Document ID: EPA-HQ-OPP-2014-0922-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2015-04-06T04:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER  

EPA Registration Division contact: Susan Lewis; (703)305-7090

Inter-Regional Research Project Number 4 (IR-4 Project)

Petition 4E8335

	EPA has received a pesticide petition (4E8335) from Inter-Regional Research Project Number 4 (IR-4 Project), Rutgers, The State University of New Jersey, 500 College Road East, Suite 201 W, Princeton, NJ 08540, proposing, 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 180.567 by establishing tolerances for residues of the sum of zoxamide (3, 5-dichloro-N-(3-chloro-1-ethyl-1-methyl-2-oxopropyl)-4-methylbenzamide) and its metabolites 3,5-dichloro-1,4-benzenedicarboxylic acid (RH-1455 and RH-141455) and 3,5-dichloro-4-hydroxymethylbenzoic acid (RH-1452 and RH-141452) calculated as the stoichiometric equivalent of zoxamide in or on the raw agricultural commodity ginseng at 0.30 parts per million (ppm) and vegetable, tuberous and corm, subgroup 1C at 0.060 ppm. Further amendment to 40 CFR part 180.567 is requested, to establish tolerances for residues, determined by measuring only zoxamide (3,5-dichloro-N-(3-chloro-1-ethyl-1-methyl-2-oxypropyl)-4-methylbenzamide, in or on raw agricultural commodity tomato subgroup 8-10A at 2.0 ppm and fruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13-07F at 5.0 ppm.

	IR-4 also proposes, upon the approval of the aforementioned tolerances, to remove established tolerances for grape at 3.0 ppm; tomato at 2.0 ppm; and potato at 0.060 ppm.

EPA has determined that the petition contains data or information regarding the elements set forth in section 408 (d)(2) of  FDDCA; however, 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. A plant metabolism study was not conducted on ginseng; a metabolism study performed on potatoes, which analyzed for zoxamide and its metabolites, is referenced due to the nature of the crops. The metabolism of zoxamide and its metabolites was also investigated for grapes and tomatoes.
        
	2. Analytical method. Adequate enforcement methodology is available to enforce the tolerance expression.  A tolerance enforcement analytical method for the analysis of zoxamide and its metabolites, RH-1452 and RH-1455, in/on ginseng was developed by the Analytical Chemistry Branch (ACB).

	3. Magnitude of residues. No residue data will be provided for ginseng.  The translation of potato granules/flakes tolerance of 0.30 ppm to ginseng will occur based on the following: potato is the representative commodity for crop group 1, similarity of the nature of the crops and use patterns, and low consumption of ginseng.  Furthermore, residues in ginseng are expected to be lower than the residues in potatoes since ginseng has a higher PHI and lower moisture content.

B. Toxicological Profile

      1. Acute toxicity.  Acute studies have been evaluated by the Agency and considered valid and complete.  The acute oral study (MRID No. 44731806) in both rat and mouse produced an LD50 of >5,000 m/kg (males and females combined).  A dermal study (MRID No. 44731807) in rats resulted in a toxicity category III with an LD50 > 2,000 mg/kg (males and females combined) while an inhalation study produced an LC50 > 5.3 mg/L (MRID No. 44731808).  A primary eye irritation study was performed on rabbits and resulted as a moderate irritant (MRID No. 44731809); a primary skin irritation study proved not to be an irritant (MRID No. 44731809).  Two sensitization studies conducted using both maximization and Buehler methods were performed according to guideline 870.2600.  The maximization test proved to be a skin sensitizer (MRID No. 44731811); Buehler method on guinea pigs also produced delayed hypersensitivity at all concentrations tested (MRID No.  44731812).
      Acute dietary risk assessments were not performed as no acute dietary endpoint was identified; no effects were observed in oral toxicity studies that could be attributable to a single dose.

	2. Genotoxicty. Zoxamide is not mutagenic in Ames assays, in Chinese Hamster Ovary (CHO) cells assay at the Hypoxonthine guanine phosphoribosyle transferase (HGPRT) locus, and in the mouse bone marrow micronucleus assay. Zoxamide did not induce structural chromosome aberrations in cultured CHO cells treated up to the limit of toxicity but did induce increased levels of numerical aberrations.

	3. Reproductive and developmental toxicity. A two year generation reproductive toxicity study on rats indicated that continuous exposure of rats to zoxamide technical in the diet had a No Observed Adverse Effect Level (NOAEL) for parental animal toxicity of 5,000 ppm.  The only effect seen at 20,000 ppm  was a decrease in body weight gain and feed consumption.  No adverse reproductive or developmental effects were seen at doses up to and including 20,000 ppm 
	Two developmental studies have been performed on rats and rabbits using an oral gavage method.  When zoxamide technical was administered to pregnant rats, the No Observed Effect Level (NOEL) of 1000 mg A.I./kg/day (limit dose) was achieved.  Zoxamide is not maternally toxic, embryo-feto toxic or teratogenic at doses up to and including 1,000 mg A.I./kg/day (limit dose).  When administered orally by gavage to pregnant rabbits, the NOEL for maternal toxicity was observed to be greater than or equal to 1,000 mg AI/kg.  There were no developmental toxicity or teratogenicity observed at any dose level.

	4. Subchronic toxicity. The NOAEL in a 90-day rat subchronic feeding and neurotoxicity study was 1,500 mg/kg/day in males and 1,622 mg/kg/day in females HDT.  Zoxamide did not produce neurotoxic or neuropathologic effects.
    A 90-day feeding study with mice, the NOAEL was 436 mg/kg/day in males and 574 mg/kg/day in females based on a slight decrease in weight gain among the females only at the LOAEL of 1,666 mg/kg/day.
    A 90-day dog feeding study gave a NOAEL of 55 mg/kg in males and 62 mg/kg/day in females based on increased liver weights without a corresponding clinical or histopathologic change in females only at 322 mg/kg/day.
    No signs of systemic toxicity were observed when zoxamide was administered dermally to rats for 28-30 days at a limit dose of 1,000 mg/kg/day).  This occurred despite skin irritation at all doses tested (150, 400, and 1,000 mg/kg/day).  Similarly, in vivo dermal absorption was shown to be low regardless of concentration or formulation type (i.e., 1-6% of the administered dose was systemically absorbed after 24 hrs.)

	5. Chronic toxicity. In a combined rat chronic/oncogenicity study, the NOAEL for chronic toxicity was 51 mg/kg/day in males and 65 mg/kg/day in females based on an equivocal increase in relative liver weight at a LOAEL of 328 mg/kg/day in females at the interim sacrifice only.  The NOAEL was considered to be 1,058 mg/kg/day in males and 1331 mg/kg/day in females (HDT, limit dose).  No carcinogenicity was observed.
    An 18-month mouse oncogenicity study (MRID No. 44731819) showed no signs of carcinogenicity or of any other compound-related effect at dosage levels up to 1021 mg/kg/day in males and 1,289 mg/kg/day in females (limit dose).
    The NOAEL in a 1-year feeding study in dogs was 255 mg/kg/day in males and 48 mg/kg/day in females based on minimal effects on body weight and body weight gain and increased liver weights in females only at a LOAEL of 278 mg/kg/day (MRID No. 44731817).

	6. Animal metabolism. In pharmacokinetic and metabolism studies in the rat, zoxamide was extensively absorbed following oral dosing, rapidly and extensively metabolized to a large number of metabolites, and rapidly eliminated from the body.  No evidence of accumulation of the parent compound or its metabolites was observed).

	7. Metabolite toxicology. The tolerances requested for ginseng are for the sum of zoxamide (3, 5-dichloro-N-(3-chloro-1-ethyl-1-methyl-2-oxopropyl)-4-methylbenzamide) and its metabolites 3,5-dichloro-1,4-benzenedicarboxylic acid (RH-1455 and RH-141455) and 3,5-dichloro-4-hydroxymethylbenzoic acid (RH-1452 and RH-141452) calculated as the stoichiometric equivalent of zoxamide.
	Neither metabolite RH-141455 nor metabolite RH-141452 (MRID No. 44731835) is mutagenic in a Salmonella gene mutation assay.

	8. Endocrine disruption. Zoxamide is listed in the November 2012 U.S. Environmental Protection Agency Endocrine Disruptor Screening Program Universe of Chemicals.
      Zoxamide is unlikely to exhibit endocrine activity based on structure-activity and mode of action information as well as the lack of developmental and reproductive toxicity,  There was no evidence of a functional or histopathologic change in the male or female reproductive tract, and no indicators of an endocrine effect of any kind below limit doses in mammalian subchronic or chronic studies or in mammalian and avian reproduction studies.  A slight thyroid effect at the limit dose (994-1139 mg/kg/day) in the subchronic and chronic dog studies was secondary to liver hypertrophy and enlargement at that dose.  Collectively, the weight of evidence provides no indication of an endocrine effect of zoxamide.

C. Aggregate Exposure

	1. Dietary exposure. Tolerances are established for residues of the fungicide zoxamide (3, 5-dichloro- N -(3-chloro-1-ethyl-1-methyl-2-oxopropyl)-4-methylbenzamide),  in or on grape (3.0 ppm), grape, raisin (15.0 ppm), tomato (2.0 ppm), and vegetable cucurbit, group 9 (1.0 ppm).  Tolerances are also established for the combined residues of zoxamide and its metabolites 3,5-dichloro-1,4-benzenedicarboxylic acid (RH-1455 and RH-141455) and 3,5-dichloro-4-hydroxymethylbenzoic acid (RH-1452 and RH-141452) in or on potatoes (0.060 ppm), potato granules/flakes (0.30 ppm), and wet peel potatoes (0.10 ppm).  
      IR-4 Project seeks to establish a tolerance for the sum of zoxamide and its metabolites (RH-1455 and RH-141455; RH-1452 and 141452) calculated as the stoichiometric equivalent of zoxamide in or on ginseng at 0.30 ppm.  No residue trials were conducted.  
      Current mancozeb tolerances published in 40 CFR §180.176 support ginseng uses.

	i. Food. A Tier I DEEM-FCID (Dietary Exposure Evaluation Model  -  Food Commodity Intake Database) Chronic analysis (Version 3.16) for zoxamide was completed for purposes of assessing the potential aggregate exposure from food under existing and proposed tolerances for zoxamide.  The model was performed assuming 100% crop treated.
      A chronic dog NOEL of 48 mg/kg bw/day determined for zoxamide in a 1-year toxicity study in dogs was used for the DEEM.

	ii. Drinking water. PRZM/EXAMS and SCI-GROW models illustrate that the EECs of zoxamide for chronic exposures are estimated to be 21.8 parts per billion (ppb) for surface water and 2.1 ppb for ground water.

	2. Non-dietary exposure. Zoxamide is not registered for residential uses; therefore, residential exposure is not expected.

D. Cumulative Effects

	EPA does not have available data to determine whether zoxamide has a common mechanism of toxicity with other substances or how to include this pesticide in a cumulative risk assessment.  Zoxamide does not appear to produce a toxic metabolite produced by other substances.  For the purposes of this tolerance action, therefore, EPA has not assumed that zoxamide has a common mechanism of toxicity with other substances.

E. Safety Determination

	1. U.S. population. Chronic dietary exposure to zoxamide from food (including ginseng) utilizes 1.4% of the cPAD (0.48 mg/kg/day) for the total U.S. population. The chronic (non-cancer) exposure to zoxamide is 0.48 mg/kg/day.

	2. Infants and children. Chronic dietary exposure to zoxamide from food (including ginseng) utilizes 10% of the Chronic Population Adjusted Dose (cPAD) for infants and children ages 1-12 years of age.
F. International Tolerances

	Neither Codex Alimentarius, Canada nor Mexico have established Maximum Residue Levels (MRLs) for zoxamide on ginseng.  Therefore, no compatibility issues exist with regard to the proposed U.S. ginseng tolerance.