches taken by Monsanto and Dow (in separate models) to evalua te the MON 89034 x TC1507 x MON 88017 x DAS59122-7 seed blend. Monsanto and Dow addr essed larval movement implicitly (as opposed to explicitly as recommended by the SAP) and did not incorporate other important recommendations made by the SA P (i.e., epistatic resistance mechanisms, density-dependent effects). As detailed in the SAP report, this approach is likely to result in overestimates of durability. For this re ason, BPPD is unable to quantify the relative differences in durability estimates betw een refuge options (i.e., 5% MON 89034 x

TC1507 x MON 88017 x DAS-59122-7 seed blend, 5% MON 89034 x TC1507 x MON 88017 x DAS-59122-7 block refuge, and 20% single toxin block refuge).

 Despite the modeling uncertainties described above, BPPD believes that, in general, a three toxin product such as MON 89034 x TC1507 x MON 88017 x DAS-59122-7 should have greater durability than Bt corn products with two or fewer toxins and comparable refuge deployment. In other word s, a three toxin seed blend can be expected to be more durable than a two toxin product w ith the same blend percentage. Similarly, a block refuge for a three toxin product should be more durable than the same block refuge for a two toxin product. This conclusion assume s that the three toxins have high efficacy and low cross-resistance potential. BPPD cau tions, however, that the relative gain and loss in durability with multi -toxin pyramids should be eval uated on a case-by-case basis with product-specific data.

 BPPD agrees with Monsanto/Dow that the SAP's modeling analysis 1) did not include three toxins for lepidoptera (two toxins were modeled for simp licity), 2) incorporated low dose scenarios for the toxins in MON 89034 x TC1507 x MON 88017 x DAS-59122-7 ,MON 89034 x TC1507 x MON 88017 x DAS-59122-7 ( SmartStax®) B.t. Corn Seed Blend Page 15 of 39 Biopesticides Registration Action Document

and 3) neglected to consider effects of non-compliance on block refuge. The first two factors likely resulted in lower durability es timates for both block and blended refuge; the third probably led to an overestimate of dur ability for block refuges. Monsanto and Dow's revised modeling addressed these three components.

 Block refuges and seed mixes present different potential risks and benefits for resistance management. A summary of thes e factors is described below:

Block Refuges

o Pros:

 Greater durability than other refuge approaches (including seed mixes, strip refuges, and natural refuge) in simulation models;

 Allows for high production of susceptible insects;

 Refuges can be managed to preserve yield.

o Cons:

 Random mating may be less likely than with seed mixes or strip refuges if adult movement is limited (though not the case for mobile lepidoptera);

 Compliance must be monitored (i.e., w ith a compliance assurance plan);

 Non-compliance can result in no refuge deployment or inadequate refuge distance from Bt field to assure random mating (more important for high-dose PIPs such as in MON 89034 x TC1507 x MON 88017 x DAS-59122-7 ), which can increase the risk of resistance;

 Refuge may need to be treated w ith insecticides (potential economic and environmental costs);

 There have been reports of a lack of available refuge seed in some areas;

 Planting refuges can incur inconveniences and expenses for growers.

Seed Blends

o Pros:

 Non-compliance is not an issue -- all seed bags are assumed to have the same amount of refuge seed (± standard error);

 A compliance monitoring program should not be necessary (cost/resource savings);

 No separate refuge management and insecticide use are needed;

 Ease of use for growers.

o Cons:

 Lower durability (perhaps substantially ) than block refuges in simulation modeling;

 Potentially lower “effective” refuge due to damage to non-Bt plants and/or Bt pollination within the growing season, re duced larval movement from Bt onto non-Bt plants, and within-plant density-dependent mortality;

 Possible yield loss due to lodging of refuge plants within the Bt field, particularly with higher (>10%) blend percentages;

 Difficulty detecting “unexpected pest damage” (a key component of resistance monitoring);

 Increased risk of resistance for pests with greater adult dispersal and larval plantto-plant movement (driven by heterozygous genotypes).

Necessary Additional Information:MON 89034 x TC1507 x MON 88017 x DAS-59122-7 ( SmartStax®) B.t. Corn Seed Blend Page 16 of 39 Biopesticides Registration Action Document

To improve BPPD's ability to assess the risk s of resistance for a MON 89034 x TC1507 x MON 88017 x DAS-59122-7 seed blend, Monsanto and Dow n eed to address the following topics and

uncertainties:

 Revised modeling incorporating the structur al elements recommended by the SAP (i.e., explicit larval movement, switch from a fre quency-based model to one including densitydependent larval mortality, epistatic mechanis ms for resistance in target pests) with separate analyses for SWCB and ECB. N on-uniform oviposition should be modeled for both ECB and SWCB, especially (but not only) for the second generation of adults which will more likely lay eggs on Bt rather th an on damaged (or crowded out) non-Bt refuge plants in seed blends.

 Biological research on adult movement (relat ed to mating and movement from refuges), larval movement, larval feeding (i.e., sele ctive feeding within co rn ears or on pollen), survival of heterozygote genotypes on MON 89034 x TC1507 x MON 88017 x DAS59122-7 (markers may need to be determined for heterozygotes), and the potential for epistatic mechanisms of resistance (particularly with older instars).

Seed Blending –Manufacturing Considerations

1) Distribution of MON 89034 x TC1507 x MON 88017 x DAS-59122-7 and Refuge

Seeds in the Blend

Monsanto and Dow AgroSciences Position

Monsanto and Dow AgroSciences claim that a uni form in-field distribution of refuge (non-Bt) plants represents the worst case sce nario for IRM and that any deg r ee of clumping of refuge plants will tend to reduce the potenti al negative impacts of seed blends.

With a uniform distribution of refuge plants in a 5% MON 89034 x TC1507 x MON 88017 x DAS-59122-7 seed blend, a ll non-Bt plants will be s u rrounded by Bt plants. Hence, larvae moving from refuge plants onto ne ighboring plants will survive on a Bt plant (causing a

reduction in effective re f uge in seed blends compared to struc t ured refuges of equivalent size). Conversely, larvae moving off Bt plants will have a 5 % probability of arriving on a refuge plant (which may introduce the potential for sublethal ef f ects from prior Bt exposure).

A clumped distribution of refuge plants have the effect that some larvae moving off refuge p lants will arrive on other refuge plants and, therefore

, be more likely to survive than those moving from refuge plan t s onto surrounding Bt plants in a uniform distribution. In addi t ion, larvae

mov i ng off Bt plants in seed blend with a clumpe d distribution would ha ve less than a 5% probability of arriving on a refuge pl ant; this smaller pr oportion may receive sublethal exp os ure and thus there would be less differential selection of he terozygotes with a clumped versus unif o rm in-field refuge.

The in -fi eld bloc k refuge scenarios (with 100% compliance) m odeled by Monsanto, Dow , a nd

EPA ORO re p resent the extreme end of the clumped scenario (i.e. minimal larval movement
betw e en refuge and Bt plants, highest effective refuge size

, l owest relative fitness of heterozygote s ). These modeling efforts support that clumped (or block) refuge s de l ay resistance more compared to uniform distribut ed refuge plants in seed blends.MON 89034 x TC1507 x MON 88017 x DAS-59122-7 ( SmartStax®) B.t. Corn Seed Blend Page 17 of 39 Biopesticides Registration Action Document

BPPD Conclusion

BPPD has reviewed Dow's and Monsanto's argument that a seed blend with a uniform

distr i bution represents a worst-case scenario for IRM. BPPD concurs th at clumping of refuge plants should be b etter for IRM than a uniform distribution because of an increas e i n effective refuge and decreased differen tial selection on heterozygote s (as stated by the applicants), w h ich

makes inheritance of resistance more recessive (Maliet and Porter 1992; Davis and Onstad 2000). In cases , however, where greater asymmetrical dispersa l (from Bt to non-Bt) is observed or expected, s eed mixtures may prove to be more durable than structured refuges.

Euro p ean com borer (ECB) and southwestern com borer (SWCB) are the two main target pests

of MON 89034 x TC1507 x MON 88017 x DAS -59122-7 in the Com Belt. With respect to asymmetrical movement, Onstad and Gould ( 199l) modeled dispersal of neonate ECB (55- genotypes) off Bt plants with a 98% probabi l ity and o ff non-Bt plants with a 90% probability.

Their data indicate that there is little asymmetrica l dispersal between the two plant types. For SWCB, no data on differential dispersal are available in the public literature

. Because SWCB is cannibalistic, such behavior shou l d increase the probability of dispersal compared to ECB (FIFRA SAP 2011). BPPD notes that it may, ther efore, be assumed that there is no great

di s per s al differential between neonate s leaving Bt or non-Bt plant s in response to so me asymmetrica l dispersal. BPPD concludes that for ECB and SWCB it may be safe to assume th a t
a 5% MON 89034 x TC1507 x MON 88017 x DAS-59122-7 seed blend with a uniform distribution repre se nts a worse case than a b lend with a clumped distribution.

2) Blended Refuge Percentage Assurance

Both Monsanto and Dow submitted data adequately demonstrating a minimum 5% refuge of

non-Bt seed in the MON 89034 x TC1507 x MON 88017 x DAS-59122-7 blends produced at seed processors within their company.

BPPD has reviewed the information provided re garding the manufacturing process in Monsanto and Dow AgroSciences owned f acilities and concludes that:

• The seed weighing technology should guara ntee high accuracy around the determined target (mean weight or mean percentage) with very low expected variance provided that all of Monsanto's Dow’s manufacturing plants mainta in and follow the same procedures respectively;

• The seed mixing technology will be set to sati sfy growers expectation of uniformity but some degree of clumping of refuge seed may be pos sible. BPPD does not expect clumping of refuge plants in the field to impact lRM for ECB and SWCB (see BPPD 2011) because of very little expected asymmetrical movement between the tw o plant types (Bt and non-Bt) for both species as supported by Onstad and Gould (1998);

• Bt and refuge seed will be colored differently when seed blends are mixed in Monsanto or Dow AgroSciences owned manufacturing plants. Monsanto is also encouraging its seed company licensees to color the Bt and refuge seed differently. Coloring the two types of seed differently will provide an additional affirmation that the product is in fact a seed blend. It 

### will also allow the applicant to more easily test for germination of refuge seed (to assure the 5% refuge is still guaranteed).

Monsanto has submitted additional information and a generic standard operating procedure to guarantee the same accuracy and quality assurance from independent seed dealers who are in chargeMON 89034 x TC1507 x MON 88017 x DAS-59122-7 ( SmartStax®) B.t. Corn Seed Blend Page 18 of 39 Biopesticides Registration Action Document

of their own seed mixing process Unfortunately, this information was very general and not specific enough for BPPD to ascertain that the target bl end percentage will be assured in non-Monsanto

facilities.

It was not clear from reading Dow's docum ent what the actual target weight and percentage will be should a 5% MON 89034 x TC1507 x MON 88017 x DAS-59122-7 seed

blend be commercialized. This information is needed.

3. Seed Blend Monitoring under the Federal Seed Act

The United States Agricultural Ma rketing Service and State Seed Control Officials are involved with ensuring compliance to the Federal Seed Act by seed producers. Testing of seed blend products for refuge component percentage has and will be taking place. If either USDA or State Seed Control Officials obtain official samples of seed blend products, do color separations on the composite samples collected and find the percenta ge of the refuge component is lower in those samples than is represented on the label, action may be initiat ed under the Federal Seed Act.

IRM Refuge Compliance

Critical to an assessment of the likely efficacy of an IRM mitigation program is the level of compliance with that program. Data receiv ed by EPA from the Agri cultural Biotechnology Stewardship Technical Committee (ABSTC) indicat e that compliance with the paradigmatic 20% block refuge requirement for most B.t. corn crops has been st eadily decreasing. This decreased compliance increases the risk of resistance deve lopment (see, e.g., Complacency on

the Farm , CSPI 2009, and Impact of Genetically Engineered Cr ops on Farm Sustainability in the
United States, NAS 2010 )

.

Grower survey results (see Figure 1 ) show that average compliance with refuge distance requirements for ECB protected corn expressi ng single PIPs was signi ficantly higher in 2010 than in the previous ye ar (margin of error + 6.0%); compliance with refuge size remained approximately equal compared to 2009. Growers re ported to be out of compliance deviated from the 20% requirement in one way or another. Further analysis of non-compliance numbers

revealed that most farmers (87%) planted a refuge that was at least 15%, and that 5% of farmers neglected to plant a refuge at a ll. A regional analysis revealed that growers planting single ECB PIP expressing corn in eastern regions of the Co rn Belt were less compliant on average (71% for refuge size, 83% for refuge requirement) than gr owers in the western regions (81% for refuge size and 90% for distance requirement). Growers in the southern U.S. had significantly lower adherence percentages than the Corn Belt agai n; the 2010 analysis re veals, however, that compliance in the south has had a small, yet st atistically, significant increase in compliance compared to 2009 (from 40% in 2009 to 49% in 2010 for refuge size; from 63% in 2009 to 70% in 2010 for refuge distance). It is unclear whethe r the observed difference is due to the smaller sample size in the south, which was reduced by 60 % compared to the sample size in the eastern and western regions of the US. However, complia nce is still below an acceptable level in the south; possible explanations for such lower comp liance in the south could include confusion with different requirements between various PIP pro ducts or simply blatant disregard of refuge requirements by growers who plant both Bt corn and Bt cotton. ABSTC st ated in their 2009 CAP report that these regional results provided them with the opportunity to intensify future educational efforts in the southern corn gr owing regions. BPPD notes that if higher noncompliance among southern corn growers reflects a willingness to violate refuge requirementsMON 89034 x TC1507 x MON 88017 x DAS-59122-7 ( SmartStax®) B.t. Corn Seed Blend Page 19 of 39 Biopesticides Registration Action Document

rather than a lack of knowledge, then increased ef forts to educate them ma y not be fruitful. Other methods to bring these growers back into compliance may need to be considered.

Grower awareness with IRM requirements was high (94%), yet the number of growers who could recall the correct refuge size (65%) was significantly lower compared to the number of growers who recalled the correct refuge distance requirements (82%). These percentages are reflective of the compliance numbers from the online survey.

0 20 40 60 80 100 120

'02 '03 '04 '05 '06 '07 '08 '09 '10%Compliance

Planting season

Compliance with refuge requirements for ECB protected

corn PIPs

refuge size

refuge distance

Figure 1 Compliance trend from 2002-2010 for growers planting single ECB PIPs

Overall compliance (per grower) with refuge re quirements for single PIPs targeting CRW is displayed in Figure 2 . Average compliance in 2010 has agai n decreased compared to 2009 and is now at the level of compliance (73% for refuge size, 67% for refuge distance) similar to that reported in 2008. The margin of error reported for CRW PIP compliance data is ±13.3%, hence the difference measured between 2010 and 2009 comp liance is not statistically significant. The percentage of growers blatantl y disregarding refuge requirement s in 2010 was again 9%, as in 2009. Eighteen percent (18%) of all corn rootworm protected fields had no refuge associated with them; this is an increase from the 14% reported in 2009.

Grower awareness with IRM requirements in 2010 was higher than in 2009, yet, the percentage of growers who could recall the refuge size and distance requirements was extremely low (33% and 22%, respectively). That is a drastic decline from an already low awareness in 2009 of 58% and 31% for correct refuge size and refuge dist ance. These percentages are now at an all time low. BPPD believes that this decline in grower knowledge is reason fo r concern and somewhat reflective of the compliance numbers from the on line survey. ABSTC’s educational efforts have been unsuccessful at increasing grower educa tion with respect to CRW IRM requirements.MON 89034 x TC1507 x MON 88017 x DAS-59122-7 ( SmartStax®) B.t. Corn Seed Blend Page 20 of 39 Biopesticides Registration Action Document

0 20 40 60 80 100

'05 '06 '07 '08 '09 '10%Compliance

Planting season Compliance with refuge requirements for CRW
protected corn PIPs

refuge size

refuge distance

Figure 2 Compliance trend from 2005-2010 for growers planting single CRW PIPs

Overall compliance (per grower) with refuge requir ements for stacked corn PIPs is displayed in Figure 3 . In 2010, the reported margin of error for adherence with requirements was again ±4.2%; therefore, BPPD concludes that the la test national average co mpliance results were similar to those reported in prior years. A region al analysis of survey results revealed that growers’ compliance in eastern re gions of the US significantly decl ined: adherence to refuge size requirements was 74% in 2009 and declined to 69% in 2010; adherence to refuge distance was 67% in 2009 and declined to 63%. Compliance in th e western regions of the Corn Belt remained similar or slightly higher to those reported in 2009. Corn grow ers in the cotton growing regions had similar compliance in 2010 as in 2009 – 32% and 37% for adherence to refuge size and distance requirements. BPPD notes that the comp liance percentages in th e south are extremely

low.

BPPD notes that the number of growers who were able to corr ectly recall IRM requirements on

an unaided basis reached an all time low since 20 07. Only 27% of growers were able to correctly recall the correct distance requirement for the CRW portion of the PIP in 2010. This represents a further decline from the reported 32% in 2009. Only 56% of the growers surveyed recalled that refuge size for the CRW PIP was 20%. The incr eased educational outreach by ABSTC is not producing the expected results among corn growers planting stacked PIPs.MON 89034 x TC1507 x MON 88017 x DAS-59122-7 ( SmartStax®) B.t. Corn Seed Blend Page 21 of 39 Biopesticides Registration Action Document

0 20 40 60 80 100

'06 '07 '08 '09 '10%Compliance

Planting season

Compliance with refuge requirements for stacked corn

PIPs

refuge size

refuge distance

Figure 3 Compliance trend from 2006-2010 for growers planting stacked corn PIPs

Table 2 shows the percent of growers who have bl atantly disregarded refuge requirements for the individual PIP products plante d in 2009 and 2010. Unfortunatel y, this information was not provided to the Agency prior to 2009 and no historical comparison can, therefore, be made yet.

Table 2. Percent growers planting a zero % refug e for stacked Corn PIPs (data from 2009-2010) Product Type 2009 1 2010 1

Single ECB PIPs 7% 5%
Single CRW PIPs 9% 9%

Stacked ECB/CRW

PIPs 11% 12%

1 Results are listed on a per grower (not per field) basis

B. Product Characterization and Human Health Assessment

Current tolerance exemptions in 40 CFR Part 174 applicable to MON 89034 × TC1507 × MON

88017 × DAS-59122-7.

§ 174.502 Bacillus thuringiensisCry1A.105 protei n; exemption from the requirement of a

tolerance.

(a) Residues of Bacillus thuringiensis Cry1A.105 protein in or on the food and feed commodities of corn; corn, field, flour; corn, field, forage; corn, field, grain; corn, field, grits; corn, field, meal; corn, field, refined oil; corn, field, stover; corn, sweet, forage; corn, sweet, kernel plus cob with husk removed; co rn, sweet, stover; cor n, pop, grain and corn, pop, stover are exempt from the requirement of a tolerance when the Bacillus thuringiensisMON 89034 x TC1507 x MON 88017 x DAS-59122-7 ( SmartStax®) B.t. Corn Seed Blend Page 22 of 39 Biopesticides Registration Action Document

Cry1A.105 protein is used as a plant-incorporat ed protectant in these food and feed corn

commodities.

§ 174.506 Bacillus thuringiensis Cry34Ab1 and Cry35Ab1 proteins in corn; exemption from the requirement of a tolerance.

Residues of Bacillus thuringiensis Cry34Ab1 and Cry35Ab1 proteins in corn are exempted from the requirement of a tolerance when used as plan t-incorporated protectant s in the food and feed commodities of corn; corn, fiel d; corn, sweet; and corn, pop.

§ 174.507 Nucleic acids that are part of a pl ant-incorporated protectant; exemption from the requirement of a tolerance.

Residues of nucleic acids that ar e part of a plant-incorporated protectant are exempt from the requirement of a tolerance.

§ 174.518 Bacillus thuringiensis Cry3Bb1 protein in corn; exemption from the requirement of a tolerance.

Residues of Bacillus thuringiensis Cry3Bb1 protein in corn are exem pt from the requirement of a tolerance when used as plant-incorporated prot ectants in the food and f eed commodities of corn; corn, field; corn, sweet; and corn, pop.

§ 174.519 Bacillus thuringiensis Cry2Ab2 protei n in corn and cotton; exemption from the requirement of a tolerance.

Residues of Bacillus thuringiensis Cry2Ab2 protein in or on corn or cotton are exempt from the requirement of a tolerance when used as a plan t–incorporated protectant in the food and feed commodities of corn; corn, field; corn, sweet; corn, pop; and cott on seed, cotton oil, cotton meal, cotton hay, cotton hulls, cotton fora ge, and cotton gin byproducts.

§ 174.520 Bacillus thuringiensis Cry1F protein in corn; exemption from the requirement

of a tolerance.

Residues of Bacillus thuringiensis Cry1F protein in corn are exempt from the requirement of a tolerance when used as plant-incorporated prot ectants in the food and f eed commodities of corn; corn, field; corn, sweet; and corn, pop.

§ 174.523 CP4 Enolpyruvylshikimate-3-phosphate (CP4 EPSPS) synthase in all plants; exemption from the requirement of a tolerance.

Residues of the CP4 Enolpyruvylsh ikimate-3-phosphate (CP4 EPS PS) synthase enzyme in all plants are exempt from the require ment of a tolerance when used as plant-incorporat ed protectant inert ingredients in all food commodities.

§ 174.522 Phosphinothricin Acetyltransferase (PAT); exemption from the requirement of

a tolerance.

Residues of the Phosphinothricin Acetyltransf erase (PAT) enzyme are exempt from theMON 89034 x TC1507 x MON 88017 x DAS-59122-7 ( SmartStax®) B.t. Corn Seed Blend Page 23 of 39 Biopesticides Registration Action Document

requirement of a tolerance when used as plant- incorporated protectant in ert ingredients in all

food commodities.

Southern Blot Analysis

Southern blot analysis confirmed in the comb ined trait corn product MON 89034 × TC1507 × MON 88017 × DAS-59122-7 the presence of sequences id entical to sequences derived from MON 89034 and MON 88017.Hybridization patterns for the combined trait product were identical to those of the parental lines with cry 1F, cry 34Ab1 , cry 35Ab1, and the pat gene probes indicating that the TC1507

and DAS-59122-7 insertions were unaffect ed by combining with MON 89034 and MON 88017 through conventional breeding.

Expression Levels

MON 89034 x TC1507 x MON 88017 x DAS-59122-7 is a combined trait corn that produces lepidopteran-active and coleopteran-active Bacillus thuringiensis ( Bt ) proteins, as well as the 5- enolpyruvylshikimate-3-phosphate synthase protein from Agrobacterium sp. strain CP4 (CP4 EPSPS) to confer tolerance to gl yphosate herbicides and PAT to c onfer tolerance to glufosinate herbicides. The levels of the lepidopteran- active Cry1A.105, Cry2Ab2, Cry3Bb1 proteins and the CP4 EPSPS protein were determined in ti ssues from MON 89034 x TC1507 x MON 88017 x DAS59122-7 plants grown at five US fiel d sites in 2006. The test also in cluded a conventional corn as a negative control and MON 89034 and MON 88017 corns as positive controls. Leaf, root, and whole plant samples were collected over the growing s eason, as well as pollen and grain samples at the appropriate times. The samples were extracted and analyzed using enzyme-linked immunosorbent assays. The levels of the Cry1A.105, Cry2Ab2, Cr y3Bb1, and CP4 EPSPS prot eins in MON 89034 x TC1507 x MON 88017 x DAS-59122-7 corn were comp arable to those in the appropriate MON 88017 or MON 89034 positive control.

The levels of the coleopteran-active Bacillus thuringiensis ( Bt ) proteins Cry 34Ab1, Cry35Ab1, and Cry1F, and the PAT protein were determined in tissues from MON 89034 x TC1507 x MON 88017 x DAS-59122-7 plants grown at five US field s ites in 2006. The test also included a conventional corn as a negative control and TC1507 and DAS-59122- 7 parental event corn as positive controls. Leaf, root, and whole plant sample s were collected over the growi ng season, as well as pollen and grain samples at the appropriate times. The samp les were extracted and analyzed using enzymelinked immunosorbent assays (ELISA). The results indicate that the levels of Cry34Ab1, Cry35Ab1, and Cry1F in MON 89034 x TC1507 x MON 88017 x DAS- 59122-7 were comparable to the levels produced in the appropriate TC1507 or DAS-59122-7 control corn. The leve l of PAT in MON 89034 x TC1507 x MON 88017 x DAS-59122-7 was higher in the combined trait products compared to TC1507 and DAS-59122-7, likely due to the presence of multiple copies of the pat gene in the stacks (one from each of the DAS parent lines).

C. Environmental Assessment

At present, the Agency has not identified any significant adverse effects of the Cry1A.105, Cry2Ab2, Cry1F, Cry3Bb1, or Cry34Ab1/35Ab1 prot eins on the abundance of non-target organisms in any field population, whether expr essed individually or as MON 89034 x TC1507 x

MON 88017 x DAS-59122-7 combined PIP corn product. The potenti al for synergistic effects

has been evaluated and the data that were reviewed for the indi vidual parental events can be bridged to support the Sec. 3 regist ration of MON 89034 x TC1507 x MON 88017 x DAS-MON 89034 x TC1507 x MON 88017 x DAS-59122-7 ( SmartStax®) B.t. Corn Seed Blend Page 24 of 39 Biopesticides Registration Action Document

59122-7 combined PIP corn product.

It is unlikely that direct or i ndirect harmful effects to non-targetorganisms, including federallylisted threatened or endangered species, would result from the insecticidal proteins Cry1A.105, Cry2Ab2, Cry1F, Cry3Bb1, or Cry34/35Ab as a result of the proposed Sec. 3 registration. The Agency anticipates that for full commercial cult ivation, no hazard will result to the environment.

Event MON 89034 produces the Cry1A.105 and Cry2Ab2 Bt proteins, and Event TC1507 produces Cry1F. These proteins ar e intended to control or suppre ss several lepidopteran pests of corn, including European corn borer (ECB, Ostrinia nubilalis ), corn earworm (CEW, Helicoverpa zea ), fall army worm (FAW, Spodoptera frugiperda ), and black cutworm (BCW, Agrotis ipsilon ). MON 88017 produces the Cry3Bb1 prot ein, and Event DAS-59122-7 produces the Cry34Ab1 and Cry35Ab1 proteins. These tw o events provide additional control for coleopteran pests, particular ly corn rootworm pests ( Diabrotica spp.).

It has been determined that each individual event has protein expression levels that are comparable to the MON 89034 x TC1507 x MON 88017 x DAS-59122-7 corn hybrid (Kough, 2009). Therefore, the margins of exposure that we re previously determined for the insecticidal proteins in the individual events are applicable for the risk asse ssment of these proteins in the stacked hybrid. Additionally, no synergistic or an tagonistic effects were observed in several

combinations of the individual events in MON 89034 x TC1507 x MON 88017 x DAS-59122-7,

as well as the MON 89034 x TC1507 x MON 88017 x DAS-59122-7 hybrid itself. As a result, the Agency concludes that there is no indication of synergistic effects or increased levels of protein expressed in the combined PIP product, so the environmental risk assessment for the single PIP lines are applicable to the a ssessment of MON 89034 x TC1507 x MON 88017 x

DAS-59122-7.

As a result, the environmental risk assessment of the individual events, as well as an additional study submitted on the toxicity of MON 89034 x TC1507 x MON 88017 x DAS-59122-7 to a non-target insect, the Agency conc luded that there will be no unr easonable adverse effects to the environment, including endangered speci es, by MON 89034 x TC1507 x MON 88017 x DAS59122-7 combined trait corn.

D. Benefits

We expect MON 89034 x TC1507 x MON 88017 x DAS-59122-7 seed blend products to have the following benefits: (1) Reduced pesticide use in the refuge. Currently, the block refuge may be sprayed with pesticide to mitigate pest dama ge. The blended in-field refuge will not be sprayable. (2) Significantly less complicated refuge deployment for the corn rootworm and lepidopteran active ingredients. Currently, to be fully compliant with the refuge requirements, growers must accurately calculate percentage of the field, accurately determine the proper distance for the refuge field, and properly plan t the required acreage in the correct location. Moreover, there are temporal concerns, as the re fuge field must be planted at, essentially, the same time as the yield field so that emergen ce of refuge rootworms is contemporaneous with emergence of field rootworms. Anecdotal reports from growers make clear that meeting each of these requirements can be challenging in the actu al on-farm environment. A product with the refuge blended with the field seed will ease depl oyment of the refuges. (3) Grower compliance with IRM requirements for the corn rootworm and lepidopteran active ingredients. A seed blend product incorporating an effective refuge in the seed bag would l ead to 100% grower complianceMON 89034 x TC1507 x MON 88017 x DAS-59122-7 ( SmartStax®) B.t. Corn Seed Blend Page 25 of 39 Biopesticides Registration Action Document

for planting a refuge. This is a significant benefit, a lthough perhaps not as great as the raw data on refuge compliance might suggest.

In addition, indirect benefits of introducing MON 89034 x TC1507 x MON 88017 x DAS59122-7 seed blends may include reduced energy consumption for manufacture, transport, and application of chemical insecticides; reduced wa ste streams arising from pesticide manufacture; reduced disposal of pesticide waste containers; and reduced residues from pesticide applications.

III. REGULATORY RATIONALE

Section 3(c)(7)(A) of FIFRA provides for the regist ration or amendment of a pesticide when the pesticide and proposed use “...are identical or substantially simila r to any currently registered pesticide and use thereof, or differ only in ways that would not significantly increase the risk of

unreasonable adverse effects on the environmen t, and (ii) approving the registration or amendment in the manner proposed by the applicant would not significantly increase the risk of any unreasonable adverse effect on the envir onment.” Unreasonable adverse effects on the environment are defined under Section 2(bb) of FI FRA as “... any unreasonable risk to man or the environment, taking into account the economic, social, and environmental costs and benefits of the use of any pesticide...” Thus, pursuant to Section 3(c)(7)(A), EPA may conditionally register a pesticide if (1) the pesticide and its proposed use are identical or substantially similar to a currently registered pesticide; or (2) the pesticide and its proposed use differ only in ways that would not significantly increa se the risk of unreasonable a dverse effects; and (3) approving the registration would not significantly increase the risk of any unreasona ble adverse effect.

We find that the MON 89034 x TC1507 x M ON 88017 x DAS-59122-7 seed blends meet criteria (2) and (3) of Section 3(c)(7)(A) for a time-limited registration to expire October 31,

2011. MON 89034 x TC1507 x MON 88017 x DAS-59122-7 seed blends consist of a currently registered products, 95% MON 89034 x TC1507 x MON 88017 x DAS-59122-7 (MON 89034 x

TC1507 x MON 88017 x DAS-59122-7 ) and 5% non-B.t. corn. Thus, both products are substantially similar to already registered PIPs in composition and use site (field corn). These products do not meet criteria (1), however, because the proposed use of the MON 89034 x

TC1507 x MON 88017 x DAS-59122-7 s eed blends achieves the lepido pteran insect resistance management refuge via a seed mix rather than a block refuge is not substantially similar to any currently registered pesticide.

We determine, however, that the MON 89034 x TC1507 x MON 88017 x DAS-59122-7 seedblends meet criteria (2) as, when used in accordance with the terms and conditions of a timelimited registration set to expire October 31, 2011, and would not si gnificantly increase the risk

of unreasonable adverse effects on the envir onment. Since the MON 89034 x TC1507 x MON 88017 x DAS-59122-7 seed blends are substantially similar to already registered PIPs in composition and use site, EPA’s considerati on of whether these new products would significantly increase the risk of any unreasonable adverse effect on the environment is limited to the change in lepiidopteran inse ct resistance management refuge deployment, i.e., a seed blend in the bag versus a block refuge. The unreasonab le adverse effect of concern is the development of resistance to Cry1F, Cry2Ab2, and Cry1A.105 in corn. Thus, we consider: (1) how does the registration of the MON 89034 x TC1507 x MON 88017 x DAS-59122-7 seed blends contribute to the development of corn rootworm resist ance to Cry1F, Cry2Ab2, and Cry1A.105 in corn; (2) should this resistance develop, wh at risk does it pose to man or the environment; and (3) takingMON 89034 x TC1507 x MON 88017 x DAS-59122-7 ( SmartStax®) B.t. Corn Seed Blend Page 26 of 39 Biopesticides Registration Action Document

into account the economic, social, and environmental costs and benefits, does this risk constitute

an unreasonable adverse effect?

The Risk of the MON 89034 x TC1507 x MON 88017 x DAS-59122-7 Seed Blend Registrations Causing Lepidopteran Resi stance to Cry1F, Cry2Ab2, and Cry1A.105

Based on a review of the Science Advisory Pa nel (SAP) report (SAP 2011) and revised modeling submitted by Monsanto/Dow, BPPD concludes th at a 5% seed blend for MON 89034 x TC1507 x MON 88017 x DAS-59122-7 corn will likely be le ss durable (perhaps significantly so) than a comparable (5%) block refuge for the product, as is currently required for the non –seed blend

MON 89034 x TC1507 x MON 88017 x DAS-59122- 7 products under EPA registration numbers 524-581 and 69467-7. BPPD notes, how ever, that a MON 89034 x TC1507 x MON

88017 x DAS-59122-7 5% seed blend should be more durable than a 20% block refuge for a single toxin Bt corn product (of which many are currently register ed) or a comparable (5%) seed blend for a two toxin pyramid.

Should Resistance Develop, What Risk Does it Pose to Man or the Environment, and What
Economic and Social Costs?

Should Cry1F, Cry2Ab2, or Cry1A .105 resistance develop, there may be an increase in

conventional chemical insecticide use for U. S. corn production. Although there are other lepidopteran controlling PIPs in the marketpl ace and under development, Cry1F, Cry2Ab2, orCry1A.105 resistance would not only impact MON 89034 x TC1507 x MON 88017 x DAS59122-7 seed blends and non- seed blend pr oducts, but also HERCULEX®, and MON89034 .

Increased use of conventional insecticides woul d increase impacts on the environment and man. There would also be indirect impacts in increas ed consumption for manufacture, transport, and application of chemical insecticides; increased waste streams arising from pesticide manufacture; and increased disposal of pesticide waste contai ners and residues from pesticide applications.

What are the Economic, Social, and Envi ronmental Benefits of MON 89034 x TC1507 x
MON 88017 x DAS-59122-7 Seed Blend Registrations?

MON 89034 x TC1507 x MON 88017 x DAS-59122-7 s eed blends have been determined by
EPA to be efficacious in their control of European corn borer, southwester corn bor er, corn earworm (and corn rootworm).

MON 89034 x TC1507 x MON 88017 x DAS-59122-7 seed blends should increase grower compliance with lepidopteran refuge requirement s by providing an effective way of simplifying the refuge deployment process for growers as th e lepidopteran refuge is deployed as a seed blend rather than a separa te block in the field.

MON 89034 x TC1507 x MON 88017 x DAS-59122-7 seed blends should also reduce the insecticide use in the lepidopteran refuge. Indirect benefits of decreased insecticide use include reduced energy consumption for manufacture, transport, and application of chemical insecticides; reduced waste streams arising from pesticide manufacture; reduced disposal of pesticide waste containers and residu es from pesticide applications.

MON 89034 x TC1507 x MON 88017 x DAS-59122-7 seed blends should benefit growers by simplifying the planting process.MON 89034 x TC1507 x MON 88017 x DAS-59122-7 ( SmartStax®) B.t. Corn Seed Blend Page 27 of 39 Biopesticides Registration Action Document

Registration Decision

We conclude that the MON 89034 x TC1507 x M ON 88017 x DAS-59122-7 seed blends meet the criteria for registration unde r FIFRA Section 3(c)(7)(A). Our assessment supports the determination that these products are not likel y to contribute towards the development of resistance to Cry1F, Cry2Ab2, or Cry1A.105 duri ng period of the time-limited registration in effect for the 2011 growing season. Our assessment of the likely impacts concerning ease of use, increased grower compliance, efficacy, and reduced insecticide us e coupled with our

determination that the MON 89034 x TC1507 x M ON 88017 x DAS-59122-7 seed blends are not likely to increase the risk of resistance to Cry1F, Cry2A b2, or Cry1A.105 developing during the 2011growing season support the conclusion that the criteria under FIFRA Section 3(c)(7)(A) are met such that registration of the M ON 89034 x TC1507 x MON 88017 x DAS-59122-7 seed blends will not pose a risk of unreasonable adverse effects on the environment durin g this period.

On October 1, 2009, EPA announced a new policy to provide a more meani ngful opportunity for the public to participate on major registration decisi ons before they occur. According to this new policy, EPA intends to provide a public comment period prior to making a registration decision for, at minimum, the following types of applicati ons: new active ingredient s; first food use; first outdoor use; first residential use; and other actions for which the Agency anticipates that there will be significant publ ic interest.

Notwithstanding that the current actions on the MON 89034 x TC1507 x MON 88017 x DAS59122-7 seed blends qualify as "actions for whic h the Agency anticipates that there will be significant public interest," EPA believes that it is in the best interests of the public and the environment to issue the registrations for the MON 89034 x TC1507 x MON 88017 x DAS59122-7 seed blends without delay. The PRIA (Pesticide Registration Improvement Act) deadline date of April 12, 2011, is sufficiently late in the growing season that a 30-day delay would lessen the likelihood that significant acre age of these products could be planted in 2011. Given the potential benefits attendant to the blended refuge concept for both lepidopteran and corn rootworm pests, EPA concl udes that it is in the best interests of the public and the environment to issue the registrations for the MON 89034 x TC1507 x MON 88017 x DAS59122-7 seed blends without delay for 2011 growi ng season. The registration is only effective for the current growing season. Therefore, c onsistent with the Agency’s policy for making certain registration actions more transparent, EPA is issuing these time-limited registrations with an initial period to expire October 31, 2011, and, c oncurrent with their is suance, providing a 30- day public comment period on the time-limited regist rations. EPA is regist ering this product as a time-limited registration, with the understanding that public comments c ould bring to light new

information or concerns that co uld inform EPA’s initial decisi on. Any subsequent action taken on these registrations will be informed by any information received during the public comment period. At present, the Agency anticipates re newing the expiration date to October 31, 2013.

IV. TERMS AND CONDITIONS OF THE REGISTRATION(S)

1) The subject registration will automatic ally expire at midnight October 31, 2011.

2) The subject registration will be limited to MON 89034 x TC1507 x MON 88017 x DAS59122-7 seed blend in field corn.

3) Submit or cite all data required to support MON 89034 x TC1507 x MON 88017 x DAS-MON 89034 x TC1507 x MON 88017 x DAS-59122-7 ( SmartStax®) B.t. Corn Seed Blend Page 28 of 39 Biopesticides Registration Action Document

59122-7 plant-incorporated protect ant products within the timefr ames required by the terms and conditions of EPA Registration Number s 68467-7 (Dow AgroSciences) and 524-581 (Monsanto).

4) Provided the registration expiration date is extended, submit an interim report on the following data within one year and a final report within two years.

 Revised modeling incorporating the structur al elements recommended by the SAP (i.e., explicit larval movement, switch from a fre quency-based model to one including densitydependent larval mortality, epistatic mechanis ms for resistance in target pests) with separate analyses for SWCB and ECB. N on-uniform oviposition should be modeled for both ECB and SWCB, especially (but not only) for the second generation of adults which will more likely lay eggs on Bt rather th an on damaged (or crowded out) non-Bt refuge plants in seed blends.

 Biological research on adult movement (relat ed to mating and movement from refuges), larval movement, larval feeding (i.e., sele ctive feeding within co rn ears or on pollen), survival of heterozygote genotypes on MON 89034 x TC1507 x MON 88017 x DAS59122-7 (markers may need to be determined for heterozygotes), and the potential for epistatic mechanisms of resistance (particularly with older instars).

5) Do the following Insect Resistance Mana gement Program for MON 89034 x TC1507 x MON

88017 x DAS-59122-7 seed blend corn.

a) Refuge Requirements for MON 89034 x TC1507 x MON 88017 x DAS-59122-7

The following information must be included on the product bag or bag-tag as sold per respective region:

Bag or Bag-Tag for the Corn-Growing Region There are no requirements for a separate stru ctured refuge for MON 89034 x TC1507 x MON 88017 x DAS-59122-7 seed blend corn when planted in th e U.S. corn-growing region. The refuge seed of

MON 89034 x TC1507 x MON 88017 x DAS-59122-7 seed blend corn is contained in the bag resulting in a refuge configura tion that is interspersed within the field. SEE THE IRM/GROWER GUIDE FOR DETAILED IRM REQU IREMENTS, including the areas making up the corn-growing region.

Bag or Bag-Tag for th e Cotton-Growing Region Growers in the cotton-growing region of the U.S. who plant MON 89034 x TC1507 x MON 88017 x DAS-59122-7 seed blend corn are required to plant an additional 20% structured refuge (i.e. 20 acres

of non- B.t. corn for every 80 acres of MON 8903 4 x TC1507 x MON 88017 x DAS-59122-7 seed blend corn planted). The 20% refuge must be planted with corn hybrids that do not contain B.t. technologies for the control of corn rootworms or corn borers. The refuge and the MON 89034 x

TC1507 x MON 88017 x DAS-59122-7 seed blend corn sh ould be sown on the same day, or with the shortest window possible between planting dates to ensure that corn root development is similar among varieties. The structured refuge may be pl anted as an in-field or adjacent (e.g., across the road) refuge, or as a separate block that is within 1⁄2 mile of th e MON 89034 x TC1507 x MON

88017 x DAS-59122-7 seed blend corn field. S EE THE IRM/GROWER GUIDE FOR DETAILEDMON 89034 x TC1507 x MON 88017 x DAS-59122-7 ( SmartStax®) B.t. Corn Seed Blend Page 29 of 39 Biopesticides Registration Action Document

IRM REQUIREMENTS, including the area s making up the cotton-growing region.

The cotton-growing region requiring the additional 20% refuge consists of the following states: Alabama, Arkansas, Georgia, Florida, Louisian a, North Carolina, Missi ssippi, South Carolina, Oklahoma (only the counties of Beckham, Caddo, Comanche, Custer, Greer, Harmon, Jackson, Kay, Kiowa, Tillman, and Washita), Te nnessee (only the counties of Carroll, Chester, Crockett, Dyer, Fayette, Franklin, Gibson, Hardeman, Hardi n, Haywood, Lake, Lauderdale, Lincoln, Madison, Obion, Rutherford, Shelby, and Tipton), Texas (ex cept the counties of Ca rson, Dallam, Hansford, Hartley, Hutchinson, Lipscomb, Moore, Ochiltree, Roberts, and Sherman), Virginia (only the counties of Dinwiddie, Franklin City, Greensv ille, Isle of Wight, Northampton, Southampton, Suffolk City, Surrey, and Sussex) and Missouri (only the counties of Dunklin, New Madrid, Pemiscot, Scott, and Stoddard).

The following information regarding refuge placem ent for commercial production must be included

in the IRM/Grower Guide:

This product includes refuge that is interspersed within the field by planti ng a licensed seed-mixture containing MON 89034 × TC1507 × MON 88017 × DAS-59122-7 and a minimum of 5% non-PIP seed. The seed mix refuge option for MON 89034 × TC1507 × MON 88017 × DAS-59122-7 seed blend corn satisfies the refuge requirements in all regions other than in co tton growing regions where corn earworm is a significant pest as defined below.

The seed producer must ensure a minimum of 5% non-PIP refuge seed is included with the

MON 89034 × TC1507 × MON 88017 × DAS-59122-7 in each lot of seed corn.

The interspersed refuge can only be used by plan ting seed corn specifically generated by qualified seed producers/conditioners licensed by the registrant. The refuge seed in the seed mixture may not be treated with seed-applied insecticides for co rn rootworm (CRW) control unless the MON 89034 ×

TC1507 × MON 88017 × DAS-59122-7 seed in the seed mixture receives the same treatment.

Insecticidal treatments labeled fo r adult CRW control are discouraged during the time of adult CRW

emergence.

Additional refuge requirements in cotton-growin g regions where corn earworm is a significant
pest

In cotton-growing regions where corn earworm is a significant pest, as defined below, MON 89034

× TC1507 × MON 88017 × DAS-59122-7 seed blend corn requires the planti ng of an additional 20% structured refuge (i.e. 20 acres of non-Bt corn for every 80 acres of MON 89034 × TC1507 × MON 88017 × DAS-59122-7 seed blend corn planted).

The 20% refuge must be planted w ith corn hybrids that do not contain Bt technologies for the control

of corn rootworms or corn borers. Th e refuge and the MON 89034 × TC1507 × MON 88017 ×

DAS-59122-7 seed blend corn should be sown on the same day, or with the shortest window possible between planting dates to ensure that corn root development is simila r among varieties. The structured refuge may be planted as an in-field or ad jacent (e.g., across the ro ad) refuge, or as a separate block that is within 1⁄2 mile of the MON 89034 × TC1507 × MON 88017 × DAS-59122-7 seed blend corn field. In-field refuge options in clude blocks, perimeter strips (i.e., strips around the field), or in-field strips. If perimeter or in-field st rips are implemented, the st rips must be at least 4 consecutive rows wide. The refuge can be prot ected from lepidopteran damage by use of non-BtMON 89034 x TC1507 x MON 88017 x DAS-59122-7 ( SmartStax®) B.t. Corn Seed Blend Page 30 of 39 Biopesticides Registration Action Document

insecticides if the popul ation of one or more target le pidopteran pests of MON 89034 × TC1507 ×

MON 88017 × DAS-59122-7 seed blend corn in the refuge exceeds economic thresholds. In addition, the refuge can be protected from CRW da mage by an appropriate seed treatment or soil insecticide; however, insecticides labeled for a dult CRW control must be avoided in the refuge during the period of CRW adult emergence. Economi c thresholds will be determined using methods recommended by local or regional professionals (e.g., Extension Service agents, crop consultants).

The cotton-growing region requiring the additional 20% refuge consists of the following states: Alabama, Arkansas, Georgia, Florida, Louisian a, North Carolina, Missi ssippi, South Carolina, Oklahoma (only the counties of Beckham, Caddo, Comanche, Custer, Greer, Harmon, Jackson, Kay, Kiowa, Tillman, and Washita), Te nnessee (only the counties of Carroll, Chester, Crockett, Dyer, Fayette, Franklin, Gibson, Hardeman, Hardi n, Haywood, Lake, Lauderdale, Lincoln, Madison, Obion, Rutherford, Shelby, and Tipton), Texas (ex cept the counties of Ca rson, Dallam, Hansford, Hartley, Hutchinson, Lipscomb, Moore, Ochiltree, Roberts, and Sherman), Virginia (only the counties of Dinwiddie, Franklin City, Greensv ille, Isle of Wight, Northampton, Southampton, Suffolk City, Surrey, and Sussex) and Missouri (only the counties of Dunklin, New Madrid, Pemiscot, Scott, and Stoddard).

b) Grower Agreement for MON 89034 x TC 1507 x MON 88017 x DAS-59122-7 Seed Blend

Corn

1) Persons purchasing MON 89034 x TC1507 x MON 88017 x DAS-59122-7 seed blend corn must sign a grower agreement. The term “growe r agreement” refers to any grower purchase contract, license agreement, or similar legal document.

2) The grower agreement and/or specific st ewardship documents referenced in the grower agreement must clearly set forth the terms of the current IRM program. By signing the grower agreement, a grower must be contractually bound to comply with the requirements of the IRM

program.

3) Monsanto and Dow must implement a system (equivalent to what is already approved for previously registered Monsanto and Dow Bt corn products), which is reasonably likely to assure that persons purchasing MON 89034 x TC1507 x MON 88017 x DAS-59122-7 seed blend corn will affirm annually that they are contractuall y bound to comply with the requirements of the IRM program. A description of the system must be submitted to EPA within 90 days from the date of registration.

4) Monsanto and Dow must use a grower agr eement and must submit to EPA, within 90 days from the date of registration, a copy of that agreement and any specific stewardship documents referenced in the grower agreement. If Mons anto and Dow wish to change any part of the grower agreement or any specific stewardship do cuments referenced in the grower agreement

that would affect either the content of the IRM program or the lega l enforceability of the provisions of the agreement relating to the IRM program, 30 days prior to implementing a proposed change, Monsanto and Dow must submit to EPA the text of such ch anges to ensure that

it is consistent with the terms a nd conditions of this registration.

5) Monsanto and Dow must implement a system (equivalent to what is already approved for previously registered Monsanto and Dow Bt corn products), which is reasonably likely to assure that persons purchasing MON 89034 x TC1507 x MON 88017 x DAS-59122-7 seed blend cornMON 89034 x TC1507 x MON 88017 x DAS-59122-7 ( SmartStax®) B.t. Corn Seed Blend Page 31 of 39 Biopesticides Registration Action Document

sign grower agreement(s). A description of the system must be submitted to EPA within 90 days from the date of registration.

6) Monsanto and Dow shall maintain records of all MON 89034 x TC1507x MON 88017 x

DAS-59122-7 seed blend corn grower agreements for a period of three years from December 31st of the year in which the agreement was signed.

7) Beginning on January 31, 2012 and annually th ereafter, Monsanto and Dow shall provideEPA with a report on the number of units of MON 89034 x TC1507 x MON 88017 x DAS59122-7 seed blend corn seed shipped and not returned, a nd the number of such units that were sold to persons who have signed grower agreemen ts. The report shall cover the time frame of a twelve-month period. Note: The first report shall contain the specified information from the time frame starting with the date of registrati on and extending through th e 2010 growing season.

8) Monsanto and Dow must allow a review of the grower agreements and grower agreement records by EPA or by a State pesticide regulatory agency if the State agency can demonstrate that confidential business information, includ ing names, personal information, and grower license number, will be protected.

c) IRM Education and IRM Compliance Mo nitoring Program for MON 89034 x TC1507 x

MON 88017 x DAS-59122-7 Seed Blend Corn

1) Monsanto and Dow must design and impl ement a comprehensive, ongoing IRM education program designed to convey to MON 89034 x TC1507 x MON 88017 x DAS-59122-7 seed

blend corn users the importance of complying with the IRM program. The education program shall involve the use of multiple media, e.g. f ace-to-face meetings, mailing written materials, EPA-reviewed language on IRM requirements on the bag or bag tag, and electronic communications such as by internet, radio, or te levision commercials. Copies of the materials will be provided to EPA for their records. Th e program shall involve at least one written communication annually to each MON 89034 x TC1507 x MON 88017 x DAS-59122-7 seed

blend corn user separate from the grower techni cal guide. The communication shall inform the user of the current IRM requirements. Mons anto and Dow shall coordinate its education program with the educational efforts of other re gistrants and other orga nizations, such as the

National Corn Growers Associati on and state extension programs.

2) Annually, Monsanto/Dow shall revise, and expand as necessary, its education program to

take into account the informa tion collected through the comp liance survey and from other sources. The changes shall address aspects of gr ower compliance that are not sufficiently high.

3) Beginning January 31, 2012, Monsanto and Do w must provide a repor t to EPA summarizing

the activities it carried out under its education program for the pr ior year. Annually thereafter, Monsanto and Dow must provide EPA any substan tive changes to its grower education activities as part of the overall IRM compliance assurance program report. Monsanto/Dow must either submit a separate report or contribute to the re port from the industry wo rking group, Agricultural Biotechnology Stewardship T echnical Committee (ABSTC).

4) Given that MON 89034 x TC1507 x MON 88017 x DAS-59122-7 seed blend will likely have different refuge strategies for lepidoptera and CRW than other regist ered Bt corn products, Monsanto/Dow must submit a revised compliance assurance program (CAP ) within 90 days ofMON 89034 x TC1507 x MON 88017 x DAS-59122-7 ( SmartStax®) B.t. Corn Seed Blend Page 32 of 39 Biopesticides Registration Action Document

the date of registration. This revised CA P must be found acceptable by BPPD by April 1, 2012. This strategy should be specific for M ON 89034 x TC1507 x MON 88017 x DAS-59122-7 seed

blend corn and the new refuge requirements. Availa bility of non-Bt corn refuge seeds in desirable varieties must be addressed. Complian ce is an area of ongoing concern -- recent data have shown that refuge compliance for Bt corn has fallen in recent years.

d) Insect Resistance Monitoring and Remedial Action Plans for MON 89034 x TC1507 x

MON 88017 x DAS-59122-7 Corn

Existing programs for resistance monitori ng and remedial action for MON 89034 x TC1507 x

MON 88017 x DAS-59122-7 are applicable and required for MON 89034 x TC1507 x MON

88017 x DAS-59122-7 seed blend corn. Monsanto/Dow must submit a revised definition of unexpected damage in MON 89034 x TC1507 x MON 88017 x DAS-59122-7 seed blend corn for resistance monitoring must also submit a remedi al action plan within 90 days of the date of registration that must be found acceptable to BPPD by April 1, 2012.

A report on results of resistance m onitoring and investigations of da mage reports must be submitted to the Agency annually by August 31 st each year, beginning in 2012, for the duration of the conditional registration.

e) Annual Reporting Requirements for MON 89034 x TC1507 x MON 88017 x DAS-59122-

7 Seed Blend Corn

1) Annual Sales: reported and summed by st ate (county level data available by request) January 31st each year, beginning in 2012;

2) Grower Agreements: number of units of MON 89034 x TC1507 x MON 88017 x DAS59122-7 seed blend corn seed shipped or sold and not return ed, and the number of such units that were soldto persons who have signed grower agreements, January 31st each year, beginning in 2011;

3) Grower Education: substantive change s to education program completed previous year, January 31st each year, beginning in 2012;

4) Compliance Assurance Program: compliance a ssurance program activitie s and results for the prior year and plans for the compliance a ssurance program for the current year, January 31st each year, beginning in 2012;

5) Compliance Survey Results: results of a nnual surveys for the prior year and survey plans for the current year; full report January 31st each year, beginning in 2012;

6) Insect Resistance Monitoring Results: resu lts of monitoring and investigations of damage reports, August 31st each year, beginning in 2012.

f ) Refuge Assurance Program for MON 89034 x TC1507 x MON 88017 x DAS-59122-7

Seed Blend Corn

Monsanto, Monsanto’s seed company licensees, a nd Dow must continue to implement a blended seed refuge assurance program designed to ensure MON 89034 x TC1507 x MON 88017 xMON 89034 x TC1507 x MON 88017 x DAS-59122-7 ( SmartStax®) B.t. Corn Seed Blend Page 33 of 39 Biopesticides Registration Action Document

DAS-59122-7 seed blend corn product s are formulated with the appropr iate rate of refuge seeds.

The program must include th e following four elements:

1. Trait purity check on seed lots prior to blending (Monsanto and Monsanto Licensees) Trait purity check on component seed lots prior to release of the blend for sale (Dow)

2. Standard Operating Procedures for the blending process;

3. Calibration of blending equipment; and

4. Records and data retention records for seed blend products.

 Calibration records – Monsanto, Monsanto’s Licensees, and Dow will retain documentation for three (3) years on th e equipment calibration including the procedure, when it was c onducted and the results.

 Blend proportion records (w eight and kernel based) – Monsanto, Monsanto Licensees, and Dow will retain documentation for three (3) years on the kernel per pound data of the components, the calcu lations to determine the proportions based on weight and the actual weights that are blended together to make up an

MON 89034 x TC1507 x MON 88017 x DAS-5 9122-7 seed blend corn product by seed lot.

All records must be maintained at the Monsanto , Monsanto Licensees, and Dow blending facility and must be available for the EPA review upon request.

Within one year of the date of registration Monsanto will collect documentation from qualification test runs that va lidate blend percentages from their licensees/conditioners that produce MON 89034 x TC1507 x MON 88017 x DAS-59122-7 seed blend corn and submit this data to the Agency. Any licensee/conditioner that is unable to verify their blend accuracy will provide evidence demonstrating application and participation in the USDA USA Accredited Seed Conditioning Program (ASCP) as outlined in ARC 1005D Appendix, http://www.ams.usda.gov/AMSv1.0/ams.fetchTem plateData.do?template =TemplateN&navID= AccreditedSeedPrograms&rightNav1=Accredit edSeedPrograms&topNav=&leftNav=&page=AS LProgram&resultType=&acct=audrevcom

.

Should Monsanto, Monsanto’s Licencees, or Dow be notified by the USDA/AMS or State Seed Control Officials that your seed blend products have been found to have a lower percentage of the refuge component than is represented on the la bel, they must notify EPA within 30 days. This would constitute information repor table under FIFRA section 6(a)(2).

Dow must document what the actual ta rget weight and percentage will be for a 5% MON 89034

x TC1507 x MON 88017 x DAS-59122-7 seed blend within 1 year.

6) Monsanto must submit revised product labelin g that indicates one seed tag for use in both cotton and non-cotton growing areas within six months.

7) Monsanto must report on how many of their licensees (by number and percentage) color seed January 31st each year, beginning in 2012.MON 89034 x TC1507 x MON 88017 x DAS-59122-7 ( SmartStax®) B.t. Corn Seed Blend Page 34 of 39 Biopesticides Registration Action Document

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