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

EPA Registration Division contact: Elizabeth Fertich, (202) 566-2675

TEMPLATE:

BASF Corporation

[PP _______]

EPA has received a pesticide petition 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 modifying tolerances for residues of the insecticide broflanilide in certain poultry commodities.

Poultry companies in the United States are concerned about the risk of insecticide residues in poultry meat and other edible commodities from the use of these products in production houses. To ensure that their products meet residue requirements, many companies test birds 2 weeks prior to slaughter to check for insecticide residues. In order to bring a new active ingredient to the poultry market, BASF needed to check for residues in chickens raised on litter treated with the product to combat darkling beetles prior to the introduction of chickens to housing. The study included in this submission (EPA MRID 51719904) evaluates residue levels of broflanilide and its metabolites in broiler chickens at time points representative of the US poultry production timeline. Chickens can be slaughtered at as early as 5 weeks of age and up to 9 weeks of age; thus, this study examined the residue potential in tissues at 3, 5, 7, and 9 weeks of age. This study also evaluated the efficacy of broflanilide on darkling beetles (Alphitobius diaperinus) in a field-simulation setting.

On the basis of the results from this study, BASF proposes to establish new tolerances for poultry fat and meat byproducts. As residues in poultry, meat are not expected due to this use, no change in the existing tolerance (0.02 ppm) is being requested for poultry, meat. BASF proposes an increase in tolerance for poultry, fat from 0.02 ppm to 0.3 ppm and an increase in poultry, meat byproducts from 0.02 to 0.04ppm.
Compliance with the tolerance levels specified is to be determined by measuring broflanilide, (3-(benzoylmethylamino)-N-[2-bromo-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethyl) phenyl]-2-fluorobenzamide) and its metabolite DM-8007, 3-benzamido-N-[2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl]-2-fluorobenzamide, calculated as the stoichiometric equivalent of broflanilide in or on the following animal commodities: poultry, meat (0.02 ppm established); poultry, fat (0.3 ppm proposed); poultry, meat byproducts (0.04 ppm proposed).

    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 14C-broflanilide. Two different radiolabels were used in the studies: [B-ring-U-14C]-broflanilide and [C-ring-U-14C]-broflanilide. In the context of all metabolism studies conducted, both labels were applied, except for the wheat metabolism study, in which only [B-ring-U-14C]-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 represented 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. BASF Analytical Method Number D1604/01 was used for the analyses of the residue samples for this study. Using BASF Analytical Method No. D1604/01, residues of broflanilide in livestock commodities are extracted with appropriate solvents, cleaned-up by partitioning and centrifugation, and then quantified using LC/MS/MS. The method has been separately verified / validated and was the subject of a successful independent laboratory validation on livestock commodities.

	3. Magnitude of residues. A new study was carried out with the purpose to measure the magnitude of residues of broflanilide (BAS 450 I) and its two metabolites, DM-8007 and DC-DM-8007, in fat, liver, and muscle of broiler chickens following treatment of poultry houses. This study also tested the efficacy of BAS 450 06 I in controlling darkling beetles in litter with chickens present.

    Toxicological Profile

      1. Acute toxicity. Broflanilide has low 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. Genotoxicity. 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. Similarly, all mutagenicity studies were negative for the major metabolites.

	3. Reproductive and developmental toxicity. In a rat 2-generation reproduction study, there were no effects on fertility or reproductive performance at dose levels of up to 15000 ppm  -  the limit and 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. Sub-chronic 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 in these studies were typically only mildly adverse (compensatory effects, slight changes in clinical chemistry, and organ weight changes without severe histopathological findings) and occurred at relatively high dose levels, occasionally including limit dose.
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. Sub-chronic inhalation exposures of rats to broflanilide for 28 days resulted in a No Observed Adverse Effect Concentration (NOAEC) of 31 mg/m³, characterized by reversible respiratory portal of entry effects, increased adrenal weight, increased incidence of adrenal vacuolation in both sexes, increased ovarian weights and increased incidence of ovary vacuolation, at the LOAEC (193 mg/m³). In a sub-chronic 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. 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 high dose levels. These tumor incidences showed a general lack of dose response. 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 15000 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 classified as "Likely to be Carcinogenic to Humans" based on Leydig cell tumors and all ovarian tumors combined (granulosa cell benign and malignant, luteomas, thecomas and sex cord stromal tumors) observed in the rat combined chronic / carcinogenicity study. A quantification of risk using a linear approach (Q1*) of broflanilide based on male rat testicular Leydig cell tumor rates of 2.48 x10-3 in human equivalents was applied.

	6. Animal metabolism. The metabolism of broflanilide was investigated in the rat, the laying hen, and the lactating goat. All studies were performed with 14C-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 comprised 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, sub-chronic, 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 14C 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 Structure Activity Relationship (SAR) analyses. 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., sub-chronic, chronic, developmental and multigeneration reproduction studies) that suggest that broflanilide produces any endocrine disruption.

    Aggregate Exposure
	1. Dietary exposure. The tolerance expression proposed for monitoring and risk assessment in plant commodities is broflanilide, parent only (3-(benzoylmethylamino)-N-[2-bromo-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethyl)phenyl]-2-fluorobenzamide).
The proposed tolerance expression for monitoring and dietary risk assessment in animal commodities is the sum of broflanilide and its metabolite DM-8007 (expressed as broflanilide) (Sum of broflanilide, 3-(benzoylmethylamino)-N-[2-bromo-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethyl)phenyl]-2-fluorobenzamide, and its metabolite 3-benzamido-N-[2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl]-2-fluorobenzamide, calculated as the stoichiometric equivalent of broflanilide).
Exposure assessments were conducted to evaluate the potential risk due to chronic dietary exposure of the U.S. population and all sub-populations. Also, the lifetime risk was calculated via Q1* cancer assessment. 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.

Table 1-1: Summary of toxicological dose and endpoint for broflanilide in chronic dietary assessment and Q1* cancer assessment
                              Exposure/ scenario
                              Point of departure
                                 Safety factor
                                      RfD
                        Study and toxicological effects
                       Chronic dietary (all populations)
                                 3 mg/kg bw/d
                                      100
                                0.03 mg/kg bw/d
2-Generation Reproduction Toxicity Study in Wistar Rats. 
NOAEL = 3 mg/kg day based on increased adrenal weights at the LOAEL
                             Q1* cancer assessment
                                       -
                                       -
                             2.48 x 10-3 mg/kg/day
According to US EPA final rules on Broflanilide 12/17/2020, document number: 2020-27906 (EPA, 2020a)

Exposure calculation to broflanilide residues is based on the crop uses already evaluated by US EPA during the multi-lateral submission in 2017 [registered uses: Corn (Field, sweet and pop); Tuberous and corm vegetables (crop subgroup 1C.); Small seeded grains (Wheat (all types), barley, millet, oats, rye, sorghum, triticale, amaranth grain, buckwheat (all types), cañihua, chia, cram-cram, huauzontle, quinoa, and spelt); as well as use as general insect control in feed and food-handling establishments] and the new use on poultry houses supported in this submission. The exposure estimates are based on proposed tolerances from the residue trials or livestock calculations assuming 100% crop treated (CT).

For the remaining commodities (derived from the food handling use), standard values of 0.005 mg/kg were modified by the projected probability of % food handling establishment (FHE) treatment by the adjustment factor 2 of 0.0465 according to the DEEM calculation presented in EPA Memorandum "Broflanilide: New Active Ingredient Human Health Risk Assessment" (DP No. D445655), (EPA, 2020c).

To show the contributions of the different uses, three DEEM calculations for the registered crops, for FHE use and for the new poultry house use were performed. The chronic dietary exposure assessment and the Q1* cancer assessment were also combined; both are presented in unrefined and refined versions. Poultry matrices (Poultry, Turkey, Chicken) have been included in the wave 1 as well as the poultry house calculations, since their theoretical contribution to the risk cup might result from different use patterns.

For the unrefined assessments, the EPA wave 1 DEEM sheet including the used standard processing factors, FHE calculation according to EPA's presented adjustment factor 2 and the MRLs derived for poultry commodities supported by this submission are used.

For the refined assessments, the wave 1 refined inputs (means) and processing factors according to the EPA Memorandum on Broflanilide 2020b (DP No. D452911) (in the following: EPA, 2020b) and the refined inputs for poultry commodities supported by this submission are used. The FHE assessment remains the same for unrefined and refined calculations.

The wave 1 crops and their contribution to the livestock feed burden were already addressed and evaluated by the US EPA (EPA 2020a, 2020b). Therefore, no new feed burden calculation was performed since this submission contains a non-crop use on poultry houses only, which is being addressed in a separate risk assessment.

Drinking water estimates of 0.0009 mg/L for chronic assessment and 0.0007 mg/L for Q1* cancer assessment were included based on US-EPA's most recent drinking water assessment (reference: Broflanilide  -  Section 3 New Chemical Drinking Water Exposure Assessment; August 20, 2019; DP Barcode 446353) based on the US surface water model. The scenario used by EPA was for agricultural T-band application, which was later removed from broflanilide US labels after EPA's assessment. However, BASF supports use of these values at this time since EPA considers them conservative and protective relative to other broflanilide use patterns (reference: Broflanilide  -  Response to Comments on the New Chemical Risk Assessment; January 13, 2021; DP Barcode 460217), which would include the proposed poultry house use as well.

An overview of the Chronic Dietary Exposure and Q1* Cancer Assessment results is presented in Table 1-2, Table 1-3, Table 1-4 and Table 1-5.


Table 1-2: Results for Broflanilide Chronic Dietary Exposure (Food and Water) Considering All Current and Proposed Tolerances using DEEM-FCID with Unrefined Inputs
                                       
                            Cumulated RA unrefined
                              Population subgroup
                                     mg/kg
                                  body wt/day
                                Percent of RfD
                              Total US population
                                   0.000203
                                     0.70%
                                   Hispanic
                                   0.000228
                                     0.70%
                                Non-Hisp-White
                                   0.000192
                                     0.70%
                                Non-Hisp-Black
                                   0.000219
                                     0.70%
                                Non-Hisp-Other
                                   0.000231
                                     0.70%
                                Nursing Infants
                                   0.000157
                                     0.50%
                              Non-Nursing Infants
                                   0.000382
                                     1.30%
                                Female 13+ PREG
                                   0.000178
                                     0.50%
                                 Children 1-6
                                   0.000464
                                     1.50%
                                 Children 7-12
                                   0.000263
                                     0.90%
                                  Male 13-19
                                   0.000196
                                     0.60%
                                Female 13-19/NP
                                   0.000174
                                     0.60%
                                   Male 20+
                                   0.000178
                                     0.60%
                                 Female 20+/NP
                                   0.000157
                                     0.50%
                                  Seniors 55+
                                   0.000153
                                     0.50%
                                  All Infants
                                   0.000311
                                     1.10%
                                 Female 13-50
                                   0.000163
                                     0.60%
                                 Children 1-2
                                   0.000542
                                     1.80%
                                 Children 3-5
                                   0.000443
                                     1.40%
                                 Children 6-12
                                   0.000278
                                     0.90%
                                  Youth 13-19
                                   0.000184
                                     0.60%
                                 Adults 20-49
                                   0.000176
                                     0.60%
                                 Adults 50-99
                                   0.000156
                                     0.50%
                                 Female 13-49
                                   0.000164
                                     0.60%

Table 1-3: Results for Broflanilide Chronic Dietary Exposure (Food and Water) Considering All Current and Proposed Tolerances using DEEM-FCID with Refined Inputs
                                       
                             Cumulated RA refined
                              Population subgroup
                                     mg/kg
                                  body wt/day
                                Percent of RfD
                              Total US population
                                   0.000142
                                     0.50%
                                   Hispanic
                                   0.000163
                                     0.50%
                                Non-Hisp-White
                                   0.000135
                                     0.50%
                                Non-Hisp-Black
                                   0.000146
                                     0.50%
                                Non-Hisp-Other
                                   0.000165
                                     0.50%
                                Nursing Infants
                                   0.000113
                                     0.30%
                              Non-Nursing Infants
                                   0.000288
                                     1.00%
                                Female 13+ PREG
                                   0.000125
                                     0.40%
                                 Children 1-6
                                   0.000329
                                     1.10%
                                 Children 7-12
                                   0.000179
                                     0.60%
                                  Male 13-19
                                   0.000132
                                     0.40%
                                Female 13-19/NP
                                   0.000114
                                     0.40%
                                   Male 20+
                                   0.000124
                                     0.40%
                                 Female 20+/NP
                                   0.000111
                                     0.40%
                                  Seniors 55+
                                   0.000108
                                     0.40%
                                  All Infants
                                   0.000232
                                     0.80%
                                 Female 13-50
                                   0.000114
                                     0.40%
                                 Children 1-2
                                   0.000389
                                     1.30%
                                 Children 3-5
                                   0.000312
                                     1.00%
                                 Children 6-12
                                    0.00019
                                     0.60%
                                  Youth 13-19
                                   0.000123
                                     0.40%
                                 Adults 20-49
                                   0.000123
                                     0.40%
                                 Adults 50-99
                                    0.00011
                                     0.40%
                                 Female 13-49
                                   0.000114
                                     0.40%


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

Table 1-4: 	Results for Broflanilide Q1* Cancer Assessment (Food and Water) Considering All Current and Proposed Tolerances using DEEM-FCID with Unrefined Inputs
                                       
                            Cumulated RA unrefined
                              Population subgroup
                                     mg/kg
                                  body wt/day
                                 Lifetime risk
                              Total US population
                                   0.000199
                                   4.93E-07
                                 Adults 20-49
                                   0.000172
                                   4.25E-07
                                 Adults 50-99
                                   0.000152
                                   3.77E-07
                                 Female 13-49
                                    0.00016
                                   3.98E-07

Table 1-5: 	Results for Broflanilide Q1* Cancer Assessment (Food and Water) Considering All Current and Proposed Tolerances using DEEM-FCID with Refined Inputs
                                       
                             Cumulated RA refined
                              Population subgroup
                                     mg/kg
                                  body wt/day
                                 Lifetime risk
                              Total US population
                                   0.000138
                                   3.41E-07
                                 Adults 20-49
                                   0.000119
                                   2.94E-07
                                 Adults 50-99
                                   0.000106
                                   2.62E-07
                                 Female 13-49
                                    0.00011
                                   2.74E-07

The results of the Q1* cancer assessment show that for all populations, the exposures are below a level of concern (<3.0E-06 lifetime risk). Additional refinements in the dietary risk assessment (i.e., utilizing anticipated residue values and means) even further reduce the estimated exposure values.

	ii. Drinking water. The consumption of broflanilide residues in drinking water was included in the chronic dietary assessments and Q1* cancer assessments above.

	2. Non-dietary exposure.
Indoor residential uses of broflanilide have been registered which can lead to non-dietary exposure of consumers. The residential exposure and risk assessments conducted by EPA for these uses (DP Barcode D445655, October 27, 2020) served as the source of data for residential exposures included in this assessment. The residential exposures for aggregation are based on the worst-case indoor use for perimeter/spot (pin stream) 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 ARIs for the aggregate exposures are well above the target ARI of 1 indicating that these exposures are not of concern.

Table 1-6: Estimated Short-Term Aggregate Exposure and Risk for Broflanilide (Food, Drinking Water, and Residential Exposure) 
                                Sub-Population
                               Dietary Exposure
                              Inhalation Exposure
                                 Oral Exposure
                         Aggregate Risk Index (ARI)[2]
                                       
                                    mg/kg/d
                                    MOE[1]
                                    mg/kg/d
                                      MOE
                                    mg/kg/d
                                      MOE
                                       
                                     Adult
                                   0.000123
                                     24390
                                  0.00000031
                                      --
                                      NA
                                    5000000
                                      244
                               Child 1-2 yr old
                                   0.000389
                                     7712
                                   0.0000013
                                      462
                                    0.0065
                                    1192308
                                      4.4
 [1] MOEs were calculated using the following: Dietary  -  NOAEL = 3 mg/kg/day; Inhalation  -  Residential HED = 1.55 mg/kg/day; Oral NOAEL = 3 mg/kg/d.
 [2] Individual ARIs calculated using MOE and LOCs of 100 for dietary and oral exposure, and 30 for inhalation exposure. ARI Aggregate = 1/[(1/ARI dietary) + (1/ARI inhalation) + (1/ARI oral)], as applicable.

A cancer aggregate risk assessment was completed for the residential and dietary uses of broflanilide using a cancer slope factor (Q1*) of 2.48 x 10[-3]. The assessment includes the worst-case adult post-application dermal and inhalation exposures following an indoor surface directed spray. The indoor residential assessment is a conservative calculation that assumes 12 retreatments per year as allowed on the label at the maximum proposed rate, a 30-day retreatment interval, 10% dissipation of residues per day, and an exposure estimate based on exposure to residues for 365 days per year. The cancer dietary exposure estimate was for the highest exposed adult population sub-group (adults 20  -  49 years) and refined DEEM-FCID inputs as noted above. The resulting aggregate cancer risk estimate is 1.5 x 10[-6].

Table 1-7: Aggregate Cancer Estimate for Broflanilide (Food, Drinking Water, and Residential Exposure) 
                                Sub-Population
                           Cancer Slope Factor (Q1*)
                    Food and Water Exposure[1] (mg/kg/day)
                            Residential Exposure[2]
                               (LADD -mg/kg/day)
              Aggregate Cancer Risk (food, water, residential)[3]
                 Most highly exposed Adult Population Subgroup
                                    0.00248
                                   0.000119
                                   0.000498
                                    1.5E-6
     1 Cancer dietary exposure based on the Adult 20 - 49 year subpopulation.
     2 Residential exposure based on indoor perimeter pin stream application.
     3 Aggregate cancer risk = (Q1*) x (Food and Water Exposure + Residential LADD)

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 (MRLs) have been established for broflanilide. Broflanilide was submitted to JMPR in November 2020 and January 2021. Due to COVID, the assessment has been shifted to 2022.
