UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

### WASHINGTON, D.C. 20460

August 16, 2011 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION



## ---------------'pc Code:

-128i12

---- MEMORANDUM 

### DP Barcode: 390532 SUBJECT: Response to Public Comments on the Registration Review Preliminary Problem Formulation for Environmental Fate, Ecological Risk, Endangered Species, and Drinking Water Exposure Assessments for Carfentrazone-ethyl FROM: Greg Orrick, Environmental Scientist

## ~ 0

## ~**~ ~** - 16- (( Donna R. Judkins, Ph.D., Biologist

### ttf/~/~. Environmental Risk Branch 2 Environmental Fate and Effects Division (7507P) THROUGH: Brian Anderson, Chief 

# (?r /**~** 

# / 

# i1 j

- R. David Jones, Ph.D., Senior

## Agr**no:n ~1-~**  

# tl/o /2..011 fVnean Holmes, DVM, MPH, Risk Assessment Team Leader 

### fl r 

# I /J / Environmental Risk Branch 2 

## PI, h.

### (~ Environmental Fate and Effects Division (7507P) TO: Jose Gayoso, Chemical Review Manager Mary Manibusan, Chief Risk Management and Implementation Branch 2 Pesticide Re-Evaluation Division (7508P) Attached please find the Environmental Fate and Effects Division (EFED) response to public comments onthe division's preliminary problem formulation for the registration review of carfentrazone-ethyl (docket ID: EPA-HQ-OPP-201 0-0815-0002). The FMC Corporation Agricultural Products Group (FMC) provided comments primarily based onthe Agency's Carfentrazone-ethyl Registration Review Summary, dated March 30, 2011. In general, FMC cites information from studies already submitted along with a rationale explaining howthese data might negate the need for some ofthe requested studies from the Registration ReviewProblem Formulation Data Call-In. Each ofFMC'srequests was considered and responses follow below. As indicated in the summary table below, EFED recommends waiving only the requested whole sedimenttoxicitytests (OCSPP guidelines 850.1735 and 850.1740).

### Table 1. 

### Summary ofRequested EnvironmentalFate andEffects Data for Carfentrazonee

th I d It 

### A 'd Ddt

lyJ 

### an s CI**e~ra** 

### a e. Requested Data Test

by Guideline Study Type Substance FMC Response EFED Recommendation

Number 835.2240 Aqueous Photolysis Carfentrazone Waiver requested Data remain needed acid 835.4400 Anaerobic Aquatic Carfentrazone- (no response) Data remain needed Metabolism ethyl Independent Laboratorj- Paient plus 835.6100 (ILV) Validation analyzed Waiver requested Data remain needed 835.6200 (SS) Frozen Storage Stability degradates Waiver requested Data remain needed 850.1025 OysterAcute Toxicity (no response) Data remain needed 850.1075 Fish Acute Toxicity (no response) Data remain needed 850.1300 Daphnid Chronic Toxicity Waiver requested Data remain needed 850.1350 Mysid Chronic Toxicity Waiver requested Data remain needed 850.1400 Fish Early Life Stage Carfentrazone Waiver requested Data remain needed (ELS) Toxicity acid Data requirement may be satisfied by submission ofan 850

. 1500 Fish Life-Cycle Toxicity Waiver requested ELS study. However, results from an ELS study may trigger a life-cycle study. 850.1735 Acute Sediment Waiver requested Waiver recommended (Hyalella) 850.1735 Acute Sediment Carfentrazone- Waiver requested Waiver recommended (Chironomus)

850.1740 Acute Sediment Marine ethyl Waiver requested Waiver recommended 850.2100 Avian Acute Oral (no response) Data remain needed Toxicity 850.4100 Tier II Plant Toxicity- (no response) Data remain needed Seedling Emergence Typical End850.4150 Tier II Plant Toxicity

- Use Product (no response) Data remain needed Vegetative Vigor The Physician's Committee for Responsible Medicine (PCRM) also provided comments on May 31, 2011. These comments were aimed atreducing animal testing. EFED considered these comments and responded below.

2

## EFED Response to Public Comments on Carfentrazone-ethyl Problem Formulation for Registration Review Comments from FMC Corporation

1. 

### PreliminaryWorkPlan Comment 1: Anticipated RiskAssessmentDataNeeds (p. 4): FMC is a member ofthe FIFRA Endangered Species Task Force and will work withthe Agency to conduct needed assessments.


### EFED Response: Noted.


### Comment2: Ecological Risk (p. 5): FMC Response to EPA list ofdataneeds for Environmental fate and Ecological toxicity.



### a. An IL V to supportthe 1994 soil dissipation study (RAN-0270, MRID 44165039 and RAN-0270M, MRID 44165040): The 1995 soil dissipation study (MRID 44419018) was slightly modified (DCM partitionreplaced with C18 SPE) to include a 5th soil metabolite (3-0H-F8426-BAc), identified later. Acceptable method recoveries could only be obtained with C18 SPE, but not with DCM partition. Subsequently, an ILV (MRID 44165043) was conducted in support of this modified method. Each individual soil dissipation study had already been approved valid by the many acceptable concurrent method recoveries generated during the analytical phase ofeach study. Another ILV to support the 1994 soil dissipation study is not necessary and has no additional value, because the original method would not generate acceptable methodrecoveries for the 3-0HF8426-BAc metabolite.


### EFED Response: MRID 44419018 was notthe analytical method used inthe terrestrial field dissipation (TFD) study submitted under MRID 44165039. The Agency is requesting anindependent laboratory validation (ILV) ofMRID 44165040, which is the analytical method used in MRID 44165039. This method included a methylene chloride partition, did not include solid phase extraction, and did not analyze for 3-0H-F8426-BAc. Ifan ILV is not submittedto support MRID 44165040 or ifa submitted ILV indicates that the analytical method in MRID 44165040 is not quantitative, then the study classification for the TFD study it supports may be downgraded and additional terrestrial field dissipation data maybe requested.


### b. Frozen storage stability datato support aquatic field dissipation studies: FMC notes that the required storage stability data ofwater, soil and sediment in
1support ofthe two aquatic field dissipation studies [PC-028 (MRID 44419019) and P-3311 (MRID 44654701)] had already been reported in the following three reports:
• Soil storage stability data in RAN-0285 (MRID 44165049)
• Water storage stability data in PC-0281 (MRID 44419019)
• Sediment storage stability data in P-3311 (MRID 44654701)
EFED Response: Frozen storage stability data are needed to support the aquatic field dissipation study, MRID 44654701, in which these data were notprovided (MRIDs 44419019 and 46253901 have additional deficiencies that are not upgradeable). The following are the available storage stability data on carfentrazone-ethyl and its transformation products:

• MRID 44165049: This is a frozen storage stability study oftransformation products ofcarfentrazone-ethyl stored for 15 months in soil. These data may notbe relevant to the storage stability ofthese compounds in the sediment sampled in aquatic field dissipation studies. Carfentrazone-ethyl was not studied.

• MRID 44419019: This is an unacceptable aquatic field dissipation study. A storage stability study was not conducted. However, field spikes were preparedin water and stored frozen with water samples for 105-110 days. The field spikes indicated that carfentrazone-ethyl was not stable in water in storage
. Recoveries were 8±2% for Site 1 and 21±2%for Site 2

. Field spikes were notprepared in soil or sediment. The study authors indicated that carfentrazone-ethyl has notbeen includedin frozen soil stability studies because it is knownto degrade rapidly in soil, even infrozen conditions (p. 

### 13).

• MRID 44654701: This is an upgradeable aquatic field dissipation studywith no storage stability study. However, sedimentthat was spiked and stored frozen indicated that carfentrazone-ethyl degraded 67% over 9 months. Itwas not clear whether the sediment was spiked inthe field and handled and processed similarto study samples or spiked inthe laboratory. Field spikes were notprepared in soil or water. Study samples were storedfrozen for 5 months (soil), 6 months (sediment), and 107 days (water).

• MRID 46253901: This is a supplemental aquatic field dissipation studywith no storage stability study. Field spikes were prepared in water and sediment. However, they were only stored frozen for 3-6 days; whereas, study samples were stored for up to 1 month. Additionally, recoveries in water after 3-6 days were poor. The study authors followed up with laboratory spikes and additional field spikes from another site. However, the following spikes were irrelevantbecausethe original field spike results were not shownto be invalid.

2These data indicate that the transformation products ofcarfentrazone-ethyl are relatively stable in frozen storage for 15 months in soil, 110 days in water, and 9 months in sediment. However, these data indicate that carfentrazone-ethyl degrades in frozen storage in water (79-92% degradation in 110 days), in sediment (67% degradation in 9 months), and in soil (supporting data were not provided).
Frozen storage stability data are needed for carfentrazone-ethyl in soil, water, and sediment at multiple intervals withinthe maximum length ofsample storage (6 months in the case ofsediment) in the aquatic field dissipation study, MRID 44654701. The results canbe used to correct measured values ofcarfentrazoneethyl in soil, water, and sediment in MRID 44654701. Alternatively, the aquatic field dissipation study described in MRID 44654701 could be repeated following OCSPP guideline 835.6200. Field studies conducted on carfentrazone-ethyl should include steps to stabilize carfentrazone-ethyl during frozen storage. When carfentrazone-ethyl is not stabilized during frozen storage, sample concentrations reported in the study should be corrected for recoveries from frozen storage.
Lack ofstorage stability data in the media sampled in MRID 44654701 results in uncertainty in the reported concentrations and degradation kinetics of carfentrazone-ethyl. Ifdata are not submitted to upgrade the study to an acceptable classification, then additional aquatic field dissipation datamaybe requested.



### c. Photodegradation in water (carfentrazone acid) andEcological toxicity: Due to rapid degradation and nearly complete conversion ofcarfentrazone-ethyl to carfentrazone chloropropionic acid in aqueous environments, FMC believes the some studies are not needed. Existing data onparent should be sufficient. This applies to the following studies and FMC asks that they be waived:

• Aqueous photodegradation using carfentrazone-ethyl,
• Aquatic invertebrate life cycle studies for bothfresh and saltwater, and
• Fish early life-stage and fish full life cycle studies.
FMC asserts that this information has already been generated in studies of carfentrazone-ethyl (due to their duration) exposure orpresence to carfentrazone acid has alreadybeen evaluated. No additional information is expected to be obtained by conducting these studies withthe acid. Also, higher tier data in an aquatic monitoring pond study (MRID 46253901) conducted in Floridawas previously provided to EPA and includes the environmental fate and potential exposure oforganisms to carfentrazone-ethyl and carfentrazone chloropropionic acid.
3A waiver request for the whole sediment ecotox studies is made based onthe fact that neither carfentrazone-ethyl nor its metabolites were observedto accumulate in sediments basedupon chemical properties and field monitoring. FCM suggests that the risk to sediment-dwelling organisms is low.
EFED Response: Photodegradation Study: Carfentrazone acid was not detected in the submitted, acceptable aqueous photolysis study conducted with carfentrazone-ethyl (MRID 44934201). Because carfentrazone-ethyl undergoes nearly complete conversionto carfentrazone acid in aqueous environments, the environmental fate ofcarfentrazone acid in water needs to be understood. Therefore, the Agency is requesting aqueous photolysis data oncarfentrazone acid. Aquatic Invertebrate and Fish Chronic Studies: FMC contends that information onparent should be sufficient since the breakdownto acid would have occurred in a chronic study withparent. The following chronic aquatic studies withthe parent compound have been submitted to date:

MRID Reference 44419006 Knacker, T.; Schallnas, H.; Weidenauer, M. (1992) A Study on the Chronic Toxicity ofF8426 Technical to Daphnia magna: Lab ProjectNumber: A96- 4547: 91 I86-FMC: A-17-95-35. Unpublished study preparedby ECT Oekotoxikologie GmbH and Battelle. 148 p. 44424201 Liu, H.; Kranzfelder, J.; Groetsch, K. (1997) Carfentrazone-ethyl (F8426) Technical: Toxicityto Embryos and Larvae ofthe Rainbow Trout, Oncorhynchus mykiss, UnderFlow-Through Test Conditions: Lab Project Number: A96-4528: J9609004A: FMC/F8426/RTELS. Unpublished study prepared byToxikon Environmental Sciences. 121 p. 44963201 Ellenberg, W.; Rielly, P.; Glover, S. (1999) Carfentrazone-ethyl (F8426) Technical: Toxicityto Embryos and Larvae ofthe Rainbow Trout, Oncorhynchus mykiss, UnderFlow-Through Conditions: Lab Project Number: 99J0001: A99-4961: FMCIF8426IRTELS. Unpublished study prepared byToxikon Corporation. 148 p. 46037001 Ross, T.; Kendall, T.; Krueger, H. (2003) F8426: An Early Life-Stage Toxicity Test with the Rainbow Trout (Oncorhynchus**~ykiss)** Under Ultraviolet Light Conditions: Final Report. ProjectNumber: I04A1107, A2001l5397. Unpublished studypreparedby Wildlife International, Ltd. 72 p. Since carfentrazone-ethyl is applied directly to water, chronic data are required for aquatic invertebrates and fish. The rationale for asking for the acid, ratherthanthe parent, is the rapid breakdown. For aquatic

4invertebrates, the daphnid study (MRID 44419006) was classified invalid and may not be used for risk assessment. The test concentrations were too variable to use for assigning endpoints and the controls too variable. The Agency needs acceptable chronic toxicity datausing aquatic invertebrates to assess risk ofcarfentrazone acid to these taxa. Therefore, the freshwater and saltwater chronic invertebrate studies (OCSPP guidelines 850.1300 and 850.1350) oncarfentrazone acid remain requested.
For fish, MRID 44424201 is an acceptabkTainbowh'out

-early-l ife= stage (ELS) flow-through study. Based onmeanmeasured concentrations of parent, theNOAEC and LOAEC were 118 and 242**~g** a.i.lL, respectively. This was a 102-d flow-through study in which test solution had approximately 6 volume exchanges every 24 hours. The pH ranged from 6.3 to 7.2 inthe study. Carfentrazone-ethyl has an aerobic aquatic metabolism half-life of2.3-2.7 hours atpH values somewhere inthe range of5.1-8.1 (MRID 44419016). Ifcarfentrazone-ethyl degraded inthe study with a half-life ofapproximately 2.5 hours and had a retentiontime of approximately 4 hours, thenthe test organisms would likely have been exposed to a substantial amount oftransformation products as well as parent compound. This study does not satisfactorily address the chronic toxicity ofcarfentrazone-ethyl acid.
Two ofthe submitted fish ELS studies (MRIDs 44963201 and 46037001) are rainbow light-dependent peroxidizing herbicide (LDPH) studies conducted underenhanced lighting conditions to estimate the enhanced toxicity ofcarfentrazone-ethyl under strong light. These studies were modified to specifically capture this fraction ofthe total toxicity of carfentrazone-ethyl. The LDPH NOAECs ranged from 16 to 22**~g** a.i.lL in these studies, respectively. These studies were rated supplemental due to problems with dissolved oxygen and inadequate lighting. Althoughthe toxicity appears to be onthe orderoffive to ten times greaterthan under normal lighting, no endpoints were confirmed for use inrisk assessment. Also, these studies are based onparent light-enhanced toxicity and the concentration ofcarfentrazone-ethyl acid was not determined. LDPH toxicity will be evaluated inthe risk assessment, but chronic toxicity data on the major degradate (carfentrazone-ethyl acid) is needed, as well. Further, since the estimated environmental concentration (EEC) (12**~g** a.i.lL from use as an aquatic herbicide) is >0.1 ofthe ELS NOAEC (rainbowtrout parentELS NOAEC = 118**~g** a.i.fL, MRID 44424201, and LDPHtoxicity NOAEC = <16.4**~g** a.i.lL, 43189228), a life-cycle fish test is required per40 CFRPart 158.630. Therefore, the freshwater and saltwater chronic fish studies (OCSPP guidelines 850.1500 and 850.1400) oncarfentrazone acid remainrequested

. Itispossible that an early life stage study will suffice in lieu ofa full life cycle study onthe acid



### 5degradate. However, ifthe early life stage NOAEC for the acid degradate is >0.1 ofthe EEC, then a life-cycle study may be needed. Sediment tests: Thepartitioning ofcarfentrazone-ethyl between soil and water is uncertain because acceptable batch equilibrium datahave not been submitted. However, aquatic laboratory (MRID 44419016) and field studies (MRlDs 44654701, 46253901) indicate that less than 10% of applied carfentrazone-ethyl will partition to sediment. Dueto the apparent

------------- lacK: ofpartitioning of carfentrazone-etfiyl to secitment -;-

tfie requested

------- whole sediment data (OCSPP guidelines 850.1735 and 850.1740) are recommended to bewaived.


## Comments from Physicians Committee for Responsible Medicine
Comment 1: The Summary Document indicates thatthe Agency may request testing for avian acute oral toxicity. We strongly support the use ofthe newly revised OECD test guideline (TG 223) for the acute avian oral toxicity test, which has been adopted by the OECD. The new approach could reduce the total number ofanimals by up to approximately 90%. The approachprovides three testing options: (1) limit dose test, (2) LDso-slope test, and (3) LDso-only test. The test method selected will depend on whether ornot a definitive median dose (LDso) and slope ofthe dose-response curve are both needed. l
The LDso-slope and LDso-only options are sequential testing procedures. Sequential testing procedures targetthe placement ofdoses and match the precision ofthe endpoint with the precisionrequired. These sequential procedures were designed to minimize the numbers ofbirds used. A computerprogram is also available to aid the placement of doses and estimate the LDso, slope and confidence limits.
In previous responses to comments, the Agency has statedthat it is reviewing the validation infonnationfrom OECD and will detennine soon whether it will accept this TG for non-passerines, and that it does not foresee accepting the TG for passerine species, because validation ofthe sequential study design was not conducted inpasserine species. We would like to encourage the Agency to revise this position, based on several considerations. First, OECD member countries

- including the US

- adoptedthe TG in 2010, nearly a year ago. Ithas undergone complete statistical and in vivo validation, and multiple draft revisions, for over fifteen years. Please advise whenthe Agency sees acceptance ofthis guideline for non-passerine species orprovide a detailed discussing of its efforts overthe pastyear and leading up to acceptance in what we hope will be the near future.

1 OECD

. (2010). Test Guideline 223 :Avian Acute Oral Toxicity Test Method

. OECD Guidelines for the Testing ofChemicals

. Website accessed on August 5, 2010 at http://lysander.sourceoecd

.orglvl=3006812/cl=16/nw=IImsv/ij/oecdjoumals/160731Ox/v 1 n2/ s33/ pI

. 6Furthermore, there are no scientific or biological reasons why the validation ofa modification ofthe study design ofa lethal-dose test should be species specific. This sequential design mirrors similarmodifications that have been made in lethal-dose mammaliantests, which were validated using only statistical simulations. Ifpasserines, as a species, have higher background mortalitythan other, more commonbird species used in the laboratory, the final LD50 result will be more conservative, not less. Companies in the US that register products for the European market consistently use this

--------!; 'F6, and 

### themajor e;:culoxicology

-eonlract-Research Organizations run this

-testincluding for passerines. Continuedresistance to this accepted guideline bythe US without clear scientific rationale creates confusion and duplication oftesting is likelyto result. Since for this new species requirementthe Agency requests registrants consult with it before running the test, we submit that this consultation could be an exploration of whether the registrant has experience withthe 223 and could consider accepting studies conducted according to this guideline on a case-by-case basis. This study design could become the acute toxicity test for passerines from the start. As it appears that nearly every material going through the registrationreviewprocess will be tested in passerine species, a significant number ofbirds stand to be saved. EFED Response: The OECD has adopted the TG223 guideline and has issued a validation report. Atthis time, the Agency is evaluating the results ofthe OECD validation report to determine ifthe TG223 effects endpoints and dose/response information adequately address the purposes ofthe avian acute oral datarequirement as described in 40 CFRPart 158 and 40 CFR Part 161. The current plan is to have this evaluation finalized by the fall of2011. Until the Agency's evaluation ofthat validation report is completed, the Agency does not expect to be able to routinely classify avian toxicity studies performed using the TG 223 protocol. The validation report should help informthe interpretation ofstudies performed under the TG223 guideline, and should clarify what the Agency might find to be generally necessary for aviantoxicity studies done under TG 223 to be acceptable to meet our datarequirements. Validation work conducted onTG 223 test guideline to date has been limited to studies with the upland game birds (e

.g., northernbobwhite quail). The OECD TG 223 guideline states "Captive bred species with low background mortality and a lowpropensity to regurgitate are preferred. Frequently used species which fit these requirements are the northern bobwhite quail, 

### Colinus virginianus and Japanese quail, 

### Coturnixjaponica (Galliform)." Because no work has been done to date to validate this guideline for passerine species, it is doubtful that the Agency would have confidence in studies done underthis guideline for fulfilling requirements for passerine acute toxicity data unless additional validation work withpasserines is done, butthe Agency recognizes that specific situations might warrant additional examination.



### 7