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 low

dose studies. Following absorption of an oral dose, it is quickly excreted, primarily through the urine (≈90%) as parent comp ound. Clearance of sulfoxaflor is rapid, most ly occurring within the first 24 hours after an oral dose

. There fore

, 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. Sulfox aflor 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 relativel y low concentrations of X11519540 and X115794 57. Laboratory estima ted degradation half

- lives for X11719474 varied from >1,000 d ays in US soils and 85

- 381 days in EU soils. However, it is important to note that much shorter dissipation half

lives were observed in both US and EU field soils (6

- 248 days) resulting from lea ching and degradation into X11519540 and X11579457. Persistent and highly mobile

, X11719474 is expected to be highly affected by run

- off and leaching

, causing surface a nd ground water contamination. Ano ther potential source of surface water contamination is plant residue left after the crop is harvested. S hort

- term drinking water exposure is expected to be to pa rent and X117194 74 and l ong

- 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 th e corresponding vine or straw. Sulfoxaflor, X11719474 and free/conjugated X11721961 compromi se the majority of the residue. In mature let tuce only, X11519540 was prese nt 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 followin g 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, muscl e, 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 p arent and/or metabolites were not observed to accumulate in fatt y 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 1 8% was identifi ed as X11596066. In the hen metabolism study, 68% of the hen liver residue was identified as sulfoxaflor while 1 4 % was identified as X11596066 , which is consistent with the goat metabolism study . X11719540 was detected at trace levels in most of the edib le 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 metabolis m studies were conducted with 14 C

- X11719474. No metabolism of X11719474 was obse rved in animals, with generally greater than 90% of the residue in edible samples identified as X11719474. The major residue in animals fed with 14 C

- X11719474 was found to be unchanged X11719474. X11719540 and X1159606 6 w ere not detected in these metabolism studies.

I n the crop field trials that were performed

, the registrant analyzed for parent sulfoxaflor and the two major plant metabolites, X11719474 and X11721061. It s hould 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. se asonal 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 metab olites, 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.

Rati onale

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, f or 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 follow ing 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 X115794 57 . 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 toxic ity 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 C rops). 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 t han 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 par ent 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 studie s. 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, p arent 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 succ eeding 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 sulfoxaf lor 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 l evels 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 sulfoxaflo r 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 t his 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, t he 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; th erefore, it is excluded from the residue definition.

X11 5 19540 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 X11 5 19540 were <0.01
ppm in all matrices. However, d ue to the potential for increased toxicity associated with X11 5 19540 , 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 X11 5 19540 in the dietary risk assessment. As X11 5 19540 was not monitored in the livestock feeding studies, some type of ratio approach will likely need to bePage 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. C ompliance with the tolerance levels for sulfoxaflor is to be determined by measuring only

su lfoxaflor ( N

- [methyloxido[1

- [6

- (trifluoromethyl)

- 3

- pyridinyl]ethyl]

- γ 4

- sulfanylidene]cyanamide )

.Page 7 of 7

A ppendix 1

. Sulfoxaflor and its m ajor metabolites/d egradates.

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

- methanesulfonyl

ethyl)

- 2

- trifluoromethyl

pyridine

X11596066 1

- [6

- (trifluoromethyl )pyridin

3

- yl]ethane

X11579457 5

- [1

- (S

methylsulfonimidoyl)ethyl]

- 2

- (trifluoromethyl)pyridine