Document ID: EPA-HQ-OPP-2015-0390-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2015-08-28T04:00Z

EPA REGISTRATION DIVISION - COMPANY NOTICE OF FILING FOR PESTICIDE PETITION 

EPA Registration Division (RD) Contact: Susan Lewis, Director, RD (703) 305-7090 

Docket I.D. Number: EPA-HQ-OPP-2015-0390

Interregional Research Project Number 4 (IR-4)

Pesticide Petition Number: PP# 5E8363 

EPA has received a pesticide petition (5E8363) from Interregional Research Project Number 4 (IR-4), IR-4 Project Headquarters, Rutgers, The State University of New Jersey, 500 College Road East, Suite 201 W, Princeton, NJ   08540 in cooperation with Gowan Company requesting, 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 by establishing a tolerance for residues of the insecticide pyridaben [2-tert-butyl-5-(4-tert-butylbenzylthio)-4-chloropyridazin-3(2H)-one] to control various pests in or on cucumbers (greenhouse grown) at 0.5 parts per million (ppm). In addition, the petitioner proposes to amend 40 CFR 180.494 to modify existing tolerances based on new crop group definitions by establishing the following tolerances including berry, low growing, subgroup 13-07G, except cranberry at 2.5 ppm, fruit, citrus, group 10-10 at 0.5 ppm,  fruit, pome, group 11-10 at 0.75 ppm, fruit, small, vine climbing, subgroup 13-07F, except fuzzy kiwifruit at 1.5 ppm, fruit, stone, group 12-12 at 2.5 ppm and nut, tree, group 14-12 at 0.05 ppm.  Upon approval of the above tolerances, the petitioner proposes that the following currently established tolerances are deleted as they would be redundant including apple at 0.5 ppm, pear at 0.75 ppm, nut, tree, group 14 at 0.05 ppm, citrus (fruit) at 0.5 ppm, fruit, stone, group 12 at 2.5 ppm, pistachio at 0.05 ppm, grape at 1.5 ppm, and strawberry at 2.5 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 support granting of the petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

	1. Plant metabolism. The nature of the residue in plants is adequately understood. The residue of concern is pyridaben per se as specified in 40 CFR 180.494.

	2. Analytical method. The proposed analytical method involves extraction, partition, clean-up and detection of residues by gas chromatography/electron capture detector (gc/ecd).

	3. Magnitude of residues. Cucumber residue trials were conducted in green houses at four locations in NAFTA regions with two foliar directed applications. The residue trials were conducted according to a split application program depending upon location for a total of four trials in four states. Residues of pyridaben were measured by gc/ecd. The method of detection had a limit of detection of 0.01192 parts per million (ppm). Residues ranged from <0.05 to 0.25 ppm, in samples taken at 1 day PHI.

B. Toxicological Profile

	1. Acute toxicity.  In general, the acute toxicology studies conducted on technical grade pyridaben demonstrate that it has moderate to mild toxic effects. It was classified as Toxicity Category III based upon the acute oral lethal dose (LD)50 of 1,100 mg/kg in male rats and 570 mg/kg in female rats. The dermal LD50 in rabbits was greater than or equal to 2,000 mg/kg and the inhalation lethal concentrations (LC)50 were 0.66 and 0.64 mg/kg in male and female rats, respectively. The eye irritation study (rabbits) produced slight ocular irritation. Pyridaben was not a dermal irritant or sensitizer.

	2. Genotoxicty. Genotoxicity studies including Ames testing, in vitro cytogenicity (chinese hamster lung cell),in vivo micronucleus assay (mouse) and DNA damage/repair (E. coli) showed no genotoxic activity associated with pyridaben.

	3. Reproductive and developmental toxicity. In a developmental toxicity study, Sprague-Dawley rats (22/group) from Charles River, U.K., received Pyridaben (98.0% pure) via gavage at dose levels of 0, 2.5, 5.7, 13.0, or 30.0 milligram kilogram day (mg/kg/day) from gestation day 6 through 15, inclusive. Maternal toxicity, observed at 13.0 and 30.0 mg/kg/day, consisted of decreased body weight/weight gain and food consumption during the dosing period. Based on these effects, the maternal toxicity lowest observed adverse effect level (LOAEL) is 13.0 mg/ kg/day and the maternal toxicity nobserved adverse effect level (NOAEL) is 4.7 mg/kg/day (82% of 5.7 mg/kg/day based on concentration analysis). The developmental toxicity NOAEL is 13.0 mg/kg/day based on observed decreased fetal body weight and increased incomplete ossification in selected bones at 30.0 mg/kg/day LOAEL. 
	
	New Zealand white rabbits (19 or 20/group) were orally dosed with 0, 1.5, 5, or 15 mg/kg/day pyridaben from day 6 through 19 of gestation. Maternal toxicity was evidenced by a dose- dependent decrease in body weight gain and food consumption at all dose levels. There were also increased incidences of abortions and clinical signs (few feces) in the 15 mg/kg/day group. There was no evidence that the chemical had a developmental effect at any of the tested levels. The maternal NOAEL was 1.5 mg/kg/day and the Maternal LOAEL was 1.5 mg/kg/day based on decreases in body weight gain and food consumption at all dose levels. No developmental toxicity was observed at any dose level. Therefore, the NOAEL for developmental toxicity is greater than or equal to 15 mg/kg/day.
In a standard two-generation reproduction study, CD rats were administered pyridaben in the diet at doses of 0, 10, 28 or 80 ppm. The Parental/Systemic NOAEL is 28 ppm (2.20 and 2.41 mg/kg/day for males and females, respectively). The parental/ systemic LOAEL is 80 ppm (6.31 and 7.82 mg/kg/day for males and females, respectively) based on decreased body weights, body weight gains and food efficiency. There was no effect on reproductive parameters on the dose levels tested. The reproductive NOAEL is 80 ppm in males and females. The reproductive LOAEL is >80 ppm in males and females.

	4. Subchronic toxicity. In a 21 - day dermal study, rats received repeated topical applications of pyridaben (98% pure) to about 10% of the body surface area at dosages of 30, 100, 300 and 1,000 mg/kg for 21 days. The treatment produced body weight decreases in the 300 mg/kg/day females and in the 1,000 mg/kg/day males and females. The NOAEL was 100 mg/kg/day and the LOAEL was 300 mg/kg/day based on decreased body weight gain in females. The toxicology endpoints from this study were selected by the Agency for short- and intermediate-term dermal risk assessments.

A. 	5. Chronic toxicity. In a 12 - month chronic feeding study in dogs pyridaben was administered in capsules at dosages of 0, 1.0, 4.0, 16.0 or 32.0 mg/kg/day. All animals survived until the end of the study and there were no treatment-related changes in hematology, clinical chemistry, or urinalysis parameters. The NOAEL was determined to be <1.0 mg/ kg/day and the LOAEL was <1.0 mg/kg/ day based on increased incidences of clinical signs (thinness, dehydration, diarrhea, emesis, soft stool, ptyalism, and relaxed nictitans) in treatment groups of both sexes and decreased  body weight gain in females at 1.0 mg/ kg/day.
  In a follow-up study, pyridaben was administered in capsules to beagle dogs at dosages of 0 and 0.5 mg/kg/day for 1 year. The NOAEL was determined to be <0.5 mg/kg/day for males and females and the LOAEL was <0.5 mg/kg/day for males and females based on an increased incidence of clinical signs in both treated sexes and decreased weight gain in the treated females.
  Pyridaben was administered in the diet to CD-1 mice at dosages of 0, 2.5, 8.0, 25 or 80 ppm for 78 weeks. There was no evidence of a carcinogenic effect of the chemical. The NOAEL was determined to be 25 ppm (2.78 mg/kg/ day) for males and females and a   LOAEL of 80 ppm (8.88 and 9.74 mg/ kg/day for males and females, respectively). The LOAEL was determined to be 80 ppm for males and females based on decreased body weight gain, decreased food efficiency and changes in organ weights and histopathology (males). 
Pyridaben was administered in the diet to groups of Wistar rats for 104 weeks at doses of 0, 4, 10, 28 or 80 ppm to assess carcinogenicity. Additional groups (35 animals/sex/dose) received doses of 0, 4, 10, 28 or 120 ppm for 104 weeks (with an interim sacrifice at 53 weeks) to assess chronic toxicity. There was no treatment-related neoplastic or non-neoplastic pathology in either phase of the study. The NOAEL was determined to be 28 ppm in males (1.13 mg/kg/day) and 28 ppm (1.46 mg/kg/ day) in females. The LOAEL was determined to be 120 ppm (5.00 mg/kg/ day) in males and 120 ppm (6.52 mg/kg/ day) in females based on decreased body weight gain in males and females and decreased ALT levels in males in the chronic toxicity phase. There was no evidence of a carcinogenic effect of this chemical.

  	6. Animal metabolism. In an acceptable rat metabolism study by the oral route, pyridaben was mainly eliminated in the feces where 80 - 97% of the administered dose was excreted regardless of the dose or site of label (pyridazinone or benzyl ring). Nearly 20% of the excreted residue in the feces was unmetabolized parent compound and there was some evidence of glucoronide conjugate(s) in the bile. The plasma levels following a single low
oral dose (3 mg/kg) peaked at 23 hours while peak levels at the high dose (30 mg/kg) were at approximately 24 hours post-dose due, at least in part, to inter hepatic circulation (nearly 22 - 30% of an administered radioactive dose is excreted in bile within a period of 24 hours). Residual radioactivity was at or near background levels for most tissues by 72 to 168 hours. Generally, there seemed to be increased distribution to fat over time and, compared to other tissues, fat seemed to have relatively more residual radioactivity. Several metabolites, totaling up to 20 - 30, were resolved in urine and feces and some were structurally identified.

	7. Metabolite toxicology. The nature of the residue in animals is adequately understood. The residue of concern is pyridaben and its metabolites PB - 7, 2- tert-butyl-5-[4-(1-carboxy-1- methylethyl)benzylthio]-4- chloropyridazin-3(2H)-one and PB - 9, 2- tert-butyl-4-chloro-5-[4-(1,1-dimethyl-2- hydroxyethyl) benzylthio]- chloropyridazin-3(2H)-one as specified in 40 CFR 180.494.

	8. Endocrine disruption. The most common toxicity endpoint across the various studies and test species was decreased body weight/decreased body weight gain followed by decreased feed consumption and/or feed efficiency. These effects were observed in the 13 -  week feeding study in mice, in a 13 -  week rat study, in two 13 - week dog studies, in a 21 - day rat dermal study, in a 28 - day inhalation toxicity study in rats, in two 1 - year feeding studies in dogs, in a 78 - week feeding/ carcinogenicity study in mice, in a developmental toxicity study in rats, in two developmental studies in rabbits, and in a 2 - year feeding carcinogenicity study in rats. The LOAELs were always based on decreases in body weight gain/ body weight decreases or decreases in food consumption. Other effects were sporadic and involved changes in certain clinical chemistry values or increases or decreases in organ weights. Thus, there is no indication that effects on the endocrine system were responsible for any of the observed effects. 

C. Aggregate Exposure

	1. Dietary exposure. Tolerances have been established for residues in a variety of raw agricultural commodities (40 CFR 180.494). Additionally tolerances have been established for pyridaben and its metabolites in the meat byproducts of cattle, goats, hogs, horses and sheep.

	i. Food. From the acute dietary (food only) risk assessment, the calculated exposure yields dietary (food only) percentage of the acute RfD for females 13+ years old ranging from 29% for females 13+ years old -- not pregnant, non-nursing, to 42% for females 13+ years old--pregnant, not nursing. The calculated exposure yields dietary (food only) percentage of the acute RfD for the remainder of the population ranging from 9% for males 13-19 years old to 77% for nursing infants< 1 year old. This risk estimate should be viewed as highly conservative; refinement using anticipated residue values and percent crop-treated data in conjunction with a Monte Carlo analysis will result in a lower acute dietary exposure estimate. 

	ii. Drinking water. There are no established maximum contaminant levels or health advisory levels for residues of pyridaben or its metabolites in drinking water. The Pesticide Root Zone Model/Exposure Analysis Modeling System (PRZM/EXAMS) and Screening Concentration in Ground Water (SCI-GROW) models were used to estimate the maximum concentrations in surface and ground water, respectively. Pyridaben is immobile and thus unlikely to leach to groundwater. Results of environmental modeling indicate an estimated 0.215 ppm (acute) and 0.020 ppm (chronic) of pyridaben in surface water. 

	2. Non-dietary exposure. Pyridaben is a plant protection product used to control insects. This product is not considered for residential use and therefore the aggregate exposure is a result of pyridaben residues in food and water.

D. Cumulative Effects. The cumulative exposure to substances with common mechanism of toxicity must be considered. Currently, there are not available data to determine whether pyridaben has a common mechanism of toxicity with other substances or how to include this pesticide in a cumulative risk assessment. Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, pyridaben does not appear to form a toxic metabolite produced by other substances. As a result, for the purposes of this tolerance action, it is assumed that pyridaben does not have a common mechanism of toxicity with other substances.

E. Safety Determination

	1. U.S. population. Exposure estimates for the pyridaben acute dietary assessment were well under 100% of the aPAD at the 99.9th percentile. The overall general population and the most sensitive subpopulation (females 13 - 49 years) utilized 11% and 14.5% of the acute population adjusted dose (aPAD), respectively. Results from a Tier I dietary assessment of pyridaben residues in previous assessments indicates the percent aPAD for children 1 - 6 years old and females 13 - 49 years old were 3%. Therefore considering all current and pending  commodities,  including cucumbers, the percent chronic reference dose (%cRfD) and percent chronic population dose (%cPAD) will be below 20% for all population subgroups.

	2. Infants and children. Results from Tier I dietary assessment of pyridaben residues in previous assessments indicate that the percent cPAD for children 1-6 years old and females of child bearing years (13 -4 years) were in the range of 7 to 13%, respectively.  Therefore, considering all uses including cucumbers, the %cRfD and %cPAD will be below 100% for all population subgroups. Further refinements including additional percent crop treated, processing factors, cooking factors actual residue values (that used default values and tolerance levels) for the remaining commodities would further reduce the exposure.  

The aggregate exposure (food and drinking water) of pyridaben will not exceed the U.S. EPA's level of concern (100% of RfD). Over all we can conclude that reasonable certainty of no harm will occur from either acute or chronic aggregate exposure of pyridaben residues as a result of use on greenhouse grown cucumbers.

F. International Tolerances. There are no CODEX, Canadian, or Mexican Maximum Residue Limits (MRL) established for pyridaben on cucumbers.