Document ID: EPA-HQ-OPP-2018-0053-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2020-01-14T05:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER  

EPA Registration Division contact: Elizabeth Fertich, (703) 347-8560

TEMPLATE:

BASF Corporation

[Insert petition number]

	EPA has received a pesticide petition [Insert petition number] from BASF Corporation, 26 Davis Drive, P.O. Box 13528, Research Triangle Park, North Carolina 27709-3528 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 the insecticide broflanilide, including its metabolites and degradates, in or on the commodities in this petition.  Compliance with the tolerance levels specified below is to be determined by measuring only broflanilide, (3-(benzoylmethylamino)-N-[2-bromo-4-[1,2,2,2-tetrafluoro-1- (trifluoromethyl)ethyl]-6-(trifluoromethyl)phenyl]-2-fluorobenzamide) in or on the following raw agricultural commodities: grain, cereal, except rice, group 15; amaranth grain; quinoa, grain; spelt, grain; cañihua, grain; chia, grain; cram-cram, grain; huauzontle, grain; teff, grain; Corn, sweet, kernel plus cob with husks removed at 0.01 parts per million (ppm) and commodity vegetable, tuberous and corm, subgroup 1C at 0.04 parts per million (ppm). For food items (animal origin), the following tolerances will be proposed: cattle, meat; goat, meat; horse, meat; sheep, meat at 0.01 parts per million (ppm), and commodity milk, fat; poultry, fat at 0.02 parts per million (ppm), and commodity cattle, fat; sheep, fat; goat, fat at 0.05 parts per million (ppm). For feed items, the following tolerances will be proposed: grain, cereal, forage, fodder and straw, group 16, except rice; quinoa, hay; teff, hay; corn, sweet, stover; corn, sweet, forage at 0.01 parts per million (ppm), and commodity corn, field, milled products at 0.015 parts per million (ppm) and potato, wet peel at 0.1 parts per million (ppm)for processed commodities.

In addition, BASF is proposing to establish a tolerance of 0.01 ppm for residues of broflanilide in or on all food items in food handling establishments where food and food products are held, processed, prepared and/or served.  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.

 Residue Chemistry
   
	1. Plant metabolism. The metabolism of broflanilide was investigated in seven crops from five different OECD crop categories: tomato (fruits), Japanese radish (vegetables), cabbage (leafy crops), wheat and rice (cereals), soybean (pulses and oilseeds) and tea. The studies were performed with [14]C-broflanilide. Two different radiolabels were used in the studies: [B-ring-U-[14]C]-broflanilide and [C-ring-U-[14]C]-broflanilide. In context of all metabolism studies conducted, both labels were applied, except for the wheat metabolism study, in which only [B-ring-U-[14]C]-broflanilide was used for seed treatment. 

Broflanilide represented >= 60% of TRR in all matrices analyzed across all crops, with the exception of the wheat seed treatment study, in which due to the very low radioactive residues no metabolites were identified. In addition, in brown rice (C-label) parent broflanilide only presented 12.5% of TRR due to high amounts of radioactive residues bound to natural components such as starch and proteins. 

The results of the plant metabolism studies suggest, that after treatment with broflanilide in plant matrices unchanged broflanilide is the major component. Broflanilide is metabolized by two routes, either demethylation to metabolite DM-8007 by loss of a methyl group or formation of S(PFP-OH)-8007 by oxidative defluorination (substitution of fluorine with hydroxyl); both metabolites approach but do not exceed 10% of TRR. 

A confined rotational crop study with application of 14C-broflanilide to bare soil at the highest maximum annual application rate demonstrated low uptake and rapid degradation in the plant of those residues taken up from the soil. Neither parent nor any metabolite exceeded the level of 0.01 mg/kg in any food item at the replant intervals tested (30, 60 and 270 DAT). In feed, B-oxam-acid and B-urea metabolites exceeded the levels of 0.01 mg/kg and 10% TRR in wheat hay only.

Based on the performed studies, the metabolic pathway is considered as similar in a range of crop categories and is well understood.

	2. Analytical method. An independently validated analytical method has been submitted for analyzing residues of parent broflanilide and its metabolites S(PFP-OH)-8007 and DM-8007, each with appropriate sensitivity in all crop and processed commodities. An independently validated analytical method has been submitted for analyzing residues of parent broflanilide plus metabolites DM-8007 and DC-DM-8007 in animal matrices by LC-MS/MS with appropriate sensitivity to allow establishment of tolerances.  The food handling matrices samples were analyzed for broflanilide residues using a combination of the plant and animal methods with minor modifications.

	3. Magnitude of residues. Field trials were carried out to determine the magnitude of the residue of broflanilide and its metabolites S(PFP-OH)-8007 and DM-8007 in/on potato, corn (field and sweet), wheat and barley. The number and locations of field trials are in accordance with OPPTS Guideline 860.1500. Field trials were carried out using the maximum label rates, the maximum number of applications, the minimum retreatment interval and the minimum pre-harvest interval (PHI) for all the crops. Trials in barley and wheat were performed for seed treatment.  Residue studies in corn (in furrow) and potato were performed.  To support a food handling use, investigations were carried out simulating treatment with covered and uncovered food. For the target crops, suitable processing studies were performed indicating no concentrations of residues in humanly consumed food, and limited increases in a few feed items. A limited field rotational crops study was conducted indicating a favorable residue behavior in representative succeeding crops.  The majority of proposed tolerances are at 0.01 mg/kg; all tolerances are supported by field or experimental data.

B. Toxicological Profile

	1. Acute toxicity. Broflanilide has no significant acute toxicity via oral, dermal, and inhalation exposure routes. The test substance is not irritating to the skin or the eye and is not a dermal sensitizer
 
	2. Genotoxicty. Broflanilide was negative over a range of standard test batteries, including bacterial and mammalian mutagenicity assays as well as in-vitro and in-vivo mammalian clastogenicity studies.

	3. Reproductive and developmental toxicity. In a 2-generation reproduction study, there were no effects on fertility or reproductive performance at dose levels of up to 15000 ppm  -  the highest dose tested.  Developmental toxicity did not occur in the absence of parental toxicity and no signs of selective developmental toxicity, or evidence for increased susceptibility of the offspring were seen in the 2-generation reproduction study.  Therefore, broflanilide is not considered a reproductive toxicant.

In developmental studies with Wistar rats and New Zealand White rabbits, broflanilide was not associated with teratogenicity, developmental or maternal toxicity at dose levels of up to limit dose (1000 mg/kg bw/d).  Therefore, broflanilide is not considered to be teratogenic.

	4. Subchronic toxicity. Subchronic term exposures of broflanilide to rats, mice and dogs by the oral route resulted in some organ weight increases and histopathological findings.  The principal target organ in all studies was the adrenal gland and ovaries, as indicated by organ weight and associated histopathological changes at high doses, characterized by adrenal and ovarian vacuolation, with vacuolar lipid and cholesterol deposits.  Findings at the LOAEL were typically only mildly adverse (compensatory effects, slight changes in clinical chemistry, and organ weight changes without severe histopathological findings) and occurred at dose levels equivalent to, or exceeding kinetically derived maximum dose (KMD). 

Dermal exposure of broflanilide to rats for 28-days did not result in any treatment-related changes, up to the limit dose of 1000 mg/kg.  Subchronic inhalation exposures of rats to broflanilide for 28 days resulted in a No Observed Adverse Effect Concentration (NOAEC) of 30 mg/m³, characterized by reversible respiratory portal of entry effects at the LOAEC.  In a subchronic immunotoxicity study, broflanilide showed no signs of immunotoxicity when administered via the diet over a period of 4 weeks to male Wistar rats. The immunotoxicity and systemic effects NOAELs were determined to be the limit dose of 1020 mg/kg bw/d.

	5. Chronic toxicity.  In a rat combined chronic / carcinogenicity study statistically significantly increased incidence of benign, and unilateral, Leydig cell adenomas, ovarian benign granulosa cell tumors and uterine adenocarcinomas were seen at dose levels exceeding KMD.  These tumor incidences showed a general lack of dose response, as well as human relevance.  The carcinogenicity NOAEL for males was 1500 ppm (70 mg/kg bw/day) based on benign Leydig cell adenomas (unilateral) at limit dose.  In females, the carcinogenicity NOAEL was 300 ppm (19 mg/kg bw/day) based on benign granulosa cell tumors at 1500 ppm, albeit not at the next higher limit dose level.  Additionally, increased absolute and relative adrenal weights were observed in males and females at >300 ppm, correlating histopathologically with non-adverse but increased vacuolar lipid and cholesterol deposits.  The chronic NOAEL was 15,000 ppm equivalent to 822 and 1128 mg/kg bw/day, respectively, in males and females.

In an 18-month carcinogenicity study in mice, there was no evidence of carcinogenicity at any dose level in either sex, and the NOAEL was, therefore, 745 or 820 mg/kg bw/day for males and females, respectively.  Broflanilide is proposed to be not likely carcinogenic to humans.  However, all tumor incidences showed non-adverse thresholds and the chronic reference dose will hence be protective of any potential carcinogenicity.

	6. Animal metabolism. The metabolism of broflanilide was investigated in the rat, the laying hen and the lactating goat. All studies were performed with [14]C-broflanilide with two labels: the B-label and the C-label. The majority of excreted radioactivity was in the feces for all species across all labels.  Overall metabolic pathways in livestock and rat were noted as similar, but there was more extensive metabolism in livestock than in rat. 

The identified metabolites comprise the following phase I and phase II conversions of the parent compound broflanilide.  The most prominent metabolites in goat and hen DM-8007, DC-DM-8007 and the natural product hippuric acid, were identified in the rat metabolism studies.  Hydroxylation of the aromatic ring system followed by phase II conjugation reactions were observed in both livestock and rats. The presence of the crop metabolites DM-8007 and S(PFP-OH)-8007 was observed in both livestock species. Thus, no separate investigations are needed for covering potential feeding of plant material after treatment with broflanilide.  For broflanilide, the ruminant feeding study is relevant for swine as a similar metabolic pathway has been observed in the rat and goat metabolism studies.

	7. Metabolite toxicology. Plant, ruminant and environmental metabolites of quantitative significance were evaluated for their safety and hazard profile in multiple test systems, including acute, subchronic and genotoxicity studies.  The metabolites DM-8007 and DC-DM-8007 were not found in significant amounts in the rat metabolism studies; therefore, toxicological investigations were performed.  The metabolites B-oxam-acid and B-urea were only found in feed items during the [14]C rotational crop study after application to bare soil under worst-case conditions. Thus, the potential exposure of humans is very low. Furthermore, the structures of these two polar metabolites does not raise toxicological concerns based on SAR analysis.  Based on the studies conducted with these metabolites, the respective hazard profiles and points of departure did not differ appreciably from the parent molecule.

	8. Endocrine disruption. No special studies have been conducted to determine whether broflanilide induces estrogenic, or other endocrine effects.  However, there were no significant findings in the relevant toxicity studies (e.g., subchronic, chronic, developmental and multigeneration reproduction studies) that suggest that broflanilide produces any endocrine disruption.

C. Aggregate Exposure 

	1. Dietary exposure. The tolerance expression proposed for monitoring in plant commodities is broflanilide, parent only. The sum of broflanilide and its metabolites S(PFP-OH)-8007 and DM-8007 (expressed as broflanilide) is proposed for inclusion in the tolerance expression for risk assessment for crops.
The proposed tolerance expression for monitoring in animal commodities is broflanilide and its metabolite DM-8007 (expressed as broflanilide). The proposed tolerance expression for dietary risk assessment in animal matrices is broflanilide and its metabolites DM-8007 and DC-DM-8007 (expressed as broflanilide).
Exposure assessments were conducted to evaluate the potential risk due to chronic dietary exposure of the U.S. population and all sub-populations. The assessments were performed with DEEM-FCID version 4.02 with consumption data from the 2005-2010 NHANES surveys.

	i. Food. Because no acute reference dose is proposed, no acute dietary assessment is conducted.  The proposed endpoint for use in the chronic dietary assessment is shown below.  

Table1. Summary of toxicological dose and endpoint for broflanilide in chronic dietary assessment
                               Exposure/scenario
                              Point of departure
                                 Safety factor
                                      RfD
                        Study and toxicological effects
                       Chronic dietary (all populations)
                             NOAEL = 19 mg/kg bw/d
                                      100
                         Chronic RfD = 0.19 mg/kg bw/d
Combined Chronic Toxicity/Carcinogenicity Study in Wistar Rats. Administration via the Diet up to 24 Months
NOAEL = 300 mg/kg day based on feed

Exposure to broflanilide residues is based on the crop uses supported in this submission.  The chronic dietary exposure assessment was partially refined. The exposure estimates are based on proposed tolerances from the residue trials or livestock calculations assuming 100% CT. For remaining commodities (derived from the food handling use), tolerances of 0.01 mg/kg were modified by the projected probability of % FHE treatment.  Processing factors used include a default concentration value for dried beef and corn syrup, plus experimental values for wheat germ, corn bran and corn flour from the grain processing studies.   The default factor for dried potatoes was replaced with a value of 2.0 X based on the experimental potato processing study.

Drinking water estimation of 0.838 ug/L (0.000838 mg/L) were included in the dietary exposure assessment based on a US surface water model.  Several use patterns were reviewed: seed treatment uses on cereals, corn and potato, and the T-band/in-furrow applications on corn and potato. Of these the corn in furrow-use surface water results in the highest value. This number also accounts for the DC-8007 metabolite in a Total Toxic Residue (TTR) approach, which involves re-fitting the kinetic evaluations for the aerobic and anaerobic aquatic studies.  Furthermore, the sorption endpoint and water solubility from the DC-8007 metabolite were used in this worst-case approach. 

Dietary exposure estimates were compared against the chronic Population Adjusted Dose (cPAD) of 0.19 mg/kg b.w./day for all populations subgroups. The results of the chronic dietary assessment including food and water are presented in Table 2. The most highly exposed population sub-group was non-nursing infants and children 1-2 years of age which utilized 0.1% RfD. 

Table 2.  Results for BAS 450 I Chronic Dietary Exposure (Food and Water) Considering All Current, Pending, and Proposed Tolerances using DEEM-FCID
                                Sub-Population
                               mg/kg body wt/day
                                Percent of RfD
Total US Population
                                   0.000110
                                     0.10%
All Infants
                                   0.000203
                                     0.10%
Children 1-2
                                   0.000276
                                     0.10%
Children 3-5
                                   0.000230
                                     0.10%
Children 6-12
                                   0.000159
                                     0.10%
Youth 13-19
                                   0.000106
                                     0.10%
Adults 20-49
                                   0.000094
                                     0.00%
Adults 50-99
                                   0.000083
                                     0.00%
Female 13-49
                                   0.000088
                                     0.00%

The results of the risk assessment show that for all populations the exposures are below a level of concern (< 100% cPAD). Additional refinements in the dietary risk assessment (i.e. utilizing anticipated residue values, percent crop treated values) would further reduce the estimated exposure values.

	ii. Drinking water.  The consumption of broflanilide residues in drinking water was included in the chronic dietary assessments above. 

	2. Non-dietary exposure. 
BASF is proposing indoor residential uses of broflanilide that could lead to non-dietary exposure of consumers.   Based on review of the comprehensive toxicology database for broflanilide, BASF concludes that no dermal hazard was identified and therefore dermal exposures are not assessed.  In addition, because the inhalation NOAEL is based on portal of entry effects, inhalation exposures are not aggregated with oral exposures based on different toxicological effects.  The incidental oral exposures for aggregation are based on the worst-case indoor use for crack and crevice application for nuisance pest control.  Short-term aggregate exposure and risk for food, water and residential use are shown in the table below.  The calculated MOEs for the aggregate exposures are well above the target MOE of 100 indicating that these exposures are not of concern.

   Table 3. Estimated Short-Term Aggregate Exposure and Risk for Broflanilide (Food, Drinking Water, and Residential exposure) 
                                Sub-Population
                                  Target MOE
                         Dietary Exposure (mg/kg/day)
                     Incidental Oral Exposure (mg/kg/day)
                                Total Exposure
                                  (mg/kg/day)
                               Aggregate MOE[1]
                                   Total US
                                      100
                                   0.000110
                                      NA
                                   0.000110
                                    172727
                               Child 1-2 yr old
                                      100
                                   0.000276
                                   0.000529
                                   0.000805
                                     23613
   [1] NOAEL = 19 mg/kg bw/day
 
D. Cumulative Effects  

Section 408(b)(2)(D)(v) of the Federal Food, Drug and Cosmetic Act requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency consider "available information'' concerning the cumulative effects of a particular pesticide's residues and "other substances that have a common mechanism of toxicity." Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to broflanilide. For the purposes of this tolerance action, therefore, BASF has not assumed that broflanilide has a common mechanism of toxicity with other substances.

E. Safety Determination

	1. U.S. population. Based on this risk assessment, BASF concludes that there is a reasonable certainty that no harm will result to the general population from the aggregate exposure to broflanilide from the proposed uses.

	2. Infants and children. Based on this risk assessment, BASF concludes that there is a reasonable certainty that no harm will result to infants or children from the aggregate exposure to broflanilide from the proposed uses.

F. International Tolerances

No CODEX or European Union Maximum Residue Levels (MRL) have been established for broflanilide.