OFFICE OF CHEMICAL SAFETY

AND POLLUTION PREVENTION

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

February 4, 2016

PC Codes: 147500

MEMORANDUM DP Barcode: D431158

SUBJECT: EFED Response to Registrant Comments Regarding the Registration Review Problem 

Formulation for Pinoxaden

FROM: N.E. Federoff, Wildlife Biologist

Environmental Risk Branch 2

Environmental Fate and Effects Division (7507P)

THRU: Brian Anderson, Chief

Environmental Risk Branch 2

Environmental Fate and Effects Division (7507P)

TO: Neil Anderson, CRM

 Pesticide Re-Evaluation Division (7508P)

The Environmental Fate and Effects Division (EFED) has completed the responses to the 

Registrant (Syngenta Crop Protection, LLC) comments regarding the preliminary problem 

formulation of pinoxaden. 

EPA statement 

Additional 

Information 

Requested p. 3 

EFED requests that the registrant send copies of three ecotoxicity 

studies that support the adjuvant Adigor. 

Syngenta Comment: Syngenta will provide a courtesy copy of each study report (MRID# 

46421506, 46421507, 46421510) in a separate submission. 

EPA Response: EFED has received the submission and the studies are currently at the 

contractor for review. 

EPA statement 

5.1 Effects to Aquatic 

Organisms 

Table 6. p. 22 

Rainbow Trout 

(Oncorhynchus 

mykiss) 

96 hr LC50 = 12.3 ppm 

(407855 100EC) 

Slightly 

toxic 

472932-02, 

2007 

Syngenta Comment: The study cited above (MRID 47293202) was conducted using technical 

pinoxaden (99.1% purity) and not the 100EC formulation. This study was deemed acceptable by 

the Agency (p. 58) and should fulfill the data gap for acute test with a cold water fish. In order to 

fulfill the warm water fish requirement (previous study, MRID 46203036, was classified as 

supplemental), Syngenta will submit a 96-hour acute toxicity study with the fathead minnow using 

technical pinoxaden (conducted in 2008). 

EPA Response: EFED will review the data once submitted. EFED agrees that the study 

(MRID 472932-02) used NOA-407855 Technical (pinoxaden).
Page 2 of 5

EPA statement 

5.1 Effects to Aquatic 

Organisms 

Table 6. p. 22 

Freshwater Acute invertebrates 

Water Flea 

(Daphnia magna) 

48 hr EC50 = 6 

ppm 

(A12127R 

form + adj) 

Moderately 

toxic 

462030-31, 

2003 

Syngenta Comment: The cited study (MRID 46203031) was conducted using the Pinoxaden 

100EC formulation (A12303C) plus the ADIGOR (A12127R) adjuvant. However, per the study 

report, the 48-hour EC50 on Daphnia magna was calculated to be 8.5 mg [A12303C+ 

A12127R]/L rather than 6 mg [formulation + adj]/L cited above. 

EPA Response: The study was classified as supplemental and did not fulfill guideline 

requirements. It was considered invalid by the PMRA. Expressed as Pinoxaden, the EC50 was 

reported as 0.132 ppm ai total. Expressed as A12303C, the EC50 was reported as 1.93 ppm

nominal.

EPA statement 

5.1 Effects to Aquatic 

Organisms 

Table 6. p. 23

Green Algae 

(Pseudokirchneriella 

subcapitata) 

EC50 = 0.035ppm 

NOAEL= 0.0037 ppm 

(10.10 EC) 

462031-21, 

2003 

Syngenta Comment: The study cited (MRID 46203121) was conducted using the 100EC 

formulation (A12303C) plus the ADIGOR (A12127R) adjuvant. The values reported above are 

based on calculations of measured A12303C concentrations reported in the study. Syngenta 

believes that presenting the results in ppm active ingredient (ai) mischaracterizes the toxicity of 

pinoxaden to green algae as the effects noted in the study are not likely the result of the presence 

of pinoxaden. Syngenta has conducted a 96-hr study with Pseudokirchneriella subcapitata using 

pinoxaden technical (study to be submitted to the Agency) which resulted in an EC50 of 3.9 mg 

ai/L. 

Syngenta will submit two algal toxicity studies on Pseudokirchneriella subcapitata, the first with 

the technical pinoxaden (NOA407855) and the second with the NOA407854 degradate. Both 

studies were conducted for 96-hours as required by the guideline to fulfill the green algae data 

requirement. The previous green algal studies submitted to the Agency were conducted for 72 

hours. 

EPA Response: EFED will review the data once submitted.

EPA statement 

5.2 Effects to 

Terrestrial 

Organisms p. 

24 

Tests with the honey bee exposed via oral and contact routes of 

exposure were conducted with parent pinoxaden, the 10.1% ai 

formulation, the formulation with adjuvant, and the adjuvant alone. 

Parent pinoxaden is nontoxic to bees by both oral and contact routes of 

exposure, but the formulated product is moderately toxic via contact 

exposure. Only the formulation displayed toxicity that might be of 

concern, but an LD was not established (LD50 >6.3 μg ai/bee) nor 

shown to exceed 11 μg ai/bee. 
Page 3 of 5

Syngenta Comment: The pinoxaden 100EC formulation study cited (MRID 46203110) 

included both contact and oral routes of exposure. No mortality was observed at the highest 

treatment level in the contact study (6.4 μg ai/bee). However, the oral exposure resulted in 43% 

mortality at the highest treatment level (19.1 μg ai/bee). Overall, these results suggest that 

pinoxaden is practically non-toxic to honey bees (i.e., LD50 > 11 μg ai/bee). 

EPA Response: EFED agrees that the 100EC formulation of pinoxaden seems to be 

practically non-toxic to bees through contact. However, an acceptable oral lethal dose was not

established for the formulation. 

EPA statement 

5.2 Effects to 

Terrestrial 

Organisms p. 

24 

In a 48-hour acute oral LC50 test, the honey bee was exposed to 

NOA-407855 (Pinoxaden 100EC) at nominal concentrations of 0 

(negative and solvent controls), 6.3, 13, 25, 50 and 100 μg ai/bee. By 

48 hours, there was 0% mortality in the controls and 3, 0, 0, 3 and 3% 

in the 6.3, 13, 25, 50 and 100 μg ai/bee treatment groups, respectively. 

The LC50 and NOAEC values were >100 and 100 μg ai/bee, 

respectively. However, the recovery of NOA-407855 in the 50% 

sucrose solution was determined during the definitive acute oral 

toxicity test. The nominal 6.3, 13, 25, 50 and 100 μg ai/bee treatment 

levels yielded recoveries of 86, 75, 42, 15 and 6.5% of nominal, 

respectively. The nominal 6.3 μg ai/bee treatment diet was clear 

following preparation, the nominal 13 and 25 μg ai/bee diets were 

opaque, and the nominal 50 and 100 μg ai/bee diets contained 

particulate matter and there was residue on the glass of the volumetric 

flask used for preparation. The particulate matter and residue on the 

preparation flasks could account for the low recoveries observed at the 

three highest treatment levels (6.5-42% of nominal). 

Syngenta Comment: The study cited (MRID 47293203) used pinoxaden technical 

(NOA407855) rather than pinoxaden 100EC as cited above. EPA classified this study as invalid 

based on the recovery of pinoxaden in the 50% sucrose solution during the test. However, the 

nominal doses used in the study of 6.3, 13, 25, 50 and 100 μg ai/bee required nominal 

concentrations in the test solution of 252, 500, 1000, 2000, and 4000 mg ai/L which were above 

the water solubility limit for pinoxaden (200 mg/L). Solubility of test material is a significant 

concern in these studies considering the feeding solution contains 50% sucrose which limits the 

amount of water available to dissolve the test material. Even with the use of 1% acetone in the 

study, the practical limit of solubility of the test material is approximately 500 mg ai/L which is 

equivalent to the acute oral dose of 13 μg ai/bee. Based on these results, the LD50 can be 

estimated to be greater than 13 μg ai/bee especially considering only 43% mortality was 

observed in the 19 μg ai/bee (converted dose) from MRID 46203110. Therefore, technical 

pinoxaden can be considered practically non-toxic to honey bees. Repeating the study would 

likely result in similar difficulties in dissolving the test material and not result in toxicity below 

the practical limit of solubility. 

A previously submitted study (MRID 46203109) using pinoxaden technical (NOA407855) 

resulted in an acute oral LD50 > 100 μg ai/bee. This study was classified as supplemental. Based 
Page 4 of 5

on submitted studies, Syngenta believes that the acute oral honey bee Tier 1 requirement has 

been satisfied and that further testing would not provide additional value to the risk assessment. 

EPA Response: EFED agrees that MRID 46203109 resulted in a value >100 ug ai/bee 

(actually tested as >200 ug ai/bee) for an acute oral test. Also, in cases where solubility in 

sucrose solutions is problematic, a suspension can be tested or the conducted study should be 

shown that it was tested with a stable and homologous suspension. In this case, if this can be 

shown, further testing would likely not be required. 

EPA Statement 

Section 8. 

Endangered 

Species 

Assessments. p. 

28 

Consistent with EPA’s responsibility under the Endangered Species 

Act (ESA), the Agency will evaluate risks to federally listed 

threatened and endangered (listed) species from registered uses of 

pesticides in accordance with the Joint Interim Approaches 

developed to implement the recommendations of the April 2013 

National Academy of Sciences (NAS) report, Assessing Risks to 

Endangered and Threatened Species from Pesticides.

Syngenta Comment: Simple, deterministic screening-level assessments can facilitate rapid 

initial screening/exclusion criteria for a pesticide active ingredients’ potential to adversely affect 

listed (threatened or endangered species) and non-listed species. Screening-level assessments are 

conservative by design (to minimize potential type II errors (failure to reject a false null 

hypothesis of de minimus risk) through incorporation of safety factors and assumptions 

regarding exposure. If a pesticide exposure results in a risk quotient (RQ) below a predefined 

level of concern (LOC), then the potential risks are considered de minimus and unlikely to 

jeopardize the existence of a listed species. If, a RQ is generated that exceeds the LOC, 

additional higher-tier scientific information may be incorporated to refine the risk assessment 

and more accurately reflect potential exposures and effects to reduce potential type I errors 

(falsely rejecting the null hypothesis of de minimus risk). This information includes community

level effects data, environmental fate, higher tier exposure modelling, monitoring data, geospatial 

proximity analysis, species biology data, and a variety of refined modelling and assessment 

procedures. In addition, higher-tier risk assessments should employ probabilistic techniques to 

more accurately characterize risk. Moreover, where possible and appropriate, risk assessments 

should consider assemblage-level effects (populations, communities, and ecosystems) rather than 

deterministically oriented single species approaches. A summary of the types of higher-tier data 

and assessment refinements available to more accurately and realistically evaluate potential risks 

to endangered species is provided in MRID# 49200601 and Brain et al. (2015) (Reference). 

Syngenta will submit a courtesy copy of this publication concurrently to EPA. 

Reference: Brain R, Teed S, Bang J, Thorbek P, Perine J, Peranginangin N, Kim M, Valenti T, 

Chen W, Breton R, Rodney S, and Moore D. 2015. Risk Assessment Considerations With 

Regard to the Potential Impacts of Pesticides on Endangered Species. Integrated Environmental 

Assessment and Management 11: 102-117. 

EPA Response: In collaboration with the U.S. Fish and Wildlife Service and National Marine 

Fisheries Service, EPA is continuing to develop and refine the interim scientific methods for 

evaluation of the potential risk of pesticides to threatened and endangered species, based on 

the April 2013 National Academy of Science Report recommendations. These methods are 
Page 5 of 5

currently being developed and vetted in the context of three pilot chemicals (chlorpyrifos, 

diazinon, and malathion). Once vetted, these new methods will be incorporated, as 

appropriate, for other chemicals being evaluated as part of the registration review program.