EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: Tony Kish, PM Team 22, (703) 308

- 9443

Syngenta Crop Protection, LLC, PO Box 18300, Greensboro, NC 27419

P esticide Petition: PP# 5F8368

EPA has received a pesticide petition ( PP# 5F8368 ) from Syngenta Crop Protection, LLC, PO Box 18300, Greensboro, NC 27419 request ing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 .242 by establishing a tolerance for residues of Thiabendazole in or on the raw agricultural commodit ies Pea, field, hay at 0.15 parts per million (ppm) ; P ea, field, vine s at 0.03 parts per million (ppm) ; Vegetable, foliage of legume, group 7, except pea , field, hay and vines at 0.01 parts per million (ppm) ; and Vegetable , legume,

g roup 6 at 0.01 parts per million (ppm). Concurrently, Syngenta Crop Protection, LLC requests to amend the tolerances in 40 CFR 180.242 by removin g tolerances in or on Bean, dry, seed at 0.1 ppm; and Soybean at 0.1 ppm upon approval of the tolerance s listed above.

EPA has determined that the petition contains data or information regarding the elements

set forth in section 408 (d)(2) of FDDCA; howe ver, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data supports granting of the petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

1. Plant metabolism. The qual itative nature of the residues in plants is adequately understood based on soybean, sugar beet, and wheat metabolism studies. The residues of concern in plants include thiabendazole and benzimidazole, free and conjugated.

2. Analytical method. Adequate a nalytical methodology is available for data collection enforcement of thiabendazole residues. The Pesticide Analytical Manual (PAM) Vol. II lists four spectrophotofluorometric methods (Methods I, A, B and C) for
determi ning residues of thiabendazole per s e in or on plant commodities, and one spectrophotofluorometric method (Method D) for determining residues of thiabendazole
and 5

- hydroxy thiabendazole in milk

.

3. Magnitude of residues. Syngenta Crop Protection, LLC has submitted complete
residue data for Thiabendazole on beans and peas (as representative crops in suppor t of Pea, field, hay ; Pea, field, vines; Vegetable, foliage of legume, group 7, except pea, field, hay and vines; and Vegetable, legume, group 6)

.2

B. Toxicological Profile

1. Acute toxic ity. Thiabendazole has very low acute toxicity via oral and dermal (Category IV). For acute inhalation, Thiabendazole is classified under Category III

. Thiabendazole is minimally irritating to the eye (Category III) and not irritating to skin (Category IV)

. It is not a dermal sensitizer.

2. Genotoxic i ty. The available genetic toxicology studies on thiabendazole indicate that the compound is not mutagenic in bacteria or clastogenic in vitro in
mammalian cells. Thiabendazole did not cause DNA strand breaks in cultured rat hepatocytes and was negative for structural chromosome aberrations in rats.

3. Reproductive and developmental toxicity. In the rat development study, the observed maternal and developmental LOAEL/NOAEL of 40/10 mg/kg/day was based
on decr ease in bod y weight and food consumption.

In the mouse prenatal development toxicity study, there were reductions in maternal body weight at mid (100 mg//kg/day) and high dose (299 mg/kg/day) treatment groups. There were accompanying reductions in feed co nsumption in the HDT group. The mouse maternal and developmental LOAEL/NOEAL were 1 00/25 mg/kg/day, respectively.

In a rabbit developmental study, decreased maternal body weight gains and decreased food consumption were seen at HDT (600 mg/kg/day). There was also decreased fetal body weight and increased resorptions at 600 mg/kg. The rabbit maternal and developmental LOAEL/NOAEL were 600/150 mg/kg, respectively.

In a 2

- generation reproduction study in the rat, the parental systemic LOAEL was based
on decr eased body weight gain and food consumption seen at 30 mg/kg. The NOEAL was 10 mg/kg. The offspring LOAEL was based on decreased body weight gain in offspring during lactation seen at 30 mg/kg. The reproductive LOAEL was >90 mg/kg. The effects in the offsp ring were observed at higher dosages (90 mg/kg) than dosages (30 mg/kg) causing parental toxicity. Therefore, there was no increased susceptibility.

4. Subchronic toxicity. In a 21 day dermal toxicity study in the rabbit,
thiabendazole was administered d ermally to rabbits. No systemic or dermal toxicities were noted at doses up to 1000 mg/k g/day. The systemic and dermal NOEL w as 1000 mg/kg.

In a subchronic toxicity study, thiabendazole was ad ministered to rats in the diet. The NOEL of 10 mg/kg was based on reduced body weight gains and histopathological changes in the b one marrow, liver and thyroid.

In another subchronic toxicity study, thiabendazole was administered to rats by gavage at doses of 0, 25, 100, or 400 mg/kg/day for 14 weeks. The LOAEL for t his study was 100 mg/kg/day. The NOEL of 25 mg/kg was based on histopathological changes of the liver, thyroid, kidney s, and spleen.3

In a subchronic toxicity study in dogs, thiabendazole was administered orally in capsules to four beagle dogs at dose leve ls of 0, 35, 75, or 150 mg/kg/day for 14 weeks. The
NOEL was 150 mg/kg based on the increase of gallbladder epithelial cytoplasmic
vacuolation.

5. Chronic toxicity. In a chronic toxicity study, thiabendazole was administered orally in capsules to four be agle dogs at dose levels of 0, 10, 40, or 160 mg/kg/day for 52 weeks. The LOAEL for this study was 40 mg/kg based on increased liver weight, splenic erythropoiesis and hemosiderosis in both sexes. The LOAEL was 10 mg/kg.

In a chronic toxicity and carcinog enicity study, thiabendazole was administered to rats in the diet at dose levels of 0, 10, 30, or 90 mg/kg/day for104 weeks. The systemic LOAEL was 30 mg/kg based on increase in incidence of benign thyroid follicular cell adenoma. The NOAEL was 10 mg/kg.

In a carcinogenicity study, thiabendazole was administered to 50 mice for 105 weeks. There was an increase in mortality in all dose groups. Body weight gains were significantly lower in high dose female and male. However, no treatment

- related increase
in t umor incidence above background level was observed.

6. Animal metabolism. The rat, goat and hen metabolism studies indicate that the qualitative nature of the residues in animals is adequately understood. The residue of concern in eggs, milk, and poultry and livestock tissue is thiabendazole and 5

- hydroxy

thiabendazole (free and conjugated) and benzimidazole (free and conjugated)

.

In a rat metabolism study, radio

- labeled thiabendazole was administered to rats by gavage. Thiabendazole was readily absorbed by male and female rats following oral dosing. Within 168 hours of dosing, over 89% of the dose was excreted in urine and feces. The majority of the administered dose was recovered in the urine identified as the glucuronide conjugate of 5

- hydroxythiabenda zole and the sulfate conjugate of 5

- hydroxy thiabendazole. The data indicate that the renal excretion is the primary pathway for the elimination of thiabendazole from rats. At the low dose level, it was shown that
thiabendazole oxidizes to form 5

- hydroxyth iabendazole, followed by conjugation to form glucuronide and su l fate conjugates of 5

- hydroxythiabendazole.

7. Metabolite toxicology

. The nature of residues in plants and animals is adequately understood. Residues of concern in plants include thiabendazol e and its
metabolite benzi midazole, free and conjugated. T he residue s of concern in animal
commodities are thiabendazole and 5

- hydroxy

- thiabendazole (free and conjugated) and
benzimidazole (free and conjugated) . No additional toxicologically significant

me tabolites were detected in any of the plant or animal metabolism studies.

8. Endocrine disruption

. Thiabendazole does not belong to a class of chemicals known or suspected of having adverse effects on the endocrine system. Developmental toxicity studies in rats and rabbits and a reproduction study in rats gave no indication that4

thiabendazole might have any effects on endocrine function related to development and reproduction.

C. Aggregate Exposure

1. Dietary exposure. Tier III chronic aggregate risk a ssessments were completed for thiabendazole using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM

- FCID TM , version 4.02 ). DEEM

- FCID software incorporates food consumption data from the National Health and Nutritio n Examination Survey)/“What We Eat in America” (NHANES/WWEIA) dietary survey conducted in
200 5

- 2 0 10

. These exposure assessments included all registered uses as well as proposed uses on succulent and dry beans and peas and the foliage of beans and peas (Cro p Groups 6A, 6B, 6C, and 7). USDA

- PDP monitoring data were used for apple juice, apple sauce, apples, banana, cantaloupe, carrot, mango, mushrooms, orange juice, oranges, papaya, pears (baby food), potato, strawberry, and sweet potato in the refined probab ilistic acute dietary assessments; field trial residue data were used for all remaining commodities. Existing or proposed tolerances were used in the unrefined chronic dietary assessments.
Conversion factors for the thiabendazole metabolite benzimidazole w ere taken from EPA’s March 10, 2014 dietary exposure assessments (DP D416470). Maximum reasonably balanced diets were used with livestock transfer factors to predict residues in meat and milk commodities; poultry and egg commodities were not included in th ese assessments per current EPA practice. DEEMTM (version 7.87) default processing factors were used for all commodities. Percent crop treated (%CT) values were taken from EPA’s March 10, 2014 dietary exposure assessments for thiabendazole (DP D416470).
Dri nking water estimates were selected using the higher of the estimated drinking water concentrations (EDWCs) for surface and ground water.

i. Food. Acute Risk. The acute dietary risk assessment was performed for all population subgroups with an acute refe rence dose of 0.0 5 mg/kg

- bw/day based upon an acute neurotoxicity study in rats with a NOAEL of 50 mg/kg

- bw/day and a combined uncertainly factor of 1000X; the 1000

- fold safety factor includes intra

- (10X) and interspecies (10X) variations. An additional 1 0X uncertainly factor was applied due to
lack of a developmental thyroid study. For the purpose of aggregate risk assessment, the exposure values were expressed in terms of margin of exposure (MOE), which was calculated by dividing the NOAEL by the exposur e for each population subgroup. In addition, exposure was expressed as a percent of the reference dose (%RfD). Acute dietary exposure to the U.S. population resulted in a MOE of 3,621 (27.6% of t he aRfD of 0.05 mg/kg

- bw/day). Acute exposure to the most exp osed subpopulation (children 1 to 2 years old) resulted in a MOE of 1,391 (71.9% of t he aRfD of 0.05 mg/kg

- bw/day). Since the Benchmark MOE for this assessment is 1000 and since EPA generally has no concern for exposures above the Benchmark MOE or below 10 0% of the reference dose, Syngenta believes that there is a reasonable certainty that no harm will result from acute dietary (food only) exposure to residues arising from all current and proposed uses of
thiabendazole.

Chronic Risk. The chronic dietary ri sk assessment was performed for all population5

subgroups with a chronic reference dose of 0.033 mg/kg

- bw/day based on a 2 year chronic/carcinogenicity study in rats with a NOAEL of 10 mg/kg

- bw/day and an uncertainly factor of 300X. The 30

- fold safety facto r includes intra

- (3X) and interspecies (10X) variations; an additional 10X uncertainly factor was applied due to lack of a comparative thyroid study. For the purpose of aggregate risk assessment, the exposure values were expressed in terms of margin of ex posure (MOE), which was calculated by dividing the NOAEL by the exposure for each population subgroup. In addition, exposure was expressed as a percent of the reference dose (%RfD). Chronic dietary exposure to the U.S. population resulted in a MOE of 22,57 0 (1.3% of the cRfD of 0.033 mg/kg

- bw/day). Chronic exposure to the most exposed sub

- population (children 1 to 2 years old) resulted in a MOE of 5,561 (5.4% of the cRfD of 0.033 mg/kg

- bw/day). Since the Benchmark
MOE for this assessment is 300 and since EP A generally has no concern for exposures above the Benchmark MOE or below 100% of the reference dose, Syngenta believes that there is a reasonable certainty that no harm will result from chronic dietary (food only) exposure to residues arising from all cur rent and proposed uses of thiabendazole.

Cancer Risk. Thiabendazole has been classified as, “Likely to be carcinogenic at doses high enough to cause a disturbance of the thyroid hormonal balance but not likely to be carcinogenic at doses lower that those which could cause a disturbance of this hormonal balance. Quantification of cancer risk is not required.”

ii. Drinking water

. The Estimated Drinking Water Concentrations (EDWCs) of thiabendazole were determined using Tier l models SCI

- GROW and PRZM

- GW wh ich estimate pesticide concentration in grou nd water and Tier I model FIRST which estimates pesticide concentration in surface water. EDWCs of thiabendazole from currently registered uses plus the proposed seed treatment uses on succulent and dry beans and peas and the foliage of beans and peas (Crop Groups 6A, 6B, 6C, and 7) were determined. For groundwater, the PRZM

- GW model provided acute EDWC of 0.536 ppb
and SCI

- GROW model provided chronic EDWC of 0.061 ppb based on the current seed
treatment use on whe at. For surface water, FIRST provided acute and chronic EDWCs of 3.128 ppb and 0.384 ppb, respectively, based on the current seed treatment use on wheat (Percent Cropped Area (PCA) of 1 was used). The surface water acute and chronic
EDWCs were used for ris k assessment purposes.

Acute Exposure from Drinking Water. The acute surface water EDWC of 3.128 ppb was input directly into the DEEM

- FCIDTM software as “water, direct and indirect, all sources” to model the acute drinking water exposures. Acute drinking w ater exposure to the U.S. population resulted in a MOE of 568,182 (0.2% of the aRfD of 0.05 mg/kg

- bw/day). Acute drinking water exposure to the most exposed sub

- population (children 1

- 2 years old) resulted in a MOE of 253,807 (0.4% of the aRfD of 0.05 mg/k g

- bw/day). Since the Benchmark MOE for this assessment was 1000 and since EPA generally has no concern for exposures above the benchmark or below 100% of the reference dose, Syngenta believes that there is a reasonable certainty that no harm will result fr om acute drinking water exposure to residues arising from all current and proposed uses of thiabendazole.

Chronic Exposure from Drinking Water

. The chronic surface water EDWC of 0.384 ppb6

was input directly into the DEEM

- FCIDTM software as “water, direct a nd indirect, all sources” to model the chronic drinking water exposures. Chronic drinking water exposure to the U.S. population resulted in a MOE of >1,000,000 (<0.1% of the cRfD of 0.033 mg/kg

- bw/day). Chronic drinking water exposure to the most exposed s ub

- population (all infants, <1 year old) resulted in a MOE of 348,683 (0.1% of the cRfD of 0.033 mg/kg

bw/day). Since the Benchmark MOE for this assessment was 300 and since EPA generally has no concern for exposures above the benchmark or below 100% of th e reference dose, Syngenta believes that there is a reasonable certainty that no harm will result from chronic drinking water exposure to residues arising from all current and proposed uses of thiabendazole.

2. Non

- dietary exposure

. There are currently n o registered uses for thiabendazole registered by Syngenta that would result in residential handler (mixer/loader/applicator) or post

- application exposure. Also, there are currently no registered agricultural uses that
would result in off

- site drift. Risk assessments for thiabendazole as a paint additive were not assessed as these uses are no longer owned by Syngenta and use rates can no longer
be verified.

D. Cumulative Effects

Cumulative Exposure to Substances with a Common Mechanism of Toxicity.
Sect ion 408(b)(2)(D)(v) requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency consider available information concerning the cumulative effects of a particular pesticide’s residues and “other substances that have a comm on mechanism of toxicity”. Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to thiabendazole and any other substances
and thiab endazole does not appear to produce a toxic metabolite produced by other substances. Therefore, for the purposes of this tolerance action, EPA has not yet assumed that thiabendazole has a common mechanism of toxicity with other substances.

E. Safety Deter

mination

1. U.S. population. Using the conservative assumptions described above, and based on the completeness and reliability of the toxicity data, the acute aggregate (food plus water) exposure calculation for current and proposed uses of thiabendazole resulted in a MOE of 3,598 (27.8% of the aRfD of 0.05 mg/kg

- bw/day) for the U.S. population. The chronic aggregate (food plus water) exposure calculation for current and proposed uses of thiabendazole resulted in a MOE of 22,519 (1.3% of the cRfD of 0.033 mg/kg

bw/day) for the U.S. population. Since the acute aggregate MOE of 3,598 exceeds the acute aggregate Benchmark MOE of 1000, Syngenta believes that there is a reasonable certainty that no harm will occur to the U.S. population from acute and chronic a ggregate exposures arising from all current and proposed uses of thiabendazole.

2. Infants and children

. Using the conservative assumptions described in the exposure section above, and based on the completeness and reliability of the toxicity7

data, the a cute aggregate (food plus water) exposure calculation for current and proposed uses of thiabendazole resulted in a MOE of 1,384 (72.2% of the aRfD of 0.05 mg/kg

bw/day) for children 1

- 2 years old (the most sensitive population subgroup). The chronic

aggreg ate (food plus water) exposure calculation for current and proposed uses of thiabendazole resulted in a MOE of 5,529 (5.4% of the cRfD of 0.033 mg/kg

- bw/day) for
children 1

- 2 years old (the most sensitive population subgroup). Since the acute aggregate MOE of 1,384 exceeds the acute aggregate Benchmark MOE of 1000, Syngenta believes that there is a reasonable certainty that no harm will occur to infants or children from acute and chronic aggregate exposures arising from all current and proposed uses of thia bendazole.

F. International Tolerances

The Codex Alimentarius Commission has established maximum residue limits (MRLs) for thiabendazole in or on commodities including avocado, banana, cattle kidney, cattle liver, cattle meat, cattle milk, citrus fruits , eggs, mango, mushrooms, papaya, pome fruits, potato, poultry meat, and witloof chicory (sprouts). Codex MRLs for thiabendazole are currently expressed in terms of the parent for plant commodities and in
terms of the sum of parent and 5

- hydroxy thiabendazo le and its sulfate conjugate for
animal commodities. The tolerance expressions for U.S. tolerances inc lude residues of benzimidazole; as such, the U.S. tolerance definition is not compatible with Codex MRLs for plant commodities.