Page 3 of 7

concluded that the quantification of risk using a non-linear approach will adequately account for 

all chronic toxicity, including carcinogenicity that could result from exposure to sulfoxaflor. 

Sulfoxaflor has a high rate of oral absorption, at or greater than 90% in high- and lowdose studies. Following absorption of an oral dose, it is quickly excreted, primarily through the 

urine (≈90%) as parent compound. Clearance of sulfoxaflor is rapid, mostly occurring within the 

first 24 hours after an oral dose. Therefore, there is not a concern for bioaccumulation.

Foliar applications are currently being proposed for sulfoxaflor. Upon application, only 

limited quantities of the pesticide is expected to be carried away by drift (to adjacent terrestrial 

and aquatic systems) with the important part being deposited into target plants and later affected 

by wash-off into the soil. Sulfoxaflor reaching the soil system from foliage wash-off will be 

subjected to rapid degradation to X11719474 (main soil degradate) which degrades, in most 

soils, very slowly producing relatively low concentrations of X11519540 and X11579457. 

Laboratory estimated degradation half-lives for X11719474 varied from >1,000 days in US soils 

and 85-381 days in EU soils. However, it is important to note that much shorter dissipation halflives were observed in both US and EU field soils (6-248 days) resulting from leaching and 

degradation into X11519540 and X11579457. Persistent and highly mobile, X11719474 is 

expected to be highly affected by run-off and leaching, causing surface and ground water 

contamination. Another potential source of surface water contamination is plant residue left after 

the crop is harvested. Short- term drinking water exposure is expected to be to parent and 

X11719474 and long-term exposure will be associated mainly with X11719474 and its 

degradation products X11519540 and X11579457.

Plant metabolism studies were conducted in tomatoes, lettuce, succulent peas, and rice. 

Foliar and soil applications were studied, although currently only registration for foliar 

applications is being pursued. With a 14-day pre-harvest interval (PHI), residue levels in the 

grain or fruit were <20% of the residue level in the corresponding vine or straw. Sulfoxaflor, 

X11719474 and free/conjugated X11721961 compromise the majority of the residue. In mature 

lettuce only, X11519540 was present at <1% of the TRR. Following foliar applications, parent 

sulfoxafor, X11719474, and X11721061 conjugates commonly were found at >10% TRR. In 

contrast, X11719474 was the only residue consistently exceeding 10% TRR following soil 

applications. 

The metabolism of sulfoxaflor was studied in both ruminants and poultry. For goats 

dosed with sulfoxaflor, residue levels were highest in liver, kidney, muscle, and milk, and lower 

in fat. Total residue levels in the eggs and edible tissues from hens dosed with sulfoxaflor were 

lower than the levels observed in the ruminant. The livestock metabolism studies suggest rapid 

absorption and elimination of sulfoxaflor. The parent and/or metabolites were not observed to 

accumulate in fatty tissues. The majority of the residue in milk, eggs, and edible tissues 

consisted of the parent compound, generally >80% of the residue except in liver. Approximately 

60% of the ruminant liver residue was identified as sulfoxaflor while 18% was identified as 

X11596066. In the hen metabolism study, 68% of the hen liver residue was identified as 

sulfoxaflor while 14% was identified as X11596066, which is consistent with the goat

metabolism study. X11719540 was detected at trace levels in most of the edible samples (<2% 

of the TRR in the ruminant or ≤8% of the TRR in the hens; at levels ≤ 0.009 ppm) and 

X11721061 was also detected in the ruminant liver as a minor metabolite (3.3% of the TRR). 

No other component was detected at levels greater than 10% of the total radioactive residue 

level. The metabolic pathway is qualitatively similar in rats.
Page 4 of 7

Since X11719474 was observed as a plant metabolite, but was not formed in either the 

sulfoxaflor ruminant or poultry metabolism studies, separate animal metabolism studies were 

conducted with 14C-X11719474. No metabolism of X11719474 was observed in animals, with 

generally greater than 90% of the residue in edible samples identified as X11719474. The major 

residue in animals fed with 14C-X11719474 was found to be unchanged X11719474. 

X11719540 and X11596066 were not detected in these metabolism studies. 

In the crop field trials that were performed, the registrant analyzed for parent sulfoxaflor 

and the two major plant metabolites, X11719474 and X11721061. It should be noted that the 

application rates for the residue chemistry field trial data were in most cases conducted at a 

higher seasonal use rate (0.36 lbs. ai/A or 400 g /ha) than the label rates proposed for registration 

(at least the U.S. proposed max. seasonal use rate of 0.266 lbs. ai/A or ca. 300 g/ha). 

The parent compound, X11719474, and X11721061, are present in most of the primary 

crops tested. A few commodities have little or no residues of the parent, or residues of either of 

the two major metabolites, e.g., potato tubers, dry bulb onions, and tree nuts. In general, the 

parent compound was present if any residues were detected in that commodity. The only 

exception to this observation was potato tubers, where only X11719474 was detected. 

Rationale

Based on several toxicology studies, X11719474 is approximately 7-times less potent 

compared to the parent sulfoxaflor. An HED review committee, including CARC and HazPOC 

members, determined that X11719474 does not share the reproductive MOA that was presented 

for sulfoxaflor. However, similar to the parent sulfoxaflor, exposure to X11719474 results in 

hepatotoxicity. X11579457, a minor soil metabolite, exhibits no genotoxicity and no acute oral 

toxicity. Structurally, it is quite similar to X11719474, and is therefore considered to be 

substantially less toxic than parent sulfoxaflor. The other primary plant metabolite, X11721061, 

is also considered to be significantly less toxic than the parent based on subchronic toxicity 

studies and is not mutagenic. Little toxicity data is available for X11596066, however, it has no 

structural alerts for genotoxicity, is negative in the Ames test, is structurally similar to

X11721061, and therefore, is of low concern for human health.

Water. 

Due to rapid degradation of sulfoxaflor to X11719474, for the purposes of drinking water 

modeling, initial X11719474 levels are expected to be essentially equivalent to the amount of 

parent that reaches the soil directly following application (not intercepted by foliage) and 

amounts washed-off foliage later. In the long term, there is potential for X11719474 to degrade 

to metabolites X11519540 and X11579457. Although not detected in U.S. aerobic soil 

metabolism studies, these metabolites were observed at higher levels in European studies. 

X11579457, a minor soil metabolite, is structurally quite similar to X11719474, which exhibits 

significantly less toxicity than parent sulfoxaflor. Therefore, X11579457 is excluded from the 

residue definition due to its decreased toxicity and low overall exposure levels. However, the 

relative potency of X11519540 is greater than the parent sulfoxaflor, as demonstrated in LD50 

and 28-day studies in the rat. Therefore, despite the generally low overall exposure to 

X11519540, this metabolite should be included, along with parent sulfoxaflor and X11719474, 

for the purposes of the drinking water risk assessment and modeling. 
Page 5 of 7

Plants (Primary Crops). The parent compound together with the two main plant metabolites, 

X11719474 and X11721061, are present in most of the primary crops tested in crop field trials. 

It is noted that all field trials were conducted at higher rates than those proposed for actual use, 

making the anticipated exposure levels to these metabolites even lower than recorded in the field

studies. Due to the lower toxicity of X11719474 and X11721061, as well as generally lower 

overall exposure compared to parent sulfoxaflor, these metabolites are excluded from the residue 

definition. The metabolite X11519540 was only observed at low concentrations (<1% of the 

TRR) in the lettuce metabolism study and was not observed at all in the other plant metabolism 

studies. Consequently, X11519540 is excluded from the residue definition due to low potential 

for exposure through plant matrices. Therefore, the inclusion of only parent sulfoxaflor should 

be adequate for dietary risk assessment. For tolerance enforcement, parent sulfoxaflor is also 

considered an adequate indicator of misuse. Although the parent may not be a good marker for 

misuse in crops like potatoes, the metabolites would not be much better indicators based on the 

field trial results.

Rotational Crops –Inclusion of parent sulfoxaflor only for dietary risk assessment is appropriate. 

X11719474 is the predominant residue observed in rotational crops. However, field rotational 

crop studies demonstrate that the maximum amount of X11719474 taken up by succeeding crops 

is similar to the maximum amount present in primary crops after foliar treatments. As these 

summed levels of X11719474 are still low relative to the amount of parent sulfoxaflor in most 

primary crops, risk assessments based on parent sulfoxaflor will be protective for any 

X11719474 residues taken up by rotational crops. An exception to the preceding generalization 

regarding relative metabolite levels was noted for the root and tuber vegetables. However, for 

these crops, the maximum residue levels are low (<0.04 ppm). Thus, a separate residue of 

concern definition for rotational root and tuber vegetable crops was not considered necessary. 

Also, because there are few potential rotational crops that are not proposed for primary crop 

tolerances, concerns regarding rotational crop issues are low. Based on the above considerations 

combined with its substantially lower toxicity relative to sulfoxaflor, X11719474 is excluded 

from the residue definition. For tolerance enforcement, parent sulfoxaflor is considered an 

adequate indicator of misuse for the proposed application methods. Should there ever be soil 

directed applications of sulfoxaflor to primary crops, there is a potential for significant residues 

of X11719474 in rotated crops, requiring this decision to be revisited.

Livestock – Based on the information available to ROCKS, the inclusion of parent sulfoxaflor 

only should be sufficient for dietary risk assessment. With the exception of liver, the majority of 

the residue in milk, eggs, and edible tissues consisted of the parent compound, generally >80% 

of the residue. X11596066 was a major metabolite in ruminant and hen liver (14-18% TRR), but 

has been determined to have low overall toxicity; therefore, it is excluded from the residue 

definition. 

X11519540 was detected at trace levels in most of the edible samples (<2% of the TRR in the 

ruminant and ≤ 8% of the TRR in the hens). The actual ppm levels of X11519540 were <0.01 

ppm in all matrices. However, due to the potential for increased toxicity associated with 

X11519540, ROCKS recommends that the sulfoxaflor team consult with the HED Toxicology 

Science Advisory Council (ToxSAC) in order to adequately account for the relative potency of 

this metabolite. Following consultation with ToxSAC, the sulfoxaflor team can determine 

whether it is necessary to include X11519540 in the dietary risk assessment. As X11519540 was 

not monitored in the livestock feeding studies, some type of ratio approach will likely need to be 
Page 6 of 7

developed if this metabolite is included in dietary risk assessment. It is noted that the draft 2011 

JMPR decision excludes this metabolite from their residue definition due to the low overall 

observed concentrations. For tolerance enforcement, parent sulfoxaflor is considered an 

adequate indicator of misuse. 

 

Recommended Tolerance Expression:

The ROCKS recommends the following language for the tolerance expression for plant and 

livestock commodities:

Tolerances are established for residues of the insecticide sulfoxaflor, including its 

metabolites and degradates, in or on the commodities in the table below. Compliance 

with the tolerance levels for sulfoxaflor is to be determined by measuring only 

sulfoxaflor (N-[methyloxido[1-[6-(trifluoromethyl)-3-pyridinyl]ethyl]-γ

4

-

sulfanylidene]cyanamide).
Page 7 of 7

Appendix 1. Sulfoxaflor and its major metabolites/degradates.

Common name/code

ID No.

Chemical name 

(IUPAC, unless otherwise noted)

Chemical structure

Sulfoxaflor [methyl(oxo){1-[6-

(trifluoromethyl)-3-

pyridyl]ethyl}-λ

6

-

sulfanylidene]cyanamide

CAS: N-[methyloxido[1-[6-

(trifluoromethyl)-3-

pyridinyl]ethyl]-γ

4

-

sulfanylidene]cyanamide

X11719474 N-(methyl)oxido){1-[6-

(trifluoromethyl)pyridine-3-

yl]ethyl}-λ

4

-sulfanylidene) 

urea

X11721061 1-[6-

(trifluoromethyl)pyridin-3-

yl]ethanol

X11519540 5-(1-methanesulfonylethyl)-2-trifluoromethylpyridine

X11596066 1-[6-(trifluoromethyl)pyridin3-yl]ethane

X11579457 5-[1-(Smethylsulfonimidoyl)ethyl]

-2-(trifluoromethyl)pyridine

N

S

N

O N

F3C

N

S

N

O

N

O

F

F

F

N

OH

F

F

F

N

S

O

F O

F

F

N

F

F

F

N

S

N OH

CF3