Source: https://www.federalregister.gov/documents/2012/03/02/2012-4984/trinexapac-ethyl-pesticide-tolerances
Timestamp: 2018-04-22 11:17:08
Document Index: 762906345

Matched Legal Cases: ['art 178', 'art 178', 'art 2', 'art 180', 'art 180', 'art 158']

12740-12746 (7 pages)
FRL-9337-9
https://www.federalregister.gov/d/2012-4984 https://www.federalregister.gov/d/2012-4984
This regulation establishes tolerances for residues of trinexapac-ethyl in or on multiple commodities which are identified and discussed later in this document. Syngenta Crop Protection, Inc. requested these tolerances under the Federal Food, Drug, and Cosmetic Act (FFDCA).
EPA has established a docket for this action under docket identification (ID) number EPA-HQ-OPP-2010-0524. All documents in the docket are listed in the docket index available at http://www.regulations.gov. Although listed in the index, some information is not publicly available, e.g., Confidential Business Information (CBI) or other information whose disclosure is restricted by statute. Certain other material, such as copyrighted material, is not placed on the Internet and will be publicly available only in hard copy form. Publicly available docket materials are available in the electronic docket at http://www.regulations.gov, or, if only available in hard copy, at the OPP Regulatory Public Docket in Rm. S-4400, One Potomac Yard (South Bldg.), 2777 S. Crystal Dr., Arlington, VA. The Docket Facility is open from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The Docket Facility telephone number is (703) 305-5805.
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-2010-0524 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 May 1, 2012. 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 that does not contain any 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 a copy of your non-CBI objection or hearing request, identified by docket ID number EPA-HQ-OPP-2010-0524, by one of the following methods:
In the Federal Register of August 4, 2010, (75 FR 46925) (FRL-8834-9), EPA issued a notice pursuant to section 408(d)(3) of FFDCA, 21 U.S.C. 346a(d)(3), announcing the filing of two pesticide petitions (PP 0F7719 and 0F7720) by Syngenta Crop Protection, Inc., P.O. Box 18300, Greensboro, NC 27419. Petition 0F7719 requested that 40 CFR part 180 be amended by establishing tolerances for residues of the plant growth regulator, trinexapac-ethyl and its primary metabolite CGA-179500, in or on grass, forage, grown for seed at 1.60 parts per million (ppm); grass, hay, grown for seed at 3.5 ppm; grass, seed screenings, grown for seed at 45.0 ppm; grass, straw, grown for seed at 12 ppm; cattle (fat, meat, meat byproducts) at 0.05 ppm; goat (fat, meat, meat byproducts) at 0.05 ppm; horse (fat, meat, meat byproducts) at 0.05 ppm and sheep (fat, meat, meat byproducts) at 0.05 ppm. Petition 0F7720 requested that 40 CFR part 180 be amended by establishing tolerances for residues in or on barley, grain at 1.6 ppm; barley, hay at 0.7 ppm; barley, straw at 0.35 ppm; cattle, kidney at 0.05 ppm; hog, kidney at 0.05 ppm; oat, forage at 1.0 ppm; oat, grain at 4.1 ppm; oat, hay at 1.3 ppm; oat, straw at 0.7 ppm; sugarcane, cane at 0.8 ppm; wheat, forage at 1.0 ppm; wheat, grain at 4.1 ppm; wheat, hay at 1.3 ppm and wheat, straw at 0.7 ppm.
That notice referenced a summary of the petitions prepared by Syngenta Crop Protection, Inc., the registrant, which is available in the docket, http://www.regulations.gov.
Based upon review of the data supporting the petition, EPA has revised most of the proposed tolerance levels, added tolerances for hog fat and meat, and deleted the proposed tolerance for cattle kidney. The reasons for these changes are explained in Unit IV.D.
Consistent with section 408(b)(2)(D) of FFDCA, and the factors specified in section 408(b)(2)(D) of FFDCA, 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 trinexapac-ethyl including exposure resulting from the tolerances established by this action. EPA's assessment of exposures and risks associated with trinexapac-ethyl follows.
The acute toxicity of trinexapac-ethyl is low via the oral, eye, dermal, or inhalation routes of exposure, and it is not a dermal sensitizer.
In adult animals (rats, rabbits, mice, dogs), no systemic adverse effects are seen below the limit dose following subchronic or chronic oral exposure with the exception of dogs. The 90-day subchronic dog study showed decreased body weight gain and food consumption, diffuse thymic atrophy, and changes in the epithelial cells of the renal tubules at 516/582 milligrams/kilogram/day (mg/kg/day) (males/females). Following chronic exposure, dose-related neuropathology of the brain was seen at ≥365/357 mg/kg/day in male and female dogs respectively. The lesions remained confined to the supporting cells in the central nervous system and did not progress to more advanced or more extensive damage of the nervous tissue. They were not associated with other neuropathological findings or overt neurological signs so their biological significance is unknown. Similar lesions were not observed in the rat or mouse following acute, subchronic or chronic dietary exposure, and there was no other evidence in any other species tested to indicate a neurotoxicity potential. Furthermore, the brain lesions observed in the chronic dog study were not observed in the sub-chronic dog study up to 890 mg/kg/day and are thus not likely to develop from a short-term exposure.
Evidence of increased qualitative and quantitative susceptibility to offspring exists at or above the limit dose of the developmental and reproduction studies. Developmental toxicity was observed in the rat (increased incidence of asymmetrical sternebrae) and rabbit (decreased number of live fetuses/litter and increased post-implantation loss) at the highest dose tested, with no evidence of maternal toxicity observed in either species. In the rat reproduction study, reproductive toxicity was not observed, but decreased pup survival and decreased pup body weight/body-weight gain during lactation were observed above the limit dose with only reduced body weight and food consumption observed in the parental animals (>1,200 mg/kg/day).
Trinexapac-ethyl is classified as “Not likely to be carcinogenic to humans.” The combined chronic toxicity/carcinogenicity study in the rat did not demonstrate an increase in any tumor type that would be relevant to humans. In the mouse, there was no evidence of carcinogenicity. The mutagenicity database is also complete, with no evidence of mutagenicity.
Specific information on the studies received and the nature of the adverse effects caused by trinexapac-ethyl as well as the no-observed-adverse-effect-level and the lowest-observed-adverse-effect-level from the toxicity studies can be found at http://www.regulations.gov in the document, “Trinexapac-ethyl: Human Health Risk Assessment for the Section 3 Registration Action on Cereal Grains, Sugarcane, and Grasses Grown for Seed” p. 48 in docket ID number EPA-HQ-OPP-2010-0524.
Once a pesticide's toxicological profile is determined, EPA identifies toxicological points of departure (POD) and levels of concern (LOC) 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 (U/SF) are used in conjunction with the POD to calculate a safe exposure level—generally referred to as a population-adjusted dose (PAD) or a reference dose (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 trinexapac-ethyl used for human risk assessment is shown in Table 1 of this unit.
Table 1—Summary of Toxicological Doses and Endpoints for Trinexapac-ethyl for Use in Human Health Risk Assessment
Acute dietary (Females 13-49 years of age) NOAEL = 60 mg/kg/day. UFA = 10×. UFH = 10×. FQPA SF = 1×. Acute RfD = 0.6 mg/kg/day aPAD = 0.6 mg/kg/day Developmental rabbit study. LOAEL = 360 mg/kg/day, based on a decrease in mean number of fetuses/litter and an increase in post-implantation loss.
Acute dietary (General population including infants and children) No appropriate endpoint for the general population including infants and children
Chronic dietary (All populations) NOAEL = 31.6 mg/kg/day. UFA = 10×. UFH = 10×. FQPA SF = 1×. Chronic RfD = 0.32 mg/kg/day cPAD = 0.32 mg/kg/day Chronic oral toxicity study—dog. LOAEL = 357 mg/kg/day, based on elevated serum cholesterol values in females, mucoid feces in females and bloody feces in both sexes, and minimal, focal vacuolation of the dorsal medial hippocampus and/or lateral midbrain in both sexes.
Incidental oral (short and intermediate-term) No appropriate endpoint for the incidental oral scenario for children
Dermal & Inhalation (short- and intermediate-term-adults only) Dermal (or oral) study NOAEL = 60 mg/kg/day (dermal absorption rate = 77.5%. UFA = 10×. UFH = 10×. FQPA SF = 1×. Residential LOC for MOE = 100 Occupational LOC for MOE = 100 Developmental rabbit study. LOAEL = 360 mg/kg, based on a decrease in mean number of fetuses/litter and an increase in post-implantation loss.
UFA = extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = Food Quality Protection Act Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. Mg/kg/day—milligrams per day.
1. Dietary exposure from food and feed uses. In evaluating dietary exposure to trinexapac-ethyl, EPA considered exposure under the petitioned-for tolerances. There are no tolerances currently established for trinexapac-ethyl. EPA assessed dietary exposures from trinexapac-ethyl 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. In estimating acute dietary exposure, EPA used food consumption information from the U.S. Department of Agriculture (USDA) 1994-1996 and 1998 Nationwide Continuing Surveys of Food Intake by Individuals (CSFII). As to residue levels in food, EPA assumed that residues are present in all commodities at the tolerance level and that 100% of commodities with tolerances are treated with trinexapac-ethyl. Dietary Exposure Evaluation Model (DEEMTM) 7.81 default concentration factors were used to estimate residues of trinexapac-ethyl in processed commodities. The acute dietary exposure was only estimated for females 13 to 49 years old based on an in utero effect (decrease in mean number of fetuses/litter and an increase in post-implantation loss) identified in the rabbit developmental study. An endpoint of concern was not identified for the general U.S. population; however, the acute dietary assessment is protective of women that may become pregnant.
ii. Chronic exposure. In estimating chronic dietary exposure, EPA used food consumption information from the USDA 1994-1996 and 1998 CSFII. As to residue levels in food, EPA assumed that residues are present in all commodities at the tolerance level and that 100% of commodities with tolerances are treated with trinexapac-ethyl. DEEMTM 7.81 default concentration factors were used to estimate residues of trinexapac-ethyl in processed commodities.
iii. Cancer. Based on the data summarized in Unit III.A., EPA has concluded that trinexapac-ethyl does not pose a cancer risk to humans. Therefore, a dietary exposure assessment for the purpose of assessing cancer risk was not conducted.
Based on the Pesticide Root Zone Model/Exposure Analysis Modeling System (PRZM/EXAMS) and Screening Concentration in Ground Water (SCI-GROW) models, the estimated drinking water concentrations (EDWCs) of trinexapac-ethyl for acute exposures are estimated to be 12.61 parts per billion (ppb) for surface water and 0.009 ppb for ground water. Chronic exposures for non-cancer assessments are estimated to be 1.56 ppb for surface water and 0.009 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 of value of 12.61 ppb was used to assess the contribution to drinking water. For chronic dietary risk assessment, the water concentration of value 1.56 ppb was used to assess the contribution to drinking water.
Trinexapac-ethyl is currently registered for the following uses that could result in residential exposures: Residential lawns, athletic fields, parks, and golf courses. EPA assessed residential exposure with the assumption that homeowner handlers wear shorts, short-sleeved shirts, socks, and shoes, and that they complete all tasks associated with the use of a pesticide product including mixing/loading, if needed, as well as the application. Residential handler exposure scenarios for both dermal and inhalation are considered to be short-term only, due to the infrequent use patterns associated with homeowner products.
EPA uses the term “post-application” to describe exposure to individuals that occur as a result of being in an environment that has been previously treated with a pesticide. Trinexapac-ethyl can be used in many areas that can be frequented by the general population including residential areas (e.g., home lawns, recreational turf). As a result, individuals can be exposed by entering these areas if they have been previously treated. Therefore, short-term dermal post-application exposures and risks were also assessed for trinexapac-ethyl. There is the potential for incidental oral exposure; however, since there is no toxicological endpoint of concern for that route, a quantitative assessment was not conducted. Further information regarding EPA standard assumptions and generic inputs for residential exposures may be found at http://www.epa.gov/pesticides/trac/science/trac6a05.pdf.
2. Prenatal and postnatal sensitivity. Evidence of increased susceptibility to offspring exists at or above the limit dose of the developmental and reproduction studies. Developmental toxicity was observed in the rat (increased incidence of asymmetrical sternebrae) and rabbit (decreased number of live fetuses/litter and increased post-implantation loss) at the highest dose tested, with no evidence of maternal toxicity observed in either species. In the rat reproduction study, reproductive toxicity was not observed, but decreased pup survival and decreased pup body weight/body-weight gain during lactation were observed above the limit dose with only reduced body weight and food consumption observed in the parental animals (>1,200 mg/kg/day).
i. The toxicology database for trinexapac-ethyl is largely complete, with the exception of a subchronic neurotoxicity study, which is a new data requirement under 40 CFR part 158 for registration of a pesticide (food and non-food uses OPPTS 870.6200b). Though dose-related neuropathology of the brain was observed in the dog, EPA has concluded that there is no need for a developmental neurotoxicity (DNT) study or additional UFs to account for neurotoxicity for the following reasons:
These effects in the dog study were observed only at high doses (>357 mg/kg/day) and with chronic exposure, and no associated neurological signs or other neuropathology were observed. Furthermore, the lesions remained confined to the supporting cells in the central nervous system (CNS) and did not progress to more advanced or more extensive damage of the nervous tissue. There are clear NOAELs/LOAELs for this effect; in which the NOAEL dose is 10-fold lower than the LOAEL dose at which neuropathology is observed, and is therefore sufficiently protective. Furthermore, similar lesions were not observed in the rat or mouse following subchronic or chronic dietary exposure, and there was no other evidence in any species tested to indicate a neurotoxicity potential.
Results of the acute neurotoxicity study show no indications of neurotoxicy at the highest dose.
Although subchronic inhalation data on trinexapac-ethyl are not available and an oral study was selected for inhalation risk assessment, the selected points of departure are considered adequately protective for all exposed populations. Therefore, an additional 10x database UF was not retained for lack of inhalation toxicity data and these data are not being required.
ii. Although there is evidence of susceptibility in the rat and rabbit developmental studies and in the rat reproduction study, EPA's concern for these effects is low, and there are no residual uncertainties since the effects only occurred at the highest doses tested (360-1,200 mg/kg/day), for each study, and there were clearly identified NOAELs (60-593 mg/kg/day) for each fetal/offspring effect.
iii. There are no residual uncertainties in the exposure database. Because the acute and chronic dietary exposure estimates were based on several conservative assumptions (100% of crops treated with residues present at tolerance levels, default processing factors and screening level drinking water estimates), EPA is confident that the dietary exposure assessments do not underestimate risk to the general U.S. population and various population subgroups. Similarly, EPA does not believe that the non-dietary residential exposures are underestimated because they are based on the conservative assumptions of EPA's Draft Standard Operating Procedures (SOPs) for Residential Exposure Assessments (December 1997), and updates contained in the Science Advisory Council Policy 12 (February 2001) as well as the uses specified in the proposed labels.
1. Acute risk. Acute aggregate risk takes into account exposure to residues in food and drinking water alone. Therefore, acute aggregate risk is equivalent to the acute dietary risk as discussed in Unit III.C.1.i. All risk estimates are below EPA's level of concern. The acute dietary exposure estimate for females 13 to 49 years old will only utilize 2% of the aPAD, which is well below the Agency's level of concern (100% of the aPAD).
2. Chronic risk. Using the exposure assumptions described in this unit for chronic exposure, EPA has concluded that chronic exposure to trinexapac-ethyl from food and water will utilize 6% of the cPAD for children 1 to 2 years old, the population group receiving the greatest exposure. Based on the residential use patterns for trinexapac-ethyl, chronic residential exposure to residues is not expected.
3. Short- and intermediate-term risk. Since the short- and intermediate-term toxicological endpoints for trinexapac-ethyl are the same for each route of exposure, only short-term exposures were assessed. Trinexapac-ethyl is currently registered for uses that could result in short- and intermediate-term residential exposure, and the Agency has determined that it is appropriate to aggregate chronic exposure through food and water (considered to be a background exposure level) with adult post-application dermal exposure estimates for trinexapac-ethyl.
Using the exposure assumptions described in this unit, EPA has concluded the combined food, water, and adult post-application dermal exposures result in aggregate MOEs of 761 for liquid products and 601 for granular products. Because EPA's level of concern for trinexapac-ethyl is a MOE of 100 or below, these MOEs are not of concern.
4. Aggregate cancer risk for U.S. population. Based on the lack of evidence of carcinogenicity in two adequate rodent carcinogenicity studies, trinexapac-ethyl is not expected to pose a cancer risk to humans.
Adequate enforcement methodology (Method GRM020.01A, which utilizes high performance liquid chromatography with triple-quadrupole mass spectrometry (LC-MS/MS)) is available to enforce the tolerance expression.
There are no established or proposed Codex, Canadian, or Mexican MRLs for trinexapac-ethyl in or on any food or feed crops.
Many of the proposed tolerances are different from the tolerances being set by EPA. EPA is setting different levels than were proposed based on EPA's analysis of the field trial data using the Organization for Economic Cooperation and Development tolerance calculation procedures. Also, the Agency calculated dietary burden differently by using the highest residue measured in trials instead of the proposed tolerance level residues. Table 2.2.3, “Tolerance Summary for Trinexapac-ethyl” summarizes these differences on page 8 of the document, “Trinexapac-ethyl: Human Health Risk Assessment for the Section 3 Registration Action on Cereal Grains, Sugarcane, and Grasses Grown for Seed” which is located in docket ID number EPA-HQ-OPP-2010-0524.
Therefore, tolerances are established for residues of trinexapac-ethyl, including its metabolites and degradates, as set forth in the regulatory text. Compliance with the tolerance levels is to be determined by measuring both trinexapac-ethyl, ethyl 4-(cyclopropylhydroxymethylene)-3,5-dioxocyclohexanecarboxylate and the associated metabolite trinexpac, 4-(cyclopropylhydroxymethylene)-3,5-dioxocyclohexanecarboxylic acid, calculated as the stoichiometric equivalent of trinexapac-ethyl.
2. Section 180.662 is added to subpart C to read as follows:
(a) General. Tolerances are established for residues of the plant growth inhibitor, trinexapac-ethyl, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring both trinexapac-ethyl, ethyl 4-(cyclopropylhydroxymethylene)-3,5-dioxocyclohexanecarboxylate and the associated metabolite, trinexpac, 4-(cyclopropylhydroxymethylene)-3,5-dioxocyclohexanecarboxylic acid, calculated as the stoichiometric equivalent of trinexapac-ethyl, in or on the commodity.
Grass, forage 1.5
Grass, seed screenings 40.0
Grass, straw 10.0
Hog, kidney 0.03
Oat, grain 4.0
Oat, hay 1.5
Oat, straw 0.9
Sugarcane, cane 0.8
Wheat, grain 4.0
Wheat, middlings 6.5
Wheat, straw 0.9
[FR Doc. 2012-4984 Filed 3-1-12; 8:45 am]