Source: https://www.federalregister.gov/documents/2014/04/04/2014-07563/proquinazid-pesticide-tolerances
Timestamp: 2018-10-15 09:24:00
Document Index: 186497353

Matched Legal Cases: ['art 178', 'art 178', 'art 2', 'art 158', '§\u2009180', '§\u2009180']

Federal Register :: Proquinazid; Pesticide Tolerances
79 FR 18810
18810-18815 (6 pages)
EPA-HQ-OPP-2012-0164
FRL-9903-11
2014-07563
Proquinazid: Human Health Risk Assessment for the Tolerance on...
Notice of Filing -Proquinazid in/on Imported Grapes
https://www.federalregister.gov/d/2014-07563 https://www.federalregister.gov/d/2014-07563
The docket for this action, identified by docket identification (ID) number EPA-HQ-OPP-2012-0164, is available at http://www.regulations.gov or at the Office of Pesticide Programs Regulatory Public Docket (OPP Docket) in the Environmental Protection Agency Docket Center (EPA/DC), EPA West Start Printed Page 18811Bldg., Rm. 3334, 1301 Constitution Ave. NW., Washington, DC 20460-0001. The Public Reading Room is open from 8:30 a.m. to 4:30 p.m., Monday through Friday, excluding legal holidays. The telephone number for the Public Reading Room is (202) 566-1744, and the telephone number for the OPP Docket is (703) 305-5805. Please review the visitor instructions and additional information about the docket available at http://www.epa.gov/​dockets.
Under FFDCA section 408(g), 21 U.S.C. 346a, any person may file an objection to any aspect of this regulation and may also request a hearing on those objections. You must file your objection or request a hearing on this regulation in accordance with the instructions provided in 40 CFR part 178. To ensure proper receipt by EPA, you must identify docket ID number EPA-HQ-OPP-2012-0164 in the subject line on the first page of your submission. All objections and requests for a hearing must be in writing, and must be received by the Hearing Clerk on or before June 3, 2014. Addresses for mail and hand delivery of objections and hearing requests are provided in 40 CFR 178.25(b).
In addition to filing an objection or hearing request with the Hearing Clerk as described in 40 CFR part 178, please submit a copy of the filing (excluding any Confidential Business Information (CBI)) for inclusion in the public docket. Information not marked confidential pursuant to 40 CFR part 2 may be disclosed publicly by EPA without prior notice. Submit the non-CBI copy of your objection or hearing request, identified by docket ID number EPA-HQ-OPP-2012-0164, by one of the following methods:
In the Federal Register of May 2, 2012 (77 FR 25954) (FRL-9346-1), EPA issued a document pursuant to FFDCA section 408(d)(3), 21 U.S.C. 346a(d)(3), announcing the filing of a pesticide petition (PP 1E7972) by DuPont Crop Protection, Stine Haskell Research Center, P.O. Box 30, Newark, DE 19714-0030. The petition requested that 40 CFR 180.674 be amended by establishing tolerances for residues of the fungicide proquinazid, 6-Iodo-2-propoxy-3-propyl-3H-quinazolin-4-one, in or on imported commodities to include grape at 0.5 parts per million (ppm) and raisin at 1.0 ppm. That document referenced a summary of the petition prepared by DuPont Crop Protection., the registrant, which is available in the docket, http://www.regulations.gov. There were no comments received in response to the notice of filing.
Based upon review of the data supporting the petition, EPA has changed one of the requested commodity names from raisin; to grape, raisin; and added a significant figure to the numerical grape tolerance. The reasons for these changes are explained in Unit IV.C.
Consistent with FFDCA section 408(b)(2)(D), and the factors specified in FFDCA section 408(b)(2)(D), EPA has reviewed the available scientific data and other relevant information in support of this action. EPA has sufficient data to assess the hazards of and to make a determination on aggregate exposure for proquinazid including exposure resulting from the tolerances established by this action. EPA's assessment of exposures and risks associated with proquinazid follows.
Proquinazid has no significant acute toxicity via the oral, dermal, or inhalation routes of exposure. It is not an eye or skin irritant and does not cause skin sensitization. Based on the results of a 28-day dermal study in rats (as well as the dermal lethal dose (LD) study), proquinazid is poorly absorbed through the skin.Start Printed Page 18812
The liver and thyroid are the primary target organs for proquinazid. In rodents, body weight/body weight gain reductions, increased liver and thyroid organ weights, hypertrophy/hyperplasia, liver enzyme induction, and thyroid hormone changes were seen across varying durations and routes of exposure in rodents but not in dogs. In the 90-day oral rat study, the low dose effects of proquinazid are characterized primarily by altered thyroid hormones and associated follicular cell hypertrophy in the thyroid. Decrements in body weight and nutritional parameters, as well as histopathological changes in the liver (including hypertrophy) were observed at higher doses. In a 28-day oral rat study, hypertrophy of the thyroid and liver was completely reversible after a 6 week recovery period. In chronic rodent studies, non-neoplastic effects in both mice and rats included thyroid follicular hyperplasia and hypertrophy, with associated thyroid hormone changes (only investigated in rats), and some marked hepatic lesions, i.e., necrosis and hyperplasia (including oval cell hyperplasia in rats). In addition, chronic exposure in rats led to increases in the incidence of liver and thyroid tumors. The mode of action for the thyroid tumors in rats involves early changes in liver enzyme regulation that lead to dis-regulation of thyroid hormone homeostasis thyroid follicular hypertrophy/hyperplasia, and thyroid follicular adenoma formation. Mode of action data were submitted on the thyroid follicular cell tumors observed in male rats and the cholangiocarcinomas observed in female rats. The hypothesized mode of action (i.e., non-genotoxic) for each tumor type (i.e, the thyroid and cholangiocarcinoma) was supported by adequate studies that clearly identified the sequence of key events, dose-response concordance, and temporal relationship to the tumor types. No treatment-related tumors were observed in male or female mice. The overall weight-of-evidence was considered sufficient to demonstrate that proquinazid thyroid follicular tumors are the result of an anti-thyroidal mode of action and that a carcinogenic response would not be expected at doses below the threshold for changes in liver enzyme regulation leading to dis-regulation of thyroid hormone homeostasis. The data also shows that rats are substantially more sensitive than humans to the development of thyroid follicular cell tumors in response to thyroid hormone imbalance. Proquinazid induced cholangiocarcinomas in female rats only at doses that produced marked liver toxicity and oval cell hyperplasia microscopically. In contrast, in both male and female rats, doses that produced less severe or no hepatotoxicity or oval cell proliferation did not produce chlolangiocarcinomas. Therefore, at high enough doses, proquinazid can cause these biochemical and histopathological effects in livers of rodents but is unlikely to be carcinogenic at doses below those causing these changes. In contrast, in both male and female rats, doses that produced less severe or no hepatoxicity or oval cell proliferation did not produce cholangiocarcinomas. Therefore, at high enough doses, proquinazid can cause these biochemical and histopathological effects in livers of rodents but is unlikely to be carcinogenic at doses below those causing these changes. Therefore, the Agency determined that quantification of risk using a non-linear approach (i.e., reference dose (RfD) will adequately protect for all chronic toxicity, including carcinogenicity, that could result from exposure to proquinazid.
There is no mutagenicity concerns from in vivo or in vitro genetic toxicity assays. Proquinazid was not found to be immunotoxic. No evidence of increased quantitative or qualitative susceptibility was seen following in utero exposure to proquinazid with rats or rabbits in the prenatal developmental studies or in young rats in the 2-generation reproduction study. The 2-generation rat reproduction study resulted in no effects on reproduction or fertility. The offspring effects (decreases in F1 pup weight during lactation) occurred at the same dose which caused parental effects (thyroid hypertrophy, reduced body weight gain, and food consumption). Evidence of developmental delays were observed in developmental toxicity studies in rabbits and rats and were characterized by reduced fetal weight and an increased incidence of retarded ossification and patent ductus arteriosus, respectively. These developmental effects occurred in the presence of maternal toxicity and were considered of equal toxicity.
There is limited evidence for neurotoxicity following oral exposures to proquinazid. Following a single exposure, evidence for neurotoxicity at the lowest observed adverse effect level (LOAEL) was limited to decreased motor activity in both sexes with no behavioral or neuropathology changes. At doses above the study LOAEL other effects including decreased grip strength and food splay were observed. Following repeated (dietary) exposures, there were no treatment-related clinical signs of neurotoxicity, behavioral changes or neuropathology. Specific information on the studies received and the nature of the adverse effects caused by proquinazid as well as the no observed adverse effect level (NOAEL) and the LOAEL from the toxicity studies can be found at http://www.regulations.gov in document “Proquinazid: Human Health Risk Assessment for the Tolerance on Imported Grapes” dated September 2013 at pages 23 through 35 in docket ID number EPA-HQ-OPP-2012-0164.
Once a pesticide's toxicological profile is determined, EPA identifies toxicological points of departure (POD) and levels of concern to use in evaluating the risk posed by human exposure to the pesticide. For hazards that have a threshold below which there is no appreciable risk, the toxicological POD is used as the basis for derivation of reference values for risk assessment. PODs are developed based on a careful analysis of the doses in each toxicological study to determine the dose at which no adverse effects are observed (the NOAEL) and the lowest dose at which adverse effects of concern are identified (the LOAEL). Uncertainty/safety factors are used in conjunction with the POD to calculate a safe exposure level—generally referred to as a population-adjusted dose (PAD) or a RfD—and a safe margin of exposure (MOE). For non-threshold risks, the Agency assumes that any amount of exposure will lead to some degree of risk. Thus, the Agency estimates risk in terms of the probability of an occurrence of the adverse effect expected in a lifetime. For more information on the general principles EPA uses in risk characterization and a complete description of the risk assessment process, see http://www.epa.gov/​pesticides/​factsheets/​riskassess.htm.
A summary of the toxicological endpoints for proquinazid used for human risk assessment is shown in Table 1. of this unit. Because only oral exposure are anticipated for imported grapes, no other endpoints are relevant such as dermal and inhalation exposures.Start Printed Page 18813
Table 1—Summary of Toxicological Doses and Endpoints for Proquinazid for Use in Human Health Risk Assessment
Acute dietary (General population including infants and children) NOAEL = 50 mg/kg/bw UFA = 10x UFH = 10x FQPA SF = 10x UFDB Acute RfD = aPAD = 0.050 mg/kg/bw Acute Neurotoxicity Study-Rat. LOAEL = 100 mg/kg/bw based on decreased motor activity seen in females on day 1.
Chronic dietary (All populations) NOAEL= 1.2 mg/kg/day UFA = 13x UFH = 10x FQPA SF = 10x UFDB Chronic RfD = cPAD = 0.004 mg/kg/day Chronic Toxicity/Carcinogenicity Study-Rat. LOAEL = 12 mg/kg/day based on increases in non-neoplastic liver lesions and changes in thyroid hormones and thyroid pathology.
Cancer (Oral, dermal, inhalation) A non linear approach (i.e., RfD will adequately protect for all chronic toxicity, including carcinogenicity, that could result from exposure to proquinazid. The cPAD for proquinazid will protect for carcinogenic effects because it is below the level that caused changes in liver enzyme regulation and liver toxicity.
FQPA SF = Food Quality Protection Act Safety Factor. LOAEL = lowest observed adverse effect level. mg/kg/bw = milligram/kilogram/body weight. NOAEL = no observed adverse effect level. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFDB = to account for the absence of data or other data deficiency. UFH = potential variation in sensitivity among members of the human population (intraspecies).
1. Dietary exposure from food and feed uses. In evaluating dietary exposure to proquinazid, EPA considered exposure under the petitioned-for tolerances as well as all existing proquinazid tolerances in 40 CFR 180.674. EPA assessed dietary exposures from proquinazid in food as follows:
Such effects were identified for proquinazid. In estimating acute dietary exposure, EPA used food consumption information from the United States Department of Agriculture (USDA) 2003-2008 National Health and Nutrition Examination Survey, What We Eat in America (NHANES/WWIA). As to residue levels in food, EPA used tolerance level residues and 100% percent crop treated (PCT). Default processing factors were used for grape juice. The Agency considers these to be highly conservative assessments.
ii. Chronic exposure. In conducting the chronic dietary exposure assessment EPA used the food consumption data from the USDA 2003-2008 NHANES/WWEIA. As to residue levels in food, EPA used tolerance level residues and 100% PCT.
iii. Cancer. Quantification of risk using a non-linear approach (i.e., RfD will adequately protect for all chronic toxicity, including carcinogenicity, which could result from exposure to proquinazid. Cancer risk was assessed using the same exposure estimates as discussed in Unit III.C.1.ii., chronic exposure.
iv. Anticipated residue and PCT information. EPA did not use anticipated residue and/or PCT information in the dietary assessment for proquinazid. Tolerance level residues and/or 100% CT were assumed for all food commodities.
2. Dietary exposure from drinking water. There is no drinking water exposure in the U.S. associated with the establishment of an import tolerance.
3. From non-dietary exposure. The term “residential exposure” is used in this document to refer to non-occupational, non-dietary exposure (e.g., for lawn and garden pest control, indoor pest control, termiticides, and flea and tick control on pets). Proquinazid is not registered for any specific use patterns that would result in residential exposure.
EPA has not found proquinazid to share a common mechanism of toxicity with any other substances, and proquinazid does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has assumed that proquinazid does not have a common mechanism of toxicity with other substances. For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see EPA's Web site at http://www.epa.gov/​pesticides/​cumulative.
2. Prenatal and postnatal sensitivity. No evidence of increased quantitative or qualitative susceptibility was seen following in utero exposure to proquinazid with rats or rabbits in the prenatal developmental studies or in young rats in the 2-generation reproduction study. The 2-generation rat reproduction study resulted in no effects on reproduction or fertility. The Start Printed Page 18814offspring effects (decreases in F1 pup weight during lactation) occurred at the same dose which caused parental effects (thyroid hypertrophy, reduced body weight gain, and food consumption). Evidence of developmental delays were observed in developmental toxicity studies in rabbits and rats were characterized by reduced fetal weight and an increased incidence retarded ossification and paten ductus arteriosus, respectively. These developmental effects occurred in the presence of maternal toxicity. For the rats, the developmental effects were seen in the presence of clear maternal toxicity, including a marked reduction in body weight gain after adjustment for uterine contents and were considered to be of equal severity.
3. Conclusion. In determining whether there are reliable data to amend or remove the presumptive 10X FQPA safety factor, EPA considered the following factors:
i. The toxicity database for proquinazid required by 40 CFR Part 158 is complete. However, there remains some uncertainty regarding the potential for proquinazid effects on the thyroid in the young. Effects on the thyroid (manifested as changes in hormones, weight, and histopathology) following proquinazid exposure were consistently observed in adult animals (rats) following subchronic and chronic exposures. Thyroid effects, however, were not assessed in studies involving neo- or postnatal animals, and EPA is lacking data showing the comparative effect of proquinazid on the thyroid in adult and neo- and postnatal animals.
ii. There is only limited evidence that proquinazid is a neurotoxic chemical and there is no need for a developmental neurotoxicity study or additional UFs to account for neurotoxicity. There is limited evidence for neurotoxicity following oral exposures to proquinazid. Following a single exposure, evidence for neurotoxicity at the LOAEL was limited to decreased motor activity in both sexes with no behavioral or neuropathology changes. At doses above the study LOAEL other effects including decreased grip strength and foot splay were observed. Following repeated (dietary) exposures, there were no treatment-related clinical signs of neurotoxicity, behavioral changes, or neuropathology.
iii. As discussed in Unit III.D.2., there is no evidence that proquinazid results in increased susceptibility with in utero rats or rabbits in the prenatal developmental studies or in young rats in the 2-generation reproduction study.
iv. There are no residual uncertainties identified in the exposure databases. The dietary food exposure assessments were performed based on 100% CT and tolerance-level residues. Drinking water is not a factor because this is an import tolerance assessment. These assessments will not underestimate the exposure and risks posed by proquinazid.
Despite the lack of any indication of sensitivity in the young and the very conservative exposure assessment, EPA has determined that it lacks reliable data to choose a FQPA safety factor other than the default value of 10X given (1) the absence of data on thyroid effects on the young, including comparative thyroid data on adults and the young, and (2) the fact that thyroid effects were the most sensitive effect seen in adult animals. At the same time, after considering all of the data on proquinazid toxicity and exposure, EPA has also determined that application of a FQPA safety factor of 10X, in conjunction with inter- and intraspecies safety factors, will result in a risk assessment that protects the safety of infants and children. Although there is some uncertainty as to whether the young might have greater sensitivity to proquinazid's thyroid effects due to the absence of comparative thyroid data, two developmental studies and a reproduction study have otherwise shown no indication of sensitivity in the young to proquinazid. Additionally, the exposure assessment provides an extra margin of safety given that it is based on the conservative assumption that all grapes, and all food products derived from grapes (e.g., raisins, grape juice, wine), consumed in the United States bear residues of proquinazid at the appropriate tolerance level. This assumption is particularly conservative here because proquinazid is not registered for use in the United States. Taking into account all of these considerations, EPA concludes that no safety factor in addition to the inter- and intraspecies factors, and the default FQPA safety factor is needed to protect the safety of infants and children.
1. Acute risk. Using the exposure assumptions discussed in this unit for acute dietary exposure from food to proquinazid will occupy 18% of the aPAD for children 1-2 years old, the population group receiving the greatest exposure.
2. Chronic risk. Using the exposure assumptions described in this unit for chronic exposure, EPA has concluded that chronic exposure to proquinazid from food will utilize 47% of the cPAD for children 1-2 years old the population group receiving the greatest exposure. There are no residential uses for proquinazid. Based on the explanation in Unit III.C.3., regarding residential use patterns, chronic residential exposure to residues of proquinazid is not expected.
3. Aggregate cancer risk for U.S. population. The cPAD of 0.004 mg/kg/day will be protective of both non-cancer and cancer effects, including rat tumors (liver, thyroid, and cholangiocarcinomas). As discussed in Unit III.E., aggregate exposure to proquinazid is below the cPAD.
4. Determination of safety. Based on these risk assessments, EPA concludes that there is a reasonable certainty that no harm will result to the general population or to infants and children from aggregate exposure to proquinazid residues.
Adequate enforcement methodology (gas chromatography with electron capture detection) is available to enforce the proposed tolerances for residues of proquinazid on grape commodities.
In making its tolerance decisions, EPA seeks to harmonize U.S. tolerances with international standards whenever possible, consistent with U.S. food safety standards and agricultural practices. EPA considers the international maximum residue limits (MRLs) established by the Codex Alimentarius Commission (Codex), as required by FFDCA section 408(b)(4). The Codex Alimentarius is a joint United Nations Food and Agriculture Organization/World Health Start Printed Page 18815Organization food standards program, and it is recognized as an international food safety standards-setting organization in trade agreements to which the United States is a party. EPA may establish a tolerance that is different from a Codex MRL; however, FFDCA section 408(b)(4) requires that EPA explain the reasons for departing from the Codex level.
The Codex has not established a MRL for proquinazid. However, the tolerances established in this rule are harmonized with Canadian MRLs.
The Agency is changing the proposed commodity definition for raisins from raisin to grape, raisin. The change in the commodity definition is to make the tolerance consistent with Agency naming-conventions for commodities and crop groups. No changes are recommended for the proposed tolerance levels, but the grape tolerance is being revised from 0.5 to 0.50 to correct the number of significant figures.
Therefore, tolerances are established for residues of proquinazid in or on grape at 0.50 ppm and grape, raisin 1.0 ppm.
Marty Marnell,
2. Add § 180.674 to read as follows:
§ 180.674
(a) General. Tolerances are established for residues of the fungicide, proquinazid, including its metabolites and degradates, in or on the commodities listed in the following table. Compliance with the tolerance levels specified in the following table is to be determined by measuring only proquinazid, [6-Iodo-2-propoxy-3-propyl-3H-quinazolin-4-one), in or on the following commodities:
Grape 1 0.50
Grape, raisin 1 1.0
1 No U.S. registrations for Proquinazid.
[FR Doc. 2014-07563 Filed 4-3-14; 8:45 am]