UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON D.C., 20460 

PC Code: I 13202 

DP Ba rcode: 427946 

Date: July 22, 20 15 

MEMORANDUM 

SUBJECT: 

FROM: 

T HROUGH: 

T O: 

Response to Public Comments on the Famoxadone Registration Review Problem 

Formulation 

Freeborn G. Jewett, Biologist L_ ~ Christopher M. Koper, M.S., C"n~st ( JV-~~~ '2 . .'t 0u~ 2.o•c; 

Environmental Risk Branch I U 

Environmental Fate and Effects Division (7507P ..... j) 

Office of Pesticide Programs d / "''J.'}. 

~ tJ ~ ~\~,_1,< Gregory Orrick, Ph.D., RAPL ~ ~ ~ 

Sujatha Sankula, Ph.D., Branch Chief • ....._ · 

Environmental Risk Branch I 

Environmental f-ate and Effects Division (7507P) 

Office of Pesticide Programs 

Christina Scheltema, Chemi cal Review Manager 

Avivah Jakob, Team Leader 

Kelly Sherman, Branch Chief 

Risk Management and Implementation Branch 3 

Pesticide Re-Evaluation Division (7508P) 

In response to the '·Registration Revi ew: Problem Formulation for the Environmental Fate, 

Ecological Risk, Endangered Species, and Drinking Water Assessments for Famoxadone" 

(D423285), DuPont Crop Protection submitted comments on the "Anticipated Data Needs for the 

Famoxadone Registration Review. " The purpose of this memorandum is to address these 

comments and data submissions. 

Comments from DuPont Crop Protection: 

Comment: "GDL 835.4300 - Aerobic aquati c metabolism: DuPont believes the two systems 

selected do meet the request of EPA OPPTS 835.4300 guidelines on sediment selection: 

• OC contents: EPA OPPTS 835.4300 (low OCo/o:0.5-2.5 ; high OC%: 2.5-7.5); DuPont 

study (AMR 3662-95, MRID 44946405) (low OC%: 1.17 or OM%: 2.0 1; high QC%: 

2.62 or OM%: 4.51 ). It clearly indicates QC contents at both low and high levels are 

within the range suggested by EPA guidelines. 
 Texture difference: the guidelines of EPA OPPTS 835.4300 state that the difference in 

[clay+silt] content for the two sediments should normally be at least 20%. In DuPont 

study (ARM 3662- 95, MRID 44946405), the difference between the coarse texture and 

fine texture is equal to 72.4%-51.2% =21.2%, which does meet the guideline requirement 

of at least 20%.

 Therefore, DuPont believes the study ARM 3662-95, MRID 44946405, provided to EPA, 

does meet current study guideline and an additional system test is not necessary.

EPA Response: The Agency agrees that an additional test system is not necessary. The 

title of DuPont study AMR 3662-95 suggests that a single sediment: water system was 

tested. The organic carbon contents and texture differences of selected sediments meet 

the guideline requirements.

Comment: “GDLN 860.1380 – Storage Stability in Soil and Water: There is a GLP frozen 

storage stability study for soil, AMR 3096-94, MRID 44302453. It concludes that residues are 

stable for up to 18 months when stored frozen. Water storage stability is not necessary because 

our sample analysis standard practice states that once the samples are extracted, the samples are 

immediately analyzed.”

EPA Response: The Agency appreciates the reference for the storage stability study in 

soil. Since there are no aquatic uses for famoxadone, a storage stability in water is not 

warranted at this time. The Agency interprets the immediate analysis for aqueous 

samples is applicable to laboratory studies. 

Comment: “NON-GDLN – Pollinator Tier II Semi-field Toxicity Testing (tunnel/enclosure

studies). The criteria for conducting this test are dependent on the results from the acute and 

chronic laboratory tests. Therefore, this test should be conditionally required based on the results 

from the laboratory tests. If the risk assessment results in low risk, then the studies should no 

longer be required.

NON-GDLN – Pollinator Tier II Semi-field Toxicity Testing (feeding studies): The criteria for 

conducting this test are dependent on the results from the acute and chronic laboratory tests. 

Therefore, this test should be conditionally required based on the results from the laboratory 

tests. If the risk assessment results in low risk, then the studies should no longer be required.

EPA Response: The Agency agrees that these tests are conditionally required based on 

the results of the Tier I pollinator studies. 

Comment: “NON-GDLN – Pollinator Acute Oral Toxicity, Adult: This study has been 

conducted and the final report has been issued: AMR-5165-98.”

EPA response: The Agency appreciates the timely submission and will conduct a full 

review of the study once it is received. When the DER is completed, the Registrant will 

receive notification and a copy. 
Comment: “NON-GDLN – Pollinator Acute Oral Toxicity, Larvae DuPont Response: This 

study has been conducted and the final report has been issued: DuPont-40437.”

EPA response: The Agency appreciates the timely submission and will conduct a full 

review of the study once it is received. When the DER is completed, the Registrant will 

receive notification and a copy.

Comment: NON-GDLN – Pollinator Chronic Oral Toxicity, Adult: This study is in progress 

(DuPont-40438) and will be completed in accordance with the time specifications in the 

proposed work plan.

EPA response: The Agency will conduct a full review of the study once it is received. 

When the DER is completed, the Registrant will receive notification and a copy.

Comment: NON-GDLN – Pollinator Chronic Oral Toxicity, Larvae: There is currently no 

standardized method for this test that is currently being successfully conducted. While a study 

design has been proposed, it is currently undergoing development and ring testing and is not 

currently ready for regulatory testing. The larval oral toxicity study that DuPont has conducted 

(DuPont-40437) actually dosed the larvae for three consecutive days instead of one, with no 

effect. Because there is no standardized method for this test, DuPont recommends that this study 

should be considered for both data points.

EPA response: The Agency welcomes the submission of the DuPont study 40437 and 

will conduct a full review of the study once it is received. As with all data submitted to 

the Agency, the reviewer will determine whether the study is scientifically sound and can 

be used to fulfil guideline requirements. 

Chronic larvae studies need to be conducted with multiple doses and larvae need to be 

monitored until pupae emergence. A study with a single three-day dosage may 

potentially fulfil the acute honeybee larvae toxicity guideline requirement, but not 

the chronic guideline. The registrant is required to submit a protocol for approval 

prior to initiating the study until such time as the OCSPP 850 Pollinator Larvae 

Chronic Oral Toxicity testing guidelines are published.

Draft guidance is available: 

http://www.oecd.org/chemicalsafety/testing/Draft_GD_honeybee_larval_tox_repeated_e

xposure_25_February_2014.pdf

Comment: NON-GDLN – Whole Sediment: Chronic Invertebrates Freshwater and Marine

(using Chironomus dilutes, Hyalella azteca and/or Leptocheirus plumulosus): What is being 

requested needs further clarification. A chronic sediment test with the freshwater organism C. 

riparius is already being conducted. This study is being conducted in accordance with an OECD 

test guideline (OECD 218) and modifications that were required by EPA when designing this 

test. EPA indicated that this study (OECD 218 with modifications) would suffice the need for the 

benthic invertebrate study. Therefore, this study is not needed since an EPA agreed sediment 
study is in progress (see below) that will produce the relevant and necessary data to conduct a 

sediment risk assessment.

 It needs to be further clarified if another sediment test with a freshwater organism is 

requested as part of the proposed work plan.

 DuPont agrees with the proposal to conduct the marine chronic sediment toxicity test.

EPA response: Based on the fate properties of famoxadone, 3 chronic whole sediment 

toxicity tests are required as outlined in 40 CFR Part 158 Subpart G (USEPA 2007)1. The

chronic freshwater sediment toxicity tests must be conducted on one amphipod and one 

midge species. The study currently being conducted by the registrant using the midge

Chironomus riparius should be submitted to the Agency for review. If this study is 

determined to be scientifically sound, it will be used to fulfill guideline requirements for 

a chronic whole sediment toxicity test with a midge species. 

The midge and amphipod have different life histories, occupy different taxonomic groups 

(amphipods are crustaceans, while midges are insects) and generally interact with 

sediments in different ways. Chironomid larvae are more infaunal (submerged in the 

sediment) whereas amphipods are more epibenthic (moving in and out of the surficial 

sediment layer). As a result, the amphipod and midge may experience differences in 

chemical uptake relative to different exposure routes (pore water respiration, sediment 

ingestion, food ingestion, dermal uptake, respiration of overlying water). Furthermore, 

physiological and taxonomic differences between midges (Class: Insecta; Order: Diptera) 

and amphipods (Class: Malacostraca; Order: Amphipoda) may result in substantial 

sensitivity differences between these taxa, especially with the highly-specific modes of 

action of many pesticides. Therefore, a chronic whole sediment toxicity test is being 

requested using the amphipod species Hyalella azteca. As indicated in 40 CFR Part 158, 

the registrant is required to submit a protocol for approval prior to initiating the study 

until such time as the OCSPP 850 chronic sediment testing guidelines are published. The 

Registrant is welcome to submit a formal Waiver Request if they feel the requirement 

should be waived if there is sufficient evidence of low toxicity.

In addition, a chronic estuarine/marine sediment toxicity test is requested using the 

amphipod species Leptocheirus plumulosus. As indicated in 40 CFR Part 158, the 

registrant is required to submit a protocol for approval prior to initiating the study until 

such time as the OCSPP 850 chronic sediment testing guidelines are published.

Comment; GDLN 850.1010 – Acute Toxicity, freshwater invertebrates (Daphnia magna) –

(IN-KZ007, IN-MN467, IN-MN968, IN-MN-468-0, IN-KF015 and IN-H3310): Acute daphnid 

tests have been conducted with INKZ007 (DuPont-31078), IN-MN467 (DuPont-31080), INMN468 (HLR-848-96 [MRID 49502702], DuPont-29778), IN-KF015 (AMR 3978-96 [MRID 

49502704], DuPont-31082), and IN-H3310 (HLR 380-96 [MRID 49502703], DuPont-29777). 

An acute daphnid test has not been conducted with IN-MN968. However, it is DuPont’s position 

 

1 Specific language available in the preamble to 40 CFR Part 158 (p. 60944): U.S. Environmental Protection 

Agency. 2007. Pesticides; Data Requirements for Conventional Chemicals, Technical Amendments, and Data 

Requirements for Biochemical and Microbial Pesticides; Final Rules Federal Register / Vol. 72, No. 207 / Friday, 

October 26, 2007. 
that this study is not needed based on structural similarity with another famoxadone metabolite 

(IN-JL856) for which studies were conducted (HLR 382-96 [MRID 49502701], DuPont-31079).

 This similarity can be further confirmed based on results from ECOSAR (v1.11). The 

results for acute daphnid toxicity range from 0.676 to 43.595 mg/L. The lowest EC50 can 

be considered less toxic than famoxadone and of similar toxicity to IN-JL856 (EC50 = 

0.190 to 9.6 mg/L).

Therefore, it is DuPont’s position that an acute daphnid test with IN-MN968 is not needed.

EPA response: As indicated in the Problem Formulation, it is the opinion of the Agency 

that the ECOSAR results for famoxadone are not applicable for use in assessing the 

toxicity of the degradates because the ECOSAR-predicted and empirically-derived 

toxicity values for the parent chemical, famoxadone, are not closely aligned and cannot 

be calibrated for accuracy. 

Furthermore, the Agency does not consider the structural similarity of the degradates 

IN-MN968 and IN-JL856 sufficient evidence to assume equal toxicity, as IN-MN968

contains unique functional groups that could potentially affect reactivity. Nevertheless, 

the Agency would welcome a formal waiver request if DuPont could provide additional 

evidence to indicate that the degradates IN-MN968 and IN-JL856 are toxicologically

similar. Until data characterizing the toxicity of IN-MN968 are submitted, the Agency 

will assume equal toxicity with the most toxic degradate.