<EPA Registration Division contact: Sidney Jackson,<PHONE_NUMBER>>

<Interregional Research Project #4/Dow AgroSciences LLC

>

<8E7325>

<	EPA has received a pesticide petition (PP) 8E7325 from the Interregional Research Project No. 4 (IR-4), 500 College Road East, Suite 201W, 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, by establishing a tolerance for residues of quinoxyfen in or on the raw agricultural commodity globe artichoke at 1.4 parts per million (ppm); stone fruits crop group 12 at 0.70 ppm; winter squash at 0.20 ppm; pumpkin at 0.20 ppm; edible gourd at 0.20 ppm;.

Upon approval of the aforementioned tolerances, it is proposed that 40 CFR 180 be amended to remove the established tolerances for the residues of quinoxyfen in or on the raw agricultural commodity sweet cherry at 0.3 ppm and tart cherry at 0.3 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>

ues (> 0.003 μg/g) to succeeding crops.>

<	2. Analytical method. A practical analytical method is available to monitor and enforce the tolerances of quinoxyfen residues in crops.  The analytical method uses a capillary gas chromatography and mass selective detection (GC-MSD) with limits of quantitation (LOQ) of <0.01.  The method is adequate for collecting data and enforcing tolerances for quinoxyfen residues in/on the subject crops.>

<	3. Magnitude of residues. The residue data in support of the proposed tolerances was generated from the magnitude of residue studies on artichoke, stone fruits (peach, plum), and winter squash.

Artichoke: Three artichoke trials were conducted in California to collect data on the residues of quinoxyfen.  At each trial, four foliar applications of quinoxyfen at a rate of approximately 0.13 lb ai/A were applied, for a total of approximately 0.52 lb ai/A quinoxyfen.  The applications were made 6-7 days apart and mature artichoke buds were harvested with a PHI of 0 days.  The limit of detection (LOD) and limit of quantitation (LOQ) were calculated as 0.0033 ppm and 0.0099 ppm, respectively, for quinoxyfen.  Residues from treated field samples with a PHI of 0 days ranged from 0.63 to 1.09 ppm for quinoxyfen.  The results from the trials show that the maximum residue in artichokes following a total application of approximately 0.52 lb ai/A quinoxyfen and a pre-harvest interval (PHI) of 0 days was 1.09 ppm quinoxyfen.  Data from this study may be used to support a tolerance proposal for quinoxyfen on artichokes.

Stone Fruits, Peach:  Eleven peach trials were conducted in New York, North Carolina, New Jersey, Michigan, Texas and California.  At each trial, four foliar applications of quinoxyfen at a rate of approximately 0.13 lb ai/A were applied, for a total of approximately 0.52 lb ai/A quinoxyfen.  The applications were made 6-8 days apart and mature peaches were harvested with a PHI of 7+1 days.  Based on recoveries of samples fortified at the LLMV, the limit of detection (LOD) and limit of quantitation (LOQ) were calculated as 0.0012 ppm and 0.0037 ppm, respectively, for quinoxyfen.  Residues from treated field samples with a PHI of 7 (+ 1) days ranged from 0.057 to 0.55 ppm for quinoxyfen.  The results from the trials show that the maximum residue in peaches following a total application of approximately 0.52 lb ai/A quinoxyfen and a pre-harvest interval (PHI) of 7+1 days was 0.55 ppm quinoxyfen.

Stone Fruits, Plum:  Six residue trials were conducted with four foliar applications of Quintec EF 1295 to plum trees at nominally 0.13 lb. a.i./A for a total application rate of nominally 0.52 lb a.i./A with retreatment intervals of 6-8 days and a pre-harvest interval of 7 days.  The lowest level of method validation (LLMV) in this study was 0.010 ppm for both plums and dried plums.  Based on recoveries of fresh plum samples fortified at the LLMV, the limit of detection (LOD) and limit of quantitation (LOQ) were calculated as 0.002 ppm and 0.005 ppm respectively.  For dried pitted plums, the limit of detection (LOD) and limit of quantitation (LOQ) were calculated as 0.001 ppm and 0.004 ppm respectively based on recoveries of dried pitted plum samples fortified at the LLMV.  The maximum residue of quinoxyfen in plum fruit was 0.095 ppm after four foliar applications of 0.129- 0.131 lb a.i./A for a total application rate of 0.518 lb a.i./A during fruiting with a PHI of 7 days.  The residue of quinoxyfen in dried pitted plum fruit (one sample) was 0.030 ppm after four foliar applications of 0.128 to 0.133 lb a.i./A for a total application rate of 0.522 lb a.i./A during fruiting with a PHI of 7 days.  No residues were detected in any of the control samples analyzed.

Winter Squash:  Five winter squash trials were conducted with trials in California, Florida, Maryland, New Jersey and Ohio.  At each trial, four foliar applications of quinoxyfen at a rate of approximately 52 lb ai/A quinoxyfen.  The applications were made 6-9 days apart and mature winter squash were harvested with a PHI of 3-4 days.  Based on recoveries of samples fortified at the LLMV, the limit of detection (LOD) and limit of quantitation (LOQ) were calculated as 0.0014 ppm and 0.0041 ppm, respectively, for quinoxyfen.  The results from the trials show that the maximum residue in winter squash following a total application of approximately 0.52 lb ai/A quinoxyfen and a pre-harvest interval (PHI) of 3-4 days was 0.106 ppm quinoxyfen.]>

<B. Toxicological Profile>

<	1. Acute toxicity.  No appropriate toxicological endpoint attributable to a single exposure of quinoxyfen was identified based on the available toxicity studies including the acute neurotoxicity study in rats, the developmental toxicity studies in rats and in rabbits.  Therefore, acute risk assessment is not required.>

<	2. Genotoxicty.  Quinoxyfen was negative for genotoxicity when tested in

in vitro and in vivo systems.>

<	3. Reproductive and developmental toxicity   There was no evidence of increased> susceptibility in the oral rat or rabbit developmental studies.  There

was an increased quantitative susceptibility of young animals following

pre/postnatal exposure to rats in the reproduction study.  No maternal effects were observed up to the highest dose tested (100 milligrams/kilograms/day (mg/kg/day); however, minimally reduced F1a pup weights were noted at 100 mg/kg/day.

<	4. Subchronic toxicity.  Quinoxyfen caused increased liver weights and microscopic hepatocellular hypertrophy when given at sufficiently high dose levels in rats and mice for 13 weeks; no effects were observed in the subchronic dog study

at the highest dose tested.  Very high dietary levels were associated with slight

hepatocellular necrosis.  Similar increases in liver weights were seen in chronic studies.  In addition, increased kidney weights, and an increase in the incidence of chronic progressive glomerulonephropathy, were seen after 24 months in female rats given high dose levels of quinoxyfen.>

<	5. Chronic toxicity.  Combined chronic/carcinogenicity (rat) NOAEL = 20 mg/kg/day.  LOAEL = 80 mg/kg/day based on increases in severity of chronic progressive glomerulonephropathy in the males and minimal decreases in body weight and body weight gain in the males and females.  No evidence of carcinogenicity existed in an 18-month mouse feeding study and a 24-month rat feeding study at any dosage tested.>

<	6. Animal metabolism.  Quinoxyfen is rapidly absorbed, extensively metabolized and rapidly eliminated in the urine and feces.  Studies conducted with 14C-quinoxyfen, labeled in either the phenyl ring or the quinoline ring, indicated extensive cleavage of the diaryl ether linkage.  There were no substantive differences in the metabolism and disposition of quinoxyfen between males and females, or between single or repeated exposure.  Parent quinoxyfen was not found in the urine, though it was identified in the feces.  The major metabolites found in urine and/or feces included (1) acid-labile conjugates of the phenyl ring moiety (4-FP) and quinoline ring moiety (DCHQ); (2) lesser quantities of free 4-FP and DCHQ; and, (3) isomers of fluorophenyl-ring hydroxy-quinoxyfen, both free and glucuronide and/or sulfate conjugates.  Trace quantity of the 3-OH metabolite was also identified in the urine and feces of rats.>

<7. Metabolite toxicology.  The nature of residue studies (NOR) of quinoxyfen in plants indicated that the majority of applied radiolabeled material remained as the parent compound.  Analyses from NOR studies in a number of crops revealed low residues of metabolites (<10% TRR) identified as (1) a quinoline-ring hydroxylated metabolite, most likely 3-OH; (2) a cyclized deschloro photoproduct (CFBPQ); (3) 4-FP; and, (4) a metabolite in which the fluorine was replaced by a hydroxyl group.

Of these metabolites, 4-FP (formed by ether bridge cleavage), and DCHQ (corresponding to the other half of the molecule), as well as trace quantities of 3-OH, have been identified in rat urine and/or feces.  These data suggest that most metabolites formed in plants are similarly formed in mammals and are of little toxicologic concern, based on the existing data for quinoxyfen.>

<	8. Endocrine disruption.  There is no evidence from any studies to suggest that quinoxyfen has an effect on any endocrine system.>

<C. Aggregate Exposure>

<	1. Dietary exposure.  Risk assessments were conducted to assess dietary exposures from quinoxyfen in food as follows:>

<	i. Food.  No appropriate toxicological endpoint attributable to a single exposure was identified in the available toxicological studies on quinoxyfen.  Thus, the risk from acute exposure is considered negligible.

Based on the conservative assumptions used and using a cPAD of 0.20 mg/kg/day, the chronic dietary exposure to quinoxyfen from all registered and proposed uses without drinking water, to all population subgroups is approximately 2% of the cPAD.  Children 1-2 years old have been identified as the most highly exposed population subgroup utilizing only 2.1% of the cPAD.>

<	ii. Drinking water.  Calculation of potential acute aggregate dietary exposure from food and drinking water was not necessary.  Risk assessment for short-term and chronic exposure to quinoxyfen indicates that drinking water is not a significant exposure pathway.

Based on the FIRST and SCI-GROW models, the estimated environmental

concentrations (EECs) of quinoxyfen for chronic exposures are estimated

to be 0.84 ppb for surface water and 0.006 ppb for ground water.  For the purpose of these assessments, 8.4 ppb was used for the chronic exposure estimate for water, and this value was incorporated as a single point estimate for both “water, direct, all sources,” and “water, indirect, all sources” within DEEM-FCID( food categories exposure modeling.  Based on the conservative assumptions used and using a cPAD of 0.20 mg/kg/day, the chronic dietary exposure to quinoxyfen from all registered and proposed uses and drinking water, to all population subgroups is approximately 2% of the cPAD.  Children 1-2 years old have been identified as the most highly exposed population subgroup utilizing only 2.1% of the cPAD.>

<	2. Non-dietary exposure. Quinoxyfen is not registered for use on any sites that would result in residential exposure.  Thus, the risk from non-dietary exposure is considered negligible.>

<D. Cumulative Effects>

<	At this time, EPA does not have available data to determine whether quinoxyfen has a common mechanism of toxicity with other substances.  Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, quinoxyfen does not appear to produce a toxic metabolite generated by other substances.  For purposes of this assessment, therefore, it is assumed that quinoxyfen does not have a mechanism of toxicity common with other substances and no cumulative risk assessment is required.>

<E. Safety Determination>

<	1. U.S. population.  Using conservative exposure assumptions (Tier 1) and taking into account the completeness and reliability of the toxicity data, chronic dietary food exposure to quinoxyfen from registered uses as well as from proposed uses will utilize 1.3% of the cRfD for the general U.S. population.  The major identifiable subgroup with the highest chronic food exposure is children (1-2 years old) utilizing only 2.1% of the cRfD.  Generally, EPA has no concern for exposures below 100% of the cRfD because the chronic RfD represents the level at or below which daily dietary exposures over a lifetime will not pose appreciable risks to human health.  Additionally, the potential contribution of quinoxyfen residues in drinking water to aggregate exposure is expected to be minimal.

Short-term and intermediate-term risks are considered to be negligible because of lack of significant toxicological effects.  Therefore, based on these risk assessments, Dow AgroSciences concludes that there is reasonable certainty that no harm will result to the U.S. population from aggregate exposure to quinoxyfen residues from registered and proposed uses.>

<	2. Infants and children. EPA uses a weight of evidence approach in determining what safety factor is appropriate for assessing risks to infants and children.  This approach takes into account the nature and severity of the effects observed in pre- and post-natal studies and other information such as epidemiological data.  The completeness and adequacy of the toxicity database is also considered.

The toxicity database and exposure data for quinoxyfen are complete.  No indication of increased susceptibility of rats or rabbits to in utero and/or postnatal exposure was noted in the acceptable developmental toxicity studies in rats and rabbits as well as in a 2-generation reproductive toxicity study in rats.  EPA has previously determined that no additional safety factor to protect infants and children is necessary for quinoxyfen and that the RfD at 0.20 mg/kg/day is appropriate for assessing risk to infants and children.

Using the conservative assumptions (Tier 1) described above, the chronic dietary exposure to quinoxyfen from (food + water) will utilize 1.3% of the cPAD for the U.S. population, <1% of the cPAD for infants (< 1year old), and 2.1% of the cPAD for children (1-2 years old) the population at greatest exposure.  Even when considering the potential exposure to drinking water, the aggregate exposure is not expected to exceed 100% of the cRfD.  There are no residential uses for quinoxyfen that result in chronic residential exposure to quinoxyfen.  Therefore, based on the completeness and reliability of the toxicity data and the conservative exposure assessment, Dow AgroSciences concludes with reasonable certainty that no harm will result to infants and children from the aggregate exposure to quinoxyfen residues from registered and proposed uses.>

<F. International Tolerances>

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There are no Mexican, Canadian or Codex maximum residue limits

(MRLs) established for quinoxyfen in/on any food or feed crop.  Therefore, no compatibility issues exist for these tolerances.  International harmonization is therefore not an issue for this notification.>

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