EPA REGISTRATION DIVISION - COMPANY NOTICE OF FILING OF 

PESTICIDE PETITION

EPA Registration Division contact: Sidney Jackson (703) 305-7610 

Interregional Research Project Number 4 (IR-4)

Pesticide Petition Number: 2E8117

EPA has received a pesticide petition, 2E8117, from IR-4 Project 

Headquarters, 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 Vegetable, fruiting, group 8-10 at 

1.7 parts per million (ppm); Fruit, small, vine climbing, except fuzzy kiwifruit, 

subgroup 13-07F at 0.60 ppm; Berry, low growing, subgroup 13-07G at 0.90 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 grape at 0.60 ppm, strawberry at 0.90 ppm, pepper, bell at 

0.35 ppm, and pepper, nonbell at 1.7 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 these data support granting of the 

petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

1. Plant metabolism. The metabolism of quinoxyfen has been studied in a 

variety of crops under both outdoor (wheat, tomatoes and sugar beets) and 

glasshouse (grapes and cucumbers) conditions. The nature of residues (NOR) is 

adequately understood for the purposes of these tolerances. Based on the findings 

from these studies, quinoxyfen is the primary residue in all crops and therefore, the 

only residue of concern. Metabolites were present at low levels (<10% of total 

radioactive residue). A confined rotational crop study was conducted with 

quinoxyfen which confirmed minimal carryover of residues (> 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 (GCMSD) with limits of quantitation (LOQ) of <0.01 mg/kg. The method is adequate 

for collecting data and enforcing tolerances for quinoxyfen residues in/on the 
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subject crops.

3. Magnitude of residues. The residue data in support of the proposed 

tolerances were generated from the magnitude of residue studies on tomato.

Tomato: Supervised tomato field trials were conducted at thirteen field sites located 

in the U.S. All treatment applications targeted 0.130 pound active ingredient per 

acre (lb a.i./A) plus a non-ionic surfactant (NIS) at 0.125% volume per volume (v/v)

or an organosilicone surfactant at mid-label rate. Applications were made at 

approximately 7-day intervals, with the last application targeted 3 +/− 1 days before 

harvest (PHI=3 days). Two decline trials were conducted at 0, 3, 7, and 14 days 

before harvest (+/- 1 day) and residue generally declined over the 2 weeks period. 

Residues of quinoxyfen were extracted from 1.0 g of tomato fruit with acetonitrile 

(mixture of ACN/water for puree and paste). The results from the trials show that 

the maximum residue of quinoxyfen in tomato fruit at 2-4 day PHI was 0.32 ppm. A 

tomato processing study was conducted. The maximum quinoxyfen residue in 

tomato fruit was 0.11 ppm, the maximum quinoxyfen residue in tomato paste was 

0.089 ppm and the maximum quinoxyfen residue in tomato puree was 0.035 ppm.

Quinoxyfen residues did not concentrate in tomato fruit, paste or puree. Data from 

these studies may be used to support a tolerance proposal for quinoxyfen on tomato.

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 milligram per kilogram (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 
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rats given high dose levels of quinoxyfen.

5. Chronic toxicity. Combined chronic/carcinogenicity (rat) no-observed 

adverse effect level (NOAEL) = 20 mg/kg/day. Lowest observed adverse effect level 

(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 

toxicological 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.

9. Immunotoxicity. A 28-day immunotoxicity study on the quinoxyfen did not 

exhibit any evidence of Immunotoxicity.

10. Neurotoxicity. EPA concluded that there is no evidence of neurotoxicity as 

a result of exposure to quinoxyfen. There is no indication that quinoxyfen is a 

neurotoxic chemical and there is no need for a developmental neurotoxicity study or 

additional UFs to account for neurotoxicity.
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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 2.3% of the 

cPAD. Children 1-2 years old have been identified as the most highly exposed 

population subgroup utilizing only 4.1% 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 0.66 ppb for surface water and 0.0031 ppb for ground water. For the purpose 

of these assessments, 0.66 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.
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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 2.3% 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 4.1% 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 2.3% of the cPAD for the 

U.S. population, <2% of the cPAD for infants (< 1year old), and 4.1% 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.
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F. International Tolerances

There are no Mexican, Canadian or Codex maximum residue limits 

(MRLs) established for quinoxyfen in/on any food or feed crop considered in this 

action. Therefore, no compatibility issues exist for these tolerances. International 

harmonization is therefore not an issue for this notification.