Source: https://www.federalregister.gov/documents/2016/01/13/2016-00534/propyzamide-pesticide-tolerances
Timestamp: 2017-10-21 22:07:45
Document Index: 319518343

Matched Legal Cases: ['art 178', 'art 180', 'art 178', 'art 178', 'art 2', '§\u2009180']

Federal Register :: Propyzamide; Pesticide Tolerances
Propyzamide; Pesticide Tolerances
A Rule by the Environmental Protection Agency on 01/13/2016
This regulation is effective January 13, 2016. Objections and requests for hearings must be received on or before March 14, 2016, and must be filed in accordance with the instructions provided in 40 CFR part 178 (see also Unit I.C. of the SUPPLEMENTARY INFORMATION).
81 FR 1526
1526-1531 (6 pages)
EPA-HQ-OPP-2014-0680
FRL-9940-90
2016-00534
Pronamide (Propyzamide) Occupational and Residential Exposure...
Propyamide (Pronamide) Tier II Drinking Water Exposure...
Pronamide Acute and Chronic Aggregate Dietary (Food and...
Pronamide (Propyzamide) Harmonization of the Recommended...
Pronamide (Propyzamide) Summary of Analytical Chemistry and...
Pronamide Human Health Risk Assessment for Registration Review...
Pronamide on Leaf Lettuce 4F8301: Company Notice of Filing
https://www.federalregister.gov/d/2016-00534 https://www.federalregister.gov/d/2016-00534
This PDF is the current document as it appeared on Public Inspection on 01/12/2016 at 08:45 am.
This regulation establishes a tolerance for residues of propyzamide, also known as pronamide, in or on leaf lettuce. Dow AgroSciences, LLC requested this tolerance under the Federal Food, Drug, and Cosmetic Act (FFDCA).
The docket for this action, identified by docket identification (ID) number EPA-HQ-OPP-2014-0680, 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), West William Jefferson Clinton Bldg., 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.
You may access a frequently updated electronic version of EPA's tolerance regulations at 40 CFR part 180 through the Government Printing Office's e-CFR site at http://www.ecfr.gov/​cgi-bin/​text-idx?​&​c=​ecfr&​tpl=​/​ecfrbrowse/​Title40/​40tab_​02.tpl. To access the OCSPP test guidelines referenced in this document electronically, please go to http://www.epa.gov/​test-guidelines-pesticides-and-toxic-substances.
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 the request by the docket ID number EPA-HQ-OPP-2014-0680 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 March 14, 2016. 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-2014-0680, by one of the following methods:
Hand Delivery: To make special arrangements for hand delivery or Start Printed Page 1527delivery of boxed information, please follow the instructions at http://www.epa.gov/​dockets/​contacts.html.
In the Federal Register of Wednesday, December 17, 2014 (79 FR 75109) (FRL-9918-90), 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 4F8301) by Dow AgroSciences, LLC, 9330 Zionsville Rd., Indianapolis, IN 46268-1054. The petition requested that 40 CFR 180.317 be amended by establishing a tolerance for residues of the herbicide pronamide (propyzamide) and its metabolite containing the 3,5-dichlorobenzoyl moiety calculated as 3,5-dichloro-N-(1,1-dimethyl-2-propynyl)benzamide, in or on lettuce, leaf at 1.0 part per million (ppm). That document referenced a summary of the petition prepared by Dow AgroSciences, LLC, the registrant, which is available in the docket EPA-HQ-OPP-2014-0680 at http://www.regulations.gov. There were no comments received in response to the notice of filing.
Section 408(b)(2)(A)(i) of FFDCA allows EPA to establish a tolerance (the legal limit for a pesticide chemical residue in or on a food) only if EPA determines that the tolerance is “safe”. Section 408(b)(2)(A)(ii) of FFDCA defines “safe” to mean that “there is a reasonable certainty that no harm will result from aggregate exposure to the pesticide chemical residue, including all anticipated dietary exposures and all other exposures for which there is reliable information”. This includes exposure through drinking water and in residential settings, but does not include occupational exposure. Section 408(b)(2)(C) of FFDCA requires EPA to give special consideration to exposure of infants and children to the pesticide chemical residue in establishing a tolerance and to “ensure that there is a reasonable certainty that no harm will result to infants and children from aggregate exposure to the pesticide chemical residue * * *.”
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 propyzamide including exposure resulting from the tolerance established by this action. EPA's assessment of exposures and risks associated with propyzamide follows.
Propyzamide has low acute toxicity via the oral, dermal, and inhalation routes of exposure, is non-irritating to the eyes or skin, and is not a dermal sensitizer.
The primary target organ for propyzamide is the liver. There are other target organs as well, including the thyroid, testes, and pituitary, but effects on these organs are secondary to primary effects on the liver. Liver-related effects include increases in absolute and relative liver weights, hypertrophy, elevated levels of enzymes associated with liver damage, and histopathology of liver cells. Adverse liver effects were consistently observed in every animal species studied, with progression towards more severe effects over time ultimately leading to tumorigenesis in rats and mice. Based on the studies submitted, the rat is the most sensitive species. In most studies, there is no gender sensitivity in response to propyzamide.
Propyzamide is a carcinogen in rats and mice, causing liver tumors in mice, thyroid tumors in male rats, and testicular tumors in rats. Based on MOA studies, tumorigenesis for all three tumor types has been shown to be mediated by liver enzymes induced in response to treatment with propyzamide. In mice, the MOA data clearly show rapid induction of Cyp2b10 associated with the constitutive androstane nuclear receptor (CAR), as well as induction of peroxisomes and peroxisomal enzymes such as Cyp4a10 associated with a second nuclear receptor, PPAR-α. Induction of the nuclear receptors leads to mitogenesis followed by hepatocellular proliferation and eventually, liver tumors.
In rats, propyzamide induces Cyp2b1 200-fold over background levels, but has no effect on other CYPs commonly associated with carcinogenic modes of action. In the rat Cyp2b1 is a biological marker for the CAR receptor. The CAR pathway is associated with the activation of uridine diphosphate glucuronyl transferase (UGT) which catalyzes the condensation of glucuronic acid with thyroxine (T4), leading to enhanced biliary excretion of T4. Eventually the continued stimulus to produce more T4 leads to the formation of thyroid follicular tumors. In male rats, the tumorigenic dose of propyzamide for both thyroid tumors and Leydig cell tumors is 1,000 ppm in the diet (34-75 mg/kg/day based on age of the rats). Tumor precursor effects such as decreases in T4 levels, increases in liver weight, liver hypertrophy, and elevated testosterone metabolism occur at doses below or equivalent to the tumorigenic dose.
In nearly every oral repeated-dose study of propyzamide as well as in the 28-day dermal toxicity study in rats, there were dose-related decreases in body weight, body weight gain, and food consumption. Typically, these effects on body weight occurred at or above effects on the liver such as hypertrophy or increases in liver weight.
There was evidence of neurotoxicity in rats based on an increase in landing foot splay in females and decreases in motor activity in both genders in the acute neurotoxicity study. In the subchronic neurotoxicity study however, there was no evidence of neurotoxicity following dietary administration, and only body-weight effects were observed. There was no evidence of neurotoxicity in the rest of the toxicology database across other species or other strains of rat. There was no evidence of immunotoxicity.
There was no evidence of quantitative or qualitative increased susceptibility in the fetuses or the offspring of rats or rabbits following pre- and/or postnatal exposure to propyzamide. In the prenatal developmental toxicity study in rabbits and the multi-generation reproduction study in rats, any observed toxicity to the fetuses or offspring occurred at equivalent or higher doses than effects to parental animals.
Specific information on the studies received and the nature of the adverse effects caused by propyzamide as well as the no-observed-adverse-effect-level (NOAEL) and the lowest-observed-adverse-effect-level (LOAEL) from the toxicity studies can be found at http://www.regulations.gov in document “Pronamide Human Health Risk Assessment for Registration Review and to Support New Section 3 Use on Leaf Lettuce (Revised)” on pages 14-22 in docket ID number EPA-HQ-OPP-2014-0680.Start Printed Page 1528
A summary of the toxicological endpoints for propyzamide used for human risk assessment is shown in Table 1 of this unit.
Table 1—Summary of Toxicological Doses and Endpoints for Propyzamide for Use in Human Health Risk Assessment
Acute dietary (All populations) LOAEL = 40 mg/kg/day UFA = 10x UFH = 10x UFL = 10x FQPA SF = 1x Acute RfD = 0.04 mg/kg/day aPAD = 0.04 mg/kg/day Acute Neurotoxicity Rat Study No NOAEL established. LOAEL = 40 mg/kg/day based on increased landing foot splay and decreased motor activity.
Acute dietary (Females 13-49 years of age) No endpoint attributable to a single exposure was identified, including developmental toxicity studies in rats and rabbits.
Chronic dietary (All populations) LOAEL = 40 mg/kg/day UFA = 10x UFH = 10x UFL = 10x FQPA SF = 1x Chronic RfD = 0.04 mg/kg/day cPAD = 0.04 mg/kg/day POD = 4 mg/kg/day based on a weight-of-evidence approach from the following rat studies: Acute Neurotoxicity Study. No NOAEL established. LOAEL = 40 mg/kg/day based on increased landing foot splay and decreased motor activity POD = 4 mg/kg/day (LOAEL of 40 mg/kg/day ÷10x UFL)
Subchronic Neurotoxicity Study
NOAEL = 2.38 mg/kg/day LOAEL = 11.28 mg/kg/day based on significant decreases in body weight, body weight gain, and food consumption in males
Combined Chronic Toxicity/Carcinogenicity Study
NOAEL = 8.46/10.69 mg/kg/day
LOAEL = 42.59/55.09 mg/kg/day based on increased relative liver weight and histopathological lesions in the liver, thyroid, and ovaries
Male Pubertal Study
NOAEL = 2.5 mg/kg/day
LOAEL = 10 mg/kg/day based on decreased serum T4
Incidental oral short-term (1 to 30 days) LOAEL = 40 mg/kg/day LOC for MOE = 1,000 Same as Chronic dietary section above
UFA = 10x UFH = 10x UFL = 10x FQPA SF = 1x
Dermal short-term (1 to 30 days) and intermediate-term (1 to 6 months) NOAEL = 100 mg/kg/day (dermal absorption rate = 24%) LOC for MOE = 100 Subchronic Dermal Toxicity Rat Study LOAEL = 500 mg/kg/day based on decreases in body weight and food consumption
UFA = 10x UFH = 10x FQPA SF = 1x
Cancer (oral, dermal, inhalation) Classification: “Not Likely to be Carcinogenic to Humans” at doses that do not result in induction of hepatic cell proliferation or metabolic enzymes leading to disruption of thyroid or gonadal endocrine axes.
1. Dietary exposure from food and feed uses. In evaluating dietary exposure to propyzamide, EPA considered exposure under the petitioned-for tolerance as well as all existing propyzamide tolerances in 40 CFR 180.317. EPA assessed dietary exposures from propyzamide in food as follows:
i. Acute exposure. Quantitative acute dietary exposure and risk assessments are performed for a food-use pesticide, if a toxicological study has indicated the possibility of an effect of concern occurring as a result of a 1-day or single exposure. Such effects were identified for propyzamide. 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/WWEIA). As to residue levels in food, EPA assumed that propyzamide residues were present at tolerance levels in all commodities for which tolerances have been established or proposed, and that 100% of the crops were treated with propyzamide.
ii. Chronic exposure. In conducting the chronic dietary exposure assessment EPA used the food consumption data from the USDA 2003-2008 National Health and Nutrition Examination Survey, What We Eat in America (NHANES/WWEIA). As to residue levels in food, EPA assumed that propyzamide residues were present at tolerance levels in all commodities for which tolerances have been established or proposed, and that 100% of the crops were treated with propyzamide.
iii. Cancer. Based on the data summarized in Unit III.A., EPA has concluded that propyzamide does not pose a cancer risk to humans at doses that do not result in induction of hepatic cell proliferation or metabolic enzymes leading to disruption of thyroid or gonadal endrocrine axes. The MOAs were adequately supported by studies that clearly identified the sequence of key events, dose-response concordance and temporal relationship to the particular tumor type. Quantification of carcinogenic risk is not required. The chronic RfD would be protective of both carcinogenic and non-carcinogenic effects observed in the mouse and rat carcinogenicity studies and MOA studies conducted at higher doses. Therefore, a dietary exposure assessment for the purpose of assessing cancer risk is unnecessary.
iv. Anticipated residue and percent crop treated (PCT) information. EPA did not use anticipated residue and/or PCT information in the dietary assessment for propyzamide. Tolerance-level residues and 100 PCT were assumed for all food commodities.
2. Dietary exposure from drinking water. The Agency used Tier II screening level water exposure models in the dietary exposure analysis and risk assessment for propyzamide in drinking water. These simulation models take into account data on the physical, chemical, and fate/transport characteristics of propyzamide. Further information regarding EPA drinking water models used in pesticide exposure assessment can be found at http://www.epa.gov/​pesticide-science-and-assessing-pesticide-risks/​about-water-exposure-models-used-pesticide.
Based on the Tier II Surface Water Concentration Calculator (SWCC) and Pesticide Root Zone Model Ground Water (PRZM-GW), the estimated drinking water concentrations (EDWCs) of propyzamide for acute exposures are estimated to be 102 parts per billion (ppb) for surface water and 21 ppb for ground water; for chronic exposures for non-cancer assessments are estimated to be 47 ppb for surface water and 18.6 ppb for ground water.
Modeled estimates of drinking water concentrations were directly entered into the dietary exposure model. For acute dietary risk assessment, the water concentration value of 102 ppb was used to assess the contribution to drinking water. For chronic dietary risk assessment, the water concentration of value 47 ppb was used to assess the contribution to drinking water.
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). Propyzamide is currently registered for the following uses that could result in residential exposures: Turf grass and golf courses. EPA assessed residential exposure using the following assumptions: Post-application dermal and incidental oral exposures for children 1 to < 2 years old (physical activities on turf and hand-to-mouth ingestion of treated soil); and post-application dermal exposure for children 6 to < 11 years old (golfing), children 11 to < 16 years old (golfing and mowing), and adults (golfing, mowing, and physical activities on turf). Further information regarding EPA standard assumptions and generic inputs for residential exposures may be found at http://www.epa.gov/​pesticide-science-and-assessing-pesticide-risks/​standard-operating-procedures-residential-pesticide.
EPA has not found propyzamide to share a common mechanism of toxicity with any other substances, and propyzamide does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has assumed that propyzamide 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 Start Printed Page 1530the cumulative effects of such chemicals, see EPA's Web site at http://www.epa.gov/​pesticide-science-and-assessing-pesticide-risks/​cumulative-assessment-risk-pesticides.
2. Prenatal and postnatal sensitivity. There was no evidence of quantitative or qualitative increased susceptibility in developing fetuses or in offspring of rats or rabbits following prenatal and/or postnatal exposure to propyzamide.
3. Conclusion. EPA has determined that reliable data show the safety of infants and children would be adequately protected if the FQPA SF was reduced to 1X. This decision is based on the following findings:
i. The toxicity database for propyzamide is complete.
ii. There is no need for a developmental neurotoxicity study or additional UFs to account for neurotoxicity despite evidence of neurotoxicity in the acute study based on the increase in landing foot splay in female rats and the decrease in motor activity seen in both genders on day 1. This decision is based on no evidence of neurotoxicity in the subchronic study at dose levels tested via different routes of administration, and no evidence of neurotoxicity in the rest of the toxicology database across other species and other strains of rat.
iii. There is no evidence that propyzamide results in increased susceptibility in in utero rabbits in the prenatal developmental toxicity study or in young rats in the two-generation reproduction study.
iv. There are no residual uncertainties identified in the exposure databases. The dietary food exposure assessments were performed based on 100 PCT and tolerance-level residues. EPA made conservative (protective) assumptions in the ground and surface water modeling used to assess exposure to propyzamide in drinking water. EPA used similarly conservative assumptions to assess post-application exposure of children as well as incidental oral exposure of toddlers. These assessments will not underestimate the exposure and risks posed by propyzamide.
1. Acute risk. Using the exposure assumptions discussed in this unit for acute exposure, the acute dietary exposure from food and water to propyzamide will occupy 46% of the aPAD for all infants < 1 year old, the population subgroup receiving the greatest exposure.
2. Chronic risk. Using the exposure assumptions described in this unit for chronic exposure, EPA has concluded that chronic dietary exposure to propyzamide from food and water will utilize 11% of the cPAD for children 1 to 2 years old, the population subgroup receiving the greatest exposure. Based on the explanation in Unit III.C.3. regarding residential use patterns, chronic residential exposure to residues of propyzamide is not expected.
3. Short-term risk. Short-term aggregate exposure takes into account short-term residential exposure plus chronic exposure to food and water (considered to be background exposure level). Propyzamide is currently registered for uses that could result in short-term residential exposure, and the Agency has determined that it is appropriate to aggregate chronic exposure through food and water with short-term residential exposures.
Using the exposure assumptions described in this unit for short-term exposures, EPA has concluded that the combined short-term food, water, and residential exposure results in an aggregate MOE of 1,700 for children 1 to < 2 years old (chronic dietary exposure with post-application incidental oral exposure from turf use). Because EPA's level of concern for propyzamide is a MOE of 1,000 or below, this MOE is not of concern.
4. Intermediate-term risk. Intermediate-term aggregate exposure takes into account intermediate-term residential exposure plus chronic exposure to food and water (considered to be background exposure level). Propyzamide is currently registered for uses that could result in intermediate-term residential exposure. However, since the maximum single and yearly application rates are the same, the short-term assessment is protective of intermediate-term incidental oral exposure.
5. Aggregate cancer risk for U.S. population. As discussed in Unit III.C.iii., Propyzamide is classified as “Not Likely to be Carcinogenic to Humans” at doses that do not result in induction of hepatic cell proliferation or metabolic enzymes leading to disruption of thyroid or gonadal endocrine axes. Therefore, quantification of aggregate cancer risk is not required.
6. 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 propyzamide residues.
Adequate enforcement methodologies are available to enforce the tolerance expression of residues in/on plant commodities (PAM II Method I, using gas-liquid chromatography with electron-capture detection (GLC/ECD)) and livestock commodities (Method GRM 02.21, using gas chromatography with negative-ion chemical ionization mass spectrometry detection (GC/MS)). These methods may be requested from: Chief, Analytical Chemistry Branch, Environmental Science Center, 701 Mapes Rd., Ft. Meade, MD 20755-5350; telephone number: (410) 305-2905; email address: residuemethods@epa.gov.
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 Organization food standards program, Start Printed Page 1531and 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 any MRLs for propyzamide.
Therefore, tolerances are established for residues of propyzamide (pronamide), 3,5-dichloro-N-(1,1-dimethyl-2-propynyl)benzamide, in or on lettuce, leaf at 1.0 ppm.
2. In § 180.317, add alphabetically “Lettuce, leaf” to the table in paragraph (a) to read as follows:
Lettuce, leaf 1.0
[FR Doc. 2016-00534 Filed 1-12-16; 8:45 am]