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EPA REGISTRATION DIVISION CO MPANY NOTICE OF FILING FOR

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: [Marianne Lewis – 703-308-8043]

Mak h teshim Agan of North America, Inc.

PP#5F8351

EPA has received a pesticide petition ([ PP#5F8351] ) fro m Makhteshim Agan of North America, Inc (d/b/a A DAMA), 3120 Highwoods Blvd, Suite 100, Raleigh, N C

27604 requesting, pursuant to section 408 (d) of the Federal Food, Drug, and C osmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 .680 to revise the existing tolerance expression in the introductory paragragh (a) to read "Tolerances are established for residues of the nematicide fluensulfone, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only 3,4,4-trifluoro-but-3-ene-1-sulfonic acid."

Additionally, the petitioner proposed to establish tolerances for the nematicide fluensulfone, includin g its metabolites and d egradates, in or o n the following

commodities: root v eg etables (cr op subgroup 1B excep t su gar beet) excluding oriental

rad ish, at 3.3 parts per million (ppm ) ; leaves of root and tuber vegetables (crop group 2) at 20 ppm; radish, orien tal at 0.50 ppm; leafy ve getables (crop group 4 except b r assica

v eg etables) at 2.6 ppm; head and stem brassica subgroup (crop group 5A) at 1.3 ppm; leafy brassica subgroup (crop group 5B) at 13 ppm; an d low g r o win g b erry subgroup ( crop group 13-07G) at 0.30 ppm. Compliance with the tolerance lev els s p ecif ied b elow is to be determined by m easuring only its metabolite 3,4,4-trifluoro-but- 3- ene-1-sulfonic

acid. EPA has determined that the petiti on contains data or in f o r matio n regarding the

elements set fo rth in section 408 (d)(2) of FDDCA; however, EPA has not f u lly

evaluated the sufficien cy o f the submitted data at th is time or whether the data supports

g ranting of the petition. Ad ditional da ta may be need ed before EPA rules o n the petition.

A. Residue Chemistry

1. Plant metabolism. Fluensulfone is supported by a complete plant metabolism data package based on the proposed uses on fruiting vegetables (crop group 8) and2

cucurbit vegetables (crop group 9). In all plant matrices, whether from a primary or rotational crop, a clear patte rn was observed with TSA (M-3625) and BSA (M-3627) forming the majority of the residues follo wing the cleavage of fluensulfone. Neither compound has acute oral toxicity greater than parent fluensulfone or shows any genotoxic potential in a range of muta genicity studies. In order to harmonize with the CODEX MRLs, the residues definition for tolerances is BSA, while the residues definition for risk

assessment is fluensulfone.

2. Analytical method. Adequate analytical methods for determining fluensulfone in/on appropriate raw agricultural commodities and processed commodities have been developed and validated, includ ing LC-MS/MS methods. The an alytical procedures have been successfully validated in terms of sp ecificity, linearity, precision, accuracy and LOQ.

The MRM study demonstrates that the F DA multiresidue methods (MRMs) are

not suitable for detection and enforcement of fluensulfone resi dues as sulfonic acid metabolites in non-fatty matrices.

3. Magnitude of residues. Fluensulfone is proposed for use on a variety of crop groupings. To support these uses an extensiv e residues package has been generated at

field trial sites in the USA. Fluensulfone and M-3627 (BSA) were sought in all samples. The LOQ is 0.01 mg/kg. EPA removed the flue nsulfone metabolite methyl sulfone (M3626) and thiazole sulfonic acid (TSA, M-3625) from the residue definition therefore these were not included in the residue analysis.

Adequate data are available to propose tole rances (MRLs) and there is no unacceptable risk to consumers from the consumption of crops treated with fo rmulations containing

fluensulfone.

B. Toxicological Profile

1. Acute toxicity. The acute oral LD 50 is 671 mg/kg bw in rats. The acute dermal

LD 50 of fluensulfone is >2000 mg/k g bw. The acute inhalation LD 50 in rats is >5.1 mg/L. Fluensulfone displayed no eye irritation in rabbi ts. Fluensulfone is not irritating to the

skin and is a skin sensitizer.

2. Genotoxicty. A complete data package of in vitro and in vivo mutagenicity

studies is available for flue nsulfone. A full summary of the genotoxicity database is provided in the OECD Dossier. On the ba sis of the robust in vitro and in vivo mutagenicity data, it is concluded that fluensulfone does not possess any genotoxic potential.

3. Reproductive and developmental toxicity. The reproductive toxicity of fluensulfone was evaluated in a 2-genera tion reproduction study in rats. Developmental toxicity was assessed in rats and rabbits.

Reproductive toxicity. A 2-generation re production study in rats was conducted3

at dose levels of 0, 30, 250 and 1800 ppm (2.0, 16.2, and 122.0 mg/kg/day in males and 2.8, 23.0 and 169.1 mg/kg/day in females). Tr eatment with fluensulfone up to and including 1800 ppm, the highe st tested dose level, show ed no effects on reproductive function, including gonadal function, mating beha vior, fertility, viability of offspring, breeding, conception, gestat ion and parturition.

Parental systemic toxicity was evid ent however, with effects on body weight development throughout the study observed at 1800 ppm (the LOAEL); hence the NOAEL was set at 250 ppm (equivalent to a pproximately 16.2 mg/kg/day in males and 23.0 mg/kg /day in females). A NOAEL for ge neral toxicity in F1 and F2 pups was established at 250 ppm, based on redu ced pup weight noted at 1800 ppm.

Developmental toxicity. Flue nsulfone was not teratogenic or fetotoxic either in

rats or rabbits.

A pre-natal developmental study in rats included dose groups of 0, 7.7, 48.6, and 292.0 mg/kg/day. Maternal toxicity, manifest ed as decreased body weight gain and food consumption in rats, resulted in a lower body weight of female pups; the maternal and developmental NOAEL was set at 48.6 mg/kg/day.

A pre-natal developmental study in rabbits included dose groups of 0, 2.5, 10 and 40 mg/kg/day. Similarly, as with the study in rats, treatment of rabbits at 40 mg/kg/day resulted in slight maternal toxicity cons isting of reduction in food consumption at the onset of the treatment and between days 18 and 24, and reduced mean body weight gain at the beginning of the treatment only. As the lower fetal weights recorded at this dose level were within the range of the histori cal control data, the NOAEL for maternal and developmental toxicity was considered to be 40 mg/kg/day, the highest dose tested.

4. Subchronic toxicity. Repeated dose, oral (dieta ry) toxicity studies with fluensulfone are available for rats, mice a nd dogs. The studies c onducted include 28-day and 90-day studies in the rat, mouse, and dog. In addition, a 1-year or al toxicity study in dogs and a 28-day dermal toxicity study in rats were performed.

The rat 28-day study was conducted at dos e levels of 0, 125, 500, and 2000 ppm (0, 10.4, 42.5, and 152 mg/kg/day in males and 0, 12.2, 37.2, and 165.9 mg/kg/day in females). The NOAEL was 125 ppm (10.4 and 12.2 mg/kg day in males and females respectively),

based on results at the LOAEL of functional eff ects in the liver and kidney effects, which were considered adverse as a precaution but likely of no toxicological relevance.

The mouse 28-day study was conducted at dose levels of 0, 100, 500, and 2000 ppm (0, 30.33, 101.31, and 374.5 mg/kg/day in male s and 0, 41.32, 155.12, and 353.0 mg/kg/day in females). The NOAEL was 100 ppm (30.33 and 41.32 mg/kg/day in males and females respectively), based on results at the LOAEL of d ecreased food consumption and liver toxicity (increased relative we ight, histopathological findings).

The dog 28-day study was conducted at dose levels of 0, 50, 200, and 900 ppm (1.9, 7.3, and 30.9 mg/kg/day in males and 2.0, 7.9, a nd 29.7 mg/kg/day in females). The NOAEL4

was 200 ppm (7.3 and 7.9 mg/kg/day in males a nd females respectively), based on results at the LOAEL of slight changes in food consumption, body weight and organ weight (liver and thyroid) and on hepa tic tissue enzyme activities.

The rat subchronic 90-day study was conducte d at dose levels of 0, 60, 120, 500 and 2000 ppm (4.31, 8.26, 34.86, and 139.01 mg/kg/day in males and 4.85, 11.68, 53.10 and 148.73 mg/kg/day in females). The NOAEL was 120 ppm (8.3 and 11.7 mg/kg/day in males and females respectively), based on results at the LOAEL of decreased body weight/body weight gain in males, increased water consumption in males and increased triglycerides in females.

The mouse subchronic 90-day study was c onducted at dose levels of 0, 60, 300, and 1500 ppm (11.06, 50.85, and 228.53 mg/kg/day in males and 18.33, 68.47 and 252.49 mg/kg/day in females). The NOAEL was 60 ppm (11.06 and 18.33 mg/kg/day in males and females, respectively), based on re sults at the LOAEL of decreased food consumption in females and marginal effect s in liver and hematological findings in

males.

The dog subchronic 90-day study was conducte d at dose levels of 0, 5, 50, and 500 ppm (0.2, 1.6 and 17.1 mg/kg/day in males and 0.2, 1.8 and 18.0 mg/kg/day in females). The NOAEL was 500 ppm (17.1 and 18.0 mg/kg/day in males and females, respectively), based on only slight and reversible live r effects at the top dose tested.

The rat 28-day dermal study was conducte d at dose levels of 0, 80, 400, and 2000 mg/kg/day in males and females. Only a minimal increase in the incidence of acanthosis/hyperkeratosis was observed at the limit dose of 2000 mg/kg/day. However, because of the moderate degree recorded in co mparison to the vehicle control, the finding was considered adaptive and likely to be re versible after cessation of treatment and on this basis not adverse. The NOAEL was 2000 mg /kg/day, the highest dose tested, based on no systemic or adverse dermal eff ects at the highest dose level tested.

In all species the live r appears to be the main target organ, although often the observed effects were limited to adaptive changes (e.g. hepatocyte hypertrophy concomitant to increased weight, induction of mainly phase II activities). Investigations on liver enzyme activities in all species revealed that flue nsulfone administration does not result in significant induction of (activat ing) phase I cytochrome P450 subfamilies, but that the (conjugating) phase II enzymes were induced. Frank hepatotoxicity was observed only at very high doses, and only in mice.

The NOAEL for oral subchronic toxicity is 8.3 mg/kg bw/day based on decreased body weights in males (and supported by increased triglycerides in females at the same dietary dose) in the 90 day rat study. The NOAEL for dermal subchronic toxicity is 2000 mg/kg bw/day, based on absence of adverse effects at the highest test dose in the rat 28-day dermal toxicity study.5

5. Chronic toxicity. The long-term toxicity and ca rcinogenicity potential of fluensulfone was evaluated in dogs (one year study), rats (combined study for chronic toxicity and carcinogenicity), and mice (carcinogenicity).

In a 1-year oral toxicity study in dogs, fluensulfone was admini stered in the diet at 0, 5, 50 100 and 500 ppm (0.1, 1.5, 3.1, and 19 mg/ kg/day in males and 0.1, 1.5, 3.3, and 16.2 mg/kg/day in females) to purebred Beagle dogs for a period of 52 weeks with selected animals retained for an 8-week recovery period. The NOAEL was c onsidered to be 100 ppm (3.1 mg/kg bw/day in males and 3.3 mg/ kg bw/day in females), based on decreased body weight and body weight gains, decrease d hemoglobin, MCH, MCHC and increased kidney weights at 500 ppm (16.0 and 16.2 mg/kg/day in males and females respectively)

in the diet.

A combined chronic dietary toxi city and carcinogenicity stu dy in rats was conducted with 0, 30, 200, and 1200 ppm dose groups (1.6, 11 and 66.3 mg/kg/day after 52 weeks and 1.4, 9.6 and 57.7 mg/kg/day after 104 weeks in males; 1.9, 13.1 and 75.2 mg/kg/day after 52 weeks and 1.7, 11.6 and 69.3 mg/kg/day after 104 weeks in females). Fluensulfone showed no carcinogenic potential in this study, and the NOAEL for lifespan treatment (2- years) was set at 30 ppm (1.4 mg/kg/day in males and 1.7 mg/kg/day in females) on the

basis of chronic inters titial inflammation in the lungs of females, decreased body weight and body weight gain in males, and decrea sed hemoglobin concentration and hemoglobin concentration distribution width in females receiving 200 ppm.

A 78-week dietary carcinogenicity study in mice was conducted with 0, 30, 200, and 1200 ppm dose groups (4.2, 27.6 and 152.3 mg/ kg/day in males and 6.4, 39.0, and 188.4 in females). The overall NOEL in mice follo wing lifespan treatment was set at 30 ppm (4.2 and 6.4 mg/kg/day in males and females, respectively). In mice, treatment with

fluensulfone for 78 weeks resulted in an in creased incidence of alveolar/bronchiolar adenomas in females receiving 200 and 1200 ppm . Mechanistic studies were carried out

to determine the relevance for humans of this finding. Tumors were found to be a species-specific effect in mi ce due to activation of flue nsulfone by mouse lung Clara cells, leading to local cytotoxicity, cell pr oliferation and finally formation of benign tumors. Rats have lower metabolic activity in the lungs compared to mice (below the threshold needed to cause lung tumors upon lifetime exposure) and activity in humans is orders of magnitude lower than rats. Fluensulfone was found to be extensively metabolized by mouse lung microsomes, wher eas no metabolic activity was seen in human lung microsomes. In accordance with the International Programme on Chemical Safety (IPCS) mode of action and human re levance framework, it is concluded that fluensulfone leads to specie s-specific tumors via a non- genotoxic threshold mode of action in the mouse lung, and that these tumors are not relevant to human hazard or risk.

The NOAEL for lifespan treatment was set at 1.4 mg/kg/day on the basis of decreased body weight and body weight gain in male s (supported by chr onic interstitial inflammation in the lungs and decreased hemoglobin c oncentration and hemoglobin concentration distribution width in females).6

6. Neurotoxicity. Acute and subchronic specific neurotoxicity studies (i.e. inclusive of neuropathology) were carried out, and functional observation batteries (FOBs) and motor activity assessments were included in the rep eated dose/chronic

studies with fluensulfone. The FOBs and motor activity assessme nts conducted within the repeated dose/chronic toxicity studies revealed no effects.

In an acute oral neurotoxicit y study in rats, groups of 10 ma le and 10 female Wistar rats were administered single oral doses of 0 (control), 100, 400 and 1200 mg/kg bw of fluensulfone by oral gavage and observed fo r 14 days. No test item-related effects on absolute and relative brain weights were ev ident, and there were no findings in the nervous system during macroscopic and mi croscopic pathology examinations. The LOAEL for general toxicity is 100 mg/kg bw in males and females, based on the general systemic toxicity due to the bolus dose. The NOAEL for neurotoxi city is 100 mg/kg bw in males and females, based on reduced activ ity in the functional observation battery and decreased motor activity at 400 mg/kg in abse nce of any neuropathol ogical finding at any

dose level.

In a subchronic dietary neurotoxicit y study, groups of 12 male and 12 female RccHan:WIST (SPF) rats received fluensulfone in their diet at concentrations of 0 (control), 100, 500 and 2500 ppm (0, 6, 31, and 153 mg/kg/day in males and 0, 7, 34, and 162 mg/kg/day in females) for at least 90 days . Treatment-related effects were confined to lower food consumption, body weight and body weight gain in males and females at 2500 ppm. These treatment-related effects were at tributed to systemic toxicity, and not to neurotoxicity. No effects on functional pa rameters or neurohistopathology were observed. Therefore, the high dose level of 2500 ppm was the ‘no-observed-effect level’ (NOEL) for neurotoxicity asso ciated with dietary exposure, equivalent to 153 mg/kg bw/day in males and 162 mg/kg bw/ day in females. The no-observed-adverse-effect level (NOAEL) for systemic toxicity was 500 ppm equivalent to 31 mg/kg bw/day for males and 34 mg/kg bw/day for females.

As developmental studies did not indicate that the offspring are more sensitive than the adult, and neuropathological effects were not observed in any of the performed neurotoxicity studies, a developmental neurot oxicity study was considered not necessary.

7. Immunotoxicity

. Although immunotoxicity endpoint s were already included in the 28-day dietary study in rats and mice, flue nsulfone was tested also in mice in the 28- day sheep red blood cell assay, to evaluate its immunotoxicity potential. In addition, the

entire available data set was examined to check immunotoxicity-related endpoints. It is

concluded that fluensulfone is not an immunotoxic substance.

8. Animal metabolism. Fluensulfone (labeled at the thiazole and the butenemoieties of the molecule) administered orally to rats at nominal sing le doses of either 5 mg/kg or 500 mg/kg is rapidly metabolized. The recovery of radioac tivity was essentially complete for all groups of rats. The dispositi on and excretion of radi olabel for males and females were generally similar. There was no indication that the metabolic elimination processes were saturated by the 100-fold increase in dose level, as leve ls of radiolabel in7

urine, cage wash, feces, carcass, and gastro -intestinal (GI tract) were similar.

Urine was the major route of excretion and the only source of metabolites at ≥ 5% of the applied radiolabel. The cage wash containe d relatively high levels of radiolabeled metabolites and analysis showed that those metabolites in cage wash and urine were

similar. Low amounts of thiazole sulfonic acid were found in feces, but no other fecal

metabolites were ≥ 5% of the applied dose. Fluensulf one is not a significant residue in

either urine or feces.

In addition to investigating metabolism afte r a single dose, the tissue distribution was studied when the dosing of radioactivity was preceded by 14 days administration of

unlabelled material. The results indicate thatdistribution is comparable in both cases.

7. Metabolite toxicology

. The acute oral LD 50 of fluensulfone metabolite M-3625 was greater than 2000 mg/kg(less than that of the parent fluensulfone).

Metabolite M-3625 was tested fo r its genotoxic potential in a bacterial reverse gene mutation assay, an in vitro chromosome aberration assay in mammalian cells, and an in

vivo micronucleus assay in the bone marrow of rat. No genotoxic properties were

identified.

The acute oral LD 50 of fluensulfone metabolite M-3627 (BSA) was greater than 2000 mg/kg bw (less than that of the parent fluensulfone).

Metabolite M-3627 was tested fo r its genotoxic potential in a bacterial reverse gene mutation assay, an in vitro chromosome aberration assay in mammalian cells, and an in

vivo micronucleus assay in the bone marrow of rat. No genotoxic properties were

identified.

8. Endocrine disruption

. Evidence from the large available toxicological data set

demonstrates that fluensulfone does not exert any adverse effects on thyroid gland, reproductive system and related endocrine organs and adrenal glands. Therefore, it is concluded that fluensulfone does not po ssess any endocrine disrupting potential.

C. Aggregate Exposure

1. Dietary exposure. Acute and chronic dietary (f ood + water) exposures to fluensulfone have been estimated for the pr oposed new uses as well as existing uses. The recent drinking water modeling conducted by EP A (2014) is still relevant and results were incorporated into the assessment. In the case of meat and milk commodities, while there are feed items (carrots and radish) in the new uses, no meat a nd milk tolerances are proposed. Based on livestock metabolism st udies, no residues of concern (parent fluensulfone) are expected in milk or any an imal tissue. A Tier 1 acute dietary exposure assessment was conducted assuming toleranc e-level residues, 100% crop treated and default processing factors. Exposure wa s assessed using the acute and chronic toxicological endpoints determined by EP A (2014), which are an aPAD of 0.16 mg/kg bw/day derived from a NOAEL of 16.2 mg/kg bw/day from a 2-generation reproduction8

rat study and a cPAD of 0.03 mg/kg bw/day de rived from a NOAEL of 3.1 mg/kg bw/day from co-critical 90-day dog and chronic dog stud ies. EPA has determined that the level of

concern for fluensulfone for acute an d chronic exposures is 100 (EPA, 2014).

Acute Dietary Exposure. Acute dietary (food + water) exposures to fluensulfone, which were calculated using DEEM- FCID version 4.02, are summarized in Table 6 below. The reported exposures correspond to the 95th percentile of the exposure distributions, as is appropriat e for a Tier 1 acute dietary e xposure assessment. As shown in Table 6 below, 95th percentile acute di etary (food + water) expos ures are well below the aPAD (0.16 mg/kg/d). For all infants, the most highly expos ed subpopulation, 95th percentile acute dietary exposur es correspond to 9.13% of the aPAD. For the general U.S. Population, 95th percentile acute dietary e xposures correspond to 2.79% of the aPAD. Acute dietary exposures below 100% of the aPAD are reasonably anticipated to result in no harm to exposed populations.

Chronic Dietary Exposure

. Chronic dietary exposures to fluensulfone, which were calculated using DEEM-FCID version 4.02 , are summarized below. As shown in Table 7 below, chronic dietary exposures are less than the cPAD (0.03 mg/kg/d). For infants, the most highly exposed subpopulati on, chronic dietary exposures correspond to 15.1% of the cPAD. For the general U.S. Population, chronic dietary exposures correspond to 4.0% of the cPAD. Chronic di etary exposures belo w 100% of the cPAD are reasonably anticipated to result in no harm to exposed populations.

i. Food. Exposure to fluensulfone through food is included in the dietary

assessment section above.

ii. Drinking water. Exposure to fluensulfone thro ugh water is included in the dietary assessment section above.

2. Non-dietary exposure

. Fluensulfone is currently not registered for use on any

residential non-food site. Ther efore, residential exposure to fluensulfone residues will be through dietary exposure only.

D. Cumulative Effects

Fluensulfone is a member of a new chemi cal class of nematici des with a specific toxicological profile. It does not share a known toxicological mode of action with other pesticides. Thus, no cumulative effects are foreseen.

E. Safety Determination

1. U.S. population. Using the conservative exposure assumptions described above and based on the completeness of the toxicity data, it can be concluded that total food9

and drinking water exposure to fluensulf one from all proposed crop uses will be

2.79% of the aPAD and 4.0% of the cPAD for the overall US population.

2. Infants and children

. Using the conservative exposur e assumptions described above and based on the completeness of the toxicity da ta, it can be concluded that the total acute food and drinking water exposure to fluensulfone from all proposed crop uses will be 9.13% (all infants), 4.21% (children 1-2 yrs) , 3.53% (children 3-5 yrs), and 2.46% (6-12 yrs) of the aPAD. It can be concluded th at the total chronic food and drinking water exposure to fluensulfone from all proposed crop uses will be 15.1% (all infants), 6.2% (children 1-2 yrs), 4.9% (children 3-5 yrs), and 3.5% (children 6-12 yrs) of the cPAD.

F. International Tolerances

No Codex Maximum Residue Levels (MRLs) have been established for residues of fluensulfone on any crops. There are no es tablished tolerances for fluensulfone on any crops in Canada and Mexico, however, this su bmission is part of a Global Joint Review application involving Canada and the United States.