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 on the division's preliminary problem formulation for the registration review of 

carfentrazone-ethyl (docket ID: EPA-HQ-OPP-20 1 0-0815-0002). 

The FMC Corporation Agricultural Products Group (FMC) provided comments primarily based 

on the 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 

how these data might negate the need for some of the requested studies from the Registration 

Review Problem Formulation Data Call-In. Each of FMC's requests was considered and 

responses follow below. As indicated in the summary table below, EFED recommends waiving 

only the requested whole sediment toxicity tests (OCSPP guidelines 850.1735 and 850.1740). 
Table 1. Summary of Requested Environmental Fate and Effects Data for Carfentrazonee th lyJ I d an It s A CI 'd Ddt 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 Oyster Acute 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 of an 

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 A vian 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 at reducing animal testing. EFED considered these 

comments and responded below. 

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EFED Response to Public Comments on Carfentrazone-ethyl 

Problem Formulation for Registration Review 

Comments from FMC Corporation 

1. Preliminary Work Plan 

Comment 1: Anticipated Risk Assessment Data Needs (p. 4): FMC is a member of the 

FIFRA Endangered Species Task Force and will work with the Agency to conduct 

needed assessments. 

EFED Response: Noted. 

Comment 2: Ecological Risk (p. 5): FMC Response to EPA list of data needs for 

Environmental fate and Ecological toxicity. 

a. An IL V to support the 1994 soil dissipation study (RAN-0270, MRID 

44165039 and RAN-0270M, MRID 44165040): The 1995 soil dissipation study 

(MRID 44419018) was slightly modified (DCM partition replaced with C18 SPE) 

to include a 5th soil metabolite (3-0H-F8426-BAc), identified later. Acceptable 

method recoveries could only be obtained with C 18 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 of each study. Another IL V to support the 1994 soil 

dissipation study is not necessary and has no additional value, because the 

original method would not generate acceptable method recoveries for the 3-0HF8426-BAc metabolite. 

EFED Response: MRID 44419018 was not the analytical method used in the 

terrestrial field dissipation (TFD) study submitted under MRID 44165039. The 

Agency is requesting an independent laboratory validation (IL V) of MRID 

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. If an ILV is not submitted to support 

MRID 44165040 or if a submitted IL V 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 may be requested. 

b. Frozen storage stability data to support aquatic field dissipation studies: 

FMC notes that the required storage stability data of water, soil and sediment in 

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support of the 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 not provided 

(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 of transformation 

products of carfentrazone-ethyl stored for 15 months in soil. These data may 

not be relevant to the storage stability of these 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 

prepared in 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 not prepared in soil or sediment. The study authors indicated that 

carfentrazone-ethyl has not been included in frozen soil stability studies 

because it is known to degrade rapidly in soil, even in frozen conditions (p. 

13). 

• MRID 44654701: This is an upgradeable aquatic field dissipation study with 

no storage stability study. However, sediment that was spiked and stored 

frozen indicated that carfentrazone-ethyl degraded 67% over 9 months. It was 

not clear whether the sediment was spiked in the field and handled and 

processed similar to study samples or spiked in the laboratory. Field spikes 

were not prepared in soil or water. Study samples were stored frozen for 5 

months (soil), 6 months (sediment), and 107 days (water). 

• MRID 46253901: This is a supplemental aquatic field dissipation study with 

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 

irrelevant because the original field spike results were not shown to be invalid. 

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These data indicate that the transformation products of carfentrazone-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 within the maximum length of sample storage (6 

months in the case of sediment) in the aquatic field dissipation study, MRID 

44654701. The results can be used to correct measured values of carfentrazoneethyl 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 of storage stability data in the media sampled in MRID 44654701 results in 

uncertainty in the reported concentrations and degradation kinetics of 

carfentrazone-ethyl. If data are not submitted to upgrade the study to an 

acceptable classification, then additional aquatic field dissipation data may be 

requested. 

c. Photo degradation in water (carfentrazone acid) and Ecological toxicity: Due 

to rapid degradation and nearly complete conversion of carfentrazone-ethyl to 

carfentrazone chloropropionic acid in aqueous environments, FMC believes the 

some studies are not needed. Existing data on parent 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 both fresh 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 or presence to carfentrazone 

acid has already been evaluated. No additional information is expected to be 

obtained by conducting these studies with the acid. 

Also, higher tier data in an aquatic monitoring pond study (MRID 46253901) 

conducted in Florida was previously provided to EPA and includes the 

environmental fate and potential exposure of organisms to carfentrazone-ethyl 

and carfentrazone chloropropionic acid. 

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A waiver request for the whole sediment ecotox studies is made based on the fact 

that neither carfentrazone-ethyl nor its metabolites were observed to accumulate 

in sediments based upon 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 conversion to carfentrazone acid in aqueous 

environments, the environmental fate of carfentrazone acid in water needs 

to be understood. Therefore, the Agency is requesting aqueous photolysis 

data on carfentrazone acid. 

Aquatic Invertebrate and Fish Chronic Studies: FMC contends that 

information on parent should be sufficient since the breakdown to acid 

would have occurred in a chronic study with parent. The following 

chronic aquatic studies with the 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 Project Number: A96-

4547: 91 I 86-FMC: A-17-95-35. Unpublished study prepared by ECT 

Oekotoxikologie GmbH and Battelle. 148 p. 

44424201 Liu, H.; Kranzfelder, J.; Groetsch, K. (1997) Carfentrazone-ethyl (F8426) 

Technical: Toxicity to Embryos and Larvae of the Rainbow Trout, 

Oncorhynchus mykiss, Under Flow-Through Test Conditions: Lab Project 

Number: A96-4528: J9609004A: FMC/F8426/RT ELS. Unpublished study 

prepared by Toxikon Environmental Sciences. 121 p. 

44963201 Ellenberg, W.; Rielly, P.; Glover, S. (1999) Carfentrazone-ethyl (F8426) 

Technical: Toxicity to Embryos and Larvae of the Rainbow Trout, 

Oncorhynchus mykiss, Under Flow-Through Conditions: Lab Project 

Number: 99J0001: A99-4961: FMCIF8426IRT ELS. Unpublished study 

prepared by Toxikon 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. Project Number: I 04A11 07, 

A2001l5397. Unpublished study prepared by 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, rather than the parent, is the rapid breakdown. For aquatic 

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invertebrates, 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 data using aquatic invertebrates 

to assess risk of carfentrazone acid to these taxa. Therefore, the 

freshwater and saltwater chronic invertebrate studies (OCSPP guidelines 

850.1300 and 850.1350) on carfentrazone acid remain requested. 

For fish, MRID 44424201 is an acceptabkTainbowh'out-early-life=stage 

(ELS) flow-through study. Based on mean measured concentrations of 

parent, the NOAEC 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 in the study. Carfentrazone-ethyl has an aerobic aquatic 

metabolism half-life of2.3-2.7 hours at pH values somewhere in the range 

of5.1-8.1 (MRID 44419016). Ifcarfentrazone-ethyl degraded in the study 

with a half-life of approximately 2.5 hours and had a retention time of 

approximately 4 hours, then the test organisms would likely have been 

exposed to a substantial amount of transformation products as well as 

parent compound. This study does not satisfactorily address the chronic 

toxicity of carfentrazone-ethyl acid. 

Two of the submitted fish ELS studies (MRIDs 44963201 and 46037001) 

are rainbow light-dependent peroxidizing herbicide (LDPH) studies 

conducted under enhanced lighting conditions to estimate the enhanced 

toxicity of carfentrazone-ethyl under strong light. These studies were 

modified to specifically capture this fraction of the 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. Although the 

toxicity appears to be on the order of five to ten times greater than under 

normal lighting, no endpoints were confirmed for use in risk assessment. 

Also, these studies are based on parent light-enhanced toxicity and the 

concentration of carfentrazone-ethyl acid was not determined. LDPH 

toxicity will be evaluated in the risk assessment, but chronic toxicity data 

on the major de gradate (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 of the ELS NOAEC 

(rainbow trout parent ELS NOAEC = 118 ~g a.i.fL, MRID 44424201, and 

LDPH toxicity NOAEC = <16.4 ~g a.i.lL, 43189228), a life-cycle fish test 

is required per 40 CFR Part 158.630. Therefore, the freshwater and 

saltwater chronic fish studies (OCSPP guidelines 850.1500 and 850.1400) 

on carfentrazone acid remain requested. It is possible that an early life 

stage study will suffice in lieu of a full life cycle study on the acid 

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degradate. However, if the early life stage NOAEC for the acid degradate 

is >0.1 of the EEC, then a life-cycle study may be needed. 

Sediment tests: The partitioning of carfentrazone-ethyl between soil and 

water is uncertain because acceptable batch equilibrium data have 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. Due to the apparent 

-------------lacK: of partitioning of carfentrazone-etfiyl to secitment-;-tfie requested-------

whole sediment data (OCSPP guidelines 850.1735 and 850.1740) are 

recommended to be waived. 

Comments from Physicians Committee for Responsible Medicine 

Comment 1: The Summary Document indicates that the Agency may request testing for 

avian acute oral toxicity. We strongly support the use of the 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 of animals by up to 

approximately 90%. The approach provides three testing options: (1) limit dose test, (2) 

LDso-slope test, and (3) LDso-only test. The test method selected will depend on whether 

or not a definitive median dose (LDso) and slope of the dose-response curve are both 

needed. l 

The LDso-slope and LDso-only options are sequential testing procedures. Sequential 

testing procedures target the placement of doses and match the precision of the endpoint 

with the precision required. These sequential procedures were designed to minimize the 

numbers of birds used. A computer program 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 stated that it is reviewing the 

validation infonnation from 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 of the sequential study design was not conducted in passerine 

species. We would like to encourage the Agency to revise this position, based on several 

considerations. First, OECD member countries- including the US- adopted the TG in 

2010, nearly a year ago. It has undergone complete statistical and in vivo validation, and 

multiple draft revisions, for over fifteen years. Please advise when the Agency sees 

acceptance of this guideline for non-passerine species or provide a detailed discussing of 

its efforts over the past year 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 of Chemicals. 

Website accessed on August 5, 2010 at 

http://lysander.sourceoecd.orglvl=3006812/cl= 16/nw= IImsv/ij/oecdjoumals/160731 Ox/v 1 n2/s33/p I. 

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Furthermore, there are no scientific or biological reasons why the validation of a 

modification of the study design of a lethal-dose test should be species specific. This 

sequential design mirrors similar modifications that have been made in lethal-dose 

mammalian tests, which were validated using only statistical simulations. If passerines, as 

a species, have higher background mortality than other, more common bird 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. Continued resistance to this accepted guideline by the US 

without clear scientific rationale creates confusion and duplication of testing is likely to 

result. 

Since for this new species requirement the 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 with the 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 registration review process will be tested in passerine species, 

a significant number of birds stand to be saved. 

EFED Response: The OECD has adopted the TG 223 guideline and has issued a 

validation report. At this time, the Agency is evaluating the results of the OECD 

validation report to determine if the TG 223 effects endpoints and dose/response 

information adequately address the purposes of the avian acute oral data requirement as 

described in 40 CFR Part 158 and 40 CFR Part 161. The current plan is to have this 

evaluation finalized by the fall of2011. Until the Agency's evaluation of that 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 

inform the interpretation of studies performed under the TG 223 guideline, and should 

clarify what the Agency might find to be generally necessary for avian toxicity studies 

done under TG 223 to be acceptable to meet our data requirements. 

Validation work conducted on TG 223 test guideline to date has been limited to studies 

with the upland game birds (e.g., northern bobwhite quail). The OECD TG 223 guideline 

states "Captive bred species with low background mortality and a low propensity 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 

under this guideline for fulfilling requirements for passerine acute toxicity data unless 

additional validation work with passerines is done, but the Agency recognizes that 

specific situations might warrant additional examination. 

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