2 Mammalian Chronic Toxicity The original assessment identified the most sens itive chronic mammalian toxicity endpoint in the two-generation rat reproduction study as a NOA EL of 20 mg ai/kg-diet , based on parental thyroid weight increase and corre sponding dose-related increase in the incidence of thyroid follicular epithelial ce ll hypertrophy/hyperplasia (MRID 48119967). EFED policy is to base risk quotient (RQ) calculations on the most sensitiv e endpoints that adversely affect reproduction, growth, and survival. Upon further review, the t hyroid effects seen in th e study did not result in adverse effects on reproduction, growth, or survival. Cons equently, the NOAEL for risk quotient calculation was revised to the next most sensitive endpoint of 200 mg ai/kg-diet, which was based on decreases in offspring organ weights (thymus and spleen) and reduced pup body weight in the F 2 generation.

Chronic dietary risk quotients we re re-calculated with the new chronic endpoint. Risk quotients ranged from 0.02 to 3.18 and only thr ee uses exceeded the listed a nd non-listed species level of concern (LOC = 1): 1) hardwoods soil injection/drench (RQ = 1.3) , 2) citrus soil drench (RQ = 1.2), and 3) cucurbits drip irri gation (RQ = 3.2). The risk quotients were calculated using the conservative assumption that the mammal would c onsume 100 percent of its diet from treated plants. This assumption likely overestimates exposure because a mammal may not feed exclusively on cyantraniliprole-t reated plants. Consequently, the potential for direct risk concerns to mammals is low, as is the potential for indirect effects to any species that rely on affected mammals for food, shelter, or other res ources. Tables 1 and 2 present the RQs based on the 200 mg ai/kg-diet mammalian NOAEL.

Table 1. Mammalian Foliar, Bark Spray, and Seed Treatment Chronic Risk Quotients (Based on T-REX-Calculated EECs) for Cyantraniliprole

Feeding Category Mammalian Chronic DietaryBased RQs

Brassica leafy vegetables, leafy vegetables 2 apps at 0.175 lb ai/A and 1 app at 0.05 lb ai/A (7 days) Short grass 0.40 Tall grass 0.18 Broadleaf plants 0.23 Fruits/pods 0.03 Arthropods 0.16 Seeds 0.03

Brassica leafy vegetables, bushberries , leafy vegetables (except brassica), corm and tuberous vegetables, bulb vegetables 3 apps at 0.133 lb ai/A (5 days) Short grass 0.44 Tall grass 0.20 Broadleaf plants 0.24 Fruits/pods 0.03 Arthropods 0.173 Feeding Category Mammalian Chronic DietaryBased RQs

Seeds 0.03 Citrus, cotton, oil seeds, pome fruit, stone fruit, tree nuts 3 apps at 0.133 lb ai/A (7 days) Short grass 0.42 Tall grass 0.19 Broadleaf plants 0.24 Fruits/pods 0.03 Arthropods 0.16 Seeds 0.03
Cucurbits, fruiting vegetables 2 apps at 0.175 lb ai/A and 1 app at 0.05 lb ai/A (5 days) Short grass 0.42 Tall grass 0.19 Broadleaf plants 0.24 Fruits/pods 0.03 Arthropods 0.17 Seeds 0.03
Potatoes (seed treatment) 1 app at 0.69 lb ai/A

Seeds N/A
Potatoes (seed treatment)

1 app at 0.176 lb ai/A

Seeds N/A
Rapeseed including canola varietie s, mustard seed (seed treatment) 1 app at 0.4 lb ai/A

Seeds N/A
Sunflower (seed treatment) 1 app at 0.016 lb ai/A

Seeds N/A
Flowerbeds and groundcovers 2 apps at 0.208 lb ai/A (7 days) Short grass 0.47 Tall grass 0.21 Broadleaf plants 0.26 Fruits/pods 0.03 Arthropods 0.18 Seeds 0.03
Ornamentals treated by commercial and consumer applicators 2 apps at 0.13 lb ai/A (7 days) Short grass 0.29 Tall grass 0.134 Feeding Category Mammalian Chronic DietaryBased RQs

Broadleaf plants 0.16 Fruits/pods 0.02 Arthropods 0.11 Seeds 0.02

Ornamental plants, fruit and nut trees (non-bearing) and forest seedlings grown in greenhouses, lath and shade houses, containers, field nurseries and interiorscapes 1 app at 0.26 lb ai/A and 1 app at 0.16 lb ai/A (14 days) Short grass 0.43 Tall grass 0.20 Broadleaf plants 0.24 Fruits/pods 0.03 Arthropods 0.17 Seeds 0.03
Ornamental plants (exterior landscapes and interior plantscapes), trees (including non-bearing fruit and nut trees) shrubs, evergreens, bedding plants, flowering plants, flowers, foliage plants, groundcovers, vines, interior

plantscape plants, vegetable transplant s (fruiting, leafy, tuberous, corm), public health insect control 1 app at 0.42 lb ai/A Short grass 0.50 Tall grass 0.23 Broadleaf plants 0.28 Fruits/pods 0.03 Arthropods 0.20 Seeds 0.03
Turf, golf courses, residential lawns, commercial grounds, parks, playgrounds, athletic fields, sod farms, grassy, weedy, mulched, or bare soil areas in and around greenhouses, nurseries, interior plantscapes, lath and

shade houses, under trees and shrubs that are being grown in-ground 1 app at 0.26 lb ai/A and 1 app at 0.16 lb ai/A (30 days) Short grass 0.36 Tall grass 0.17 Broadleaf plants 0.20 Fruits/pods 0.02 Arthropods 0.14 Seeds 0.02
Fly control bait (granular) 5 apps at 0.087 lb ai/A (7 days) Short grass 0.40 Tall grass 0.18 Broadleaf plants 0.235 Feeding Category Mammalian Chronic DietaryBased RQs

Fruits/pods 0.03 Arthropods 0.16 Seeds 0.03

Table 2. Summary of Mammalian Chronic RQs for Soil Injection/Soil Drench, Potted Ornamental Drench, and Agricultural Drip Irrigation for Cyantraniliprole

Mammalian Chronic Dietary-Based RQs Soil injection/drench hardwood 0.74 Soil injection/drench hardwood 1.27*** Soil drench (citrus) 1.17*** Soil injection/drench softwood 0.34 Soil injection/drench softwood 0.58 Potted non-woody ornamental drench 0.02 Potted non-woody ornamental drench 0.05 Drip irrigation (brassica vegetables) 0.32 Drip irrigation (cucurbits) 3.18*** Drip irrigation (fruiting vegetables) 0.91 Drip irrigation (leafy vegetables) 0.27 Drip irrigation (corm and tuberous vegetables) 0.32 ***Risk quotient exceeds chronic LOC of 1

Terrestrial Monocots The original risk assessment id entified potential risk concerns to terrestrial monocots based on an absence of seedling emergence data . The vegetative vigor studie s indicated that onion was the most sensitive monocot; however, acceptable data for onion were not available for the seedling emergence endpoint (MRIDs 48120186 and 48122575). The assessment concluded that if the onion NOAEC was slightly more toxic ( ≤ 0.100 lb ai/A) than the curr ent most sensitive seedling emergence endpoint (0.134 lb ai/A), risk quotient s would exceed the LOC for listed monocots. Consequently, risk concerns were presumed.

As a further clarificati on, many of the terrestr ial plant studies for monocots and dicots were judged limited in their quantitative utility be cause many of the tested species had control performance problems. Lower-than-expected pe rformance in controls may indicate a problem with the seed stock or environmental conditions; da ta are not used from such studies because of concerns that the poor control performance may mask a valid toxicological effect of the pesticide. Consequently, a reduced vegeta tive vigor and seedling emergence dataset was available for terrestrial plants.

For the vegetative vigor endpoint, an acceptable li mit test showed that onions were the most sensitive monocot – two times more sensitive than corn, which was the only acceptable monocot endpoint available for the seedling emerge nce test (MRID 48120186). The study authors concluded the growth deficits in the onion vegetative vigor test we re statistically significant and moved to a definitive test. A NOAEC was establishe d for onion at 0.067 lb ai/A, which is half of6 the NOAEC for the most sensitive dicot (cucumber NOAEC = 0.134 lb ai/A). For the seedling emergence endpoint, onion was again much mo re sensitive than corn (MRID 48122575). However, the aforementioned control performanc e problem affected the onion study and thus precluded establishing a NOAEC fo r onion. If the relationship seen between corn and onion in the vegetative vigor test is applied to the seed ling emergence endpoints, it would be reasonable to expect the seedling emergence NOAEC for onion to be lower than corn and the other dicots with acceptable data; an endpoint some two fold lower may be a reasonable prediction, based on the observed relationship.

Consequently, in the absence of toxicity information for onion, risk concerns to terrestrial monocots cannot be excluded at this time. The risks apply only to li sted monocots (direct effects) and to other listed speci es with obligate relationships with a monocot (indirect effects). Risks are expected to be limited to monocots near the edge of the field and to taper off as distance from the field’s edge increases. A sp ray drift buffer distance can not be calculated for listed monocots because a precise toxicity value fo r onion is not available. For reference, if the toxicity value is assumed to be half the NOAEC of corn, a spray drift buffer of 20 ft would be protective at the maximum appli cation rate of 0.42 lb ai/A.

Honeybee Acute Toxicity Cyantraniliprole Compared to Other Insecticides EFED compiled additional information regarding th e toxicity of cyantraniliprole compared with alternative registered insecticides. Table 3 repor ts the highest and lowest acute contact and oral toxicity endpoints for the honeybee for several co mmon classes of insecticides (neonicotinoids, carbamates, pyrethroids, and orga nophosphates). Chemical classe s are organized alphabetically with cyantraniliprole at the bottom of the table. Tables 4 and 5 report acute honeybee toxicity on a chemical-by-chemical basis; the table is ranked with the most toxi c pesticides at the top and the least toxic at the bottom. Ins ecticides were chosen based on t hose listed as alternatives to cyantraniliprole in the Reduced Risk Rationale th at was submitted by the registrants (Baer et al., 2011; USEPA, 2011 - D392092). Toxicity data are not available for each chemical and/or for each exposure route (oral and contact), thus the da ta do not represent a complete picture of acute toxicity to honeybees. Note that lower toxicity values in the table represent insecticides of greater toxicity to honeybees.

Table 3. Summary of Cyantraniliprole, and Other Chemical Classes Acute Toxicity to Honeybees Chemical Honeybee acute contact (μg ai/bee) Honeybee acute oral (μg ai/bee)
Carbamates 0.1600 to 35 0.094 to 3.01 Neonicotinoids 0.024 to <12.5 0.0037 to >10.21 Organophosphates 0.059 to 58.9 0.056 to 0.44 Pyrethroids 0.0015 to 0.52 0.172 to 0.909 Cyantraniliprole 0.55 0.116 Cyantraniliprole/thiamethoxam
TEP 0.058 0.00627 Table 4. Comparison of Acute Contact Toxi city to Honeybees for Cyantranilprole and Other Insecticides Chemical (Class) Contact LD 50 (μg ai/bee) MRID Deltamethrin (pyrethroid) 0.0015 42114815 Spinosad (spinosyn) 0.0029 43414547 Bifenthrin (pyrethroid) 0.015 VAOTALO1 Esfenvalerate (pyrethroid) 0.017 41698402 Cypermethrin (pyrethroid) 0.023 260647 (accession number) Permethrin (pyrethroid) 0.024 42674501 Dinotefuran (neonicotinoid) 0.024 45639727 Thiamethoxam (neonicotinoid) 0.024 44714927 Spinetoram (spinosyn) 0.024 46695147 Cyfluthrin (pyrethroid) 0.037 00153638 Lambda -cyhalothrin (pyrethroid) 0.038 40052409 Clothianidin (ne onicotinoid) 0.0439 45422426 Cyantraniliprole/Thiamethoxam TEP (diamide/neonicotinoid)* 0.058 48432530

Chlorpyrifos (organophosphate) 0.059 05001991 Dicrotophos (organophosphate) 0.076 05001991 Imidacloprid (neonicotinoid) 0.078 42273003 Chlorfenapyr (pyrrole) 0.12 42770233 Methomyl (carbamate) 0.1600 45093001 Indoxacarb (oxadiazine) 0.18 44477234 Malathion (organophosphate) 0.2000 05001991 Oxamyl (carbamate) 0.31 05001991 Abamectin (avermectin) 0.408 00159162 Oxydemeton-methyl (organophosphate) 0.54 05001991

Cyantraniliprole (diamide) 0.55 48120137 Phosmet (organophosphate) 1.1 00066220 Acephate (organophosphate) 1.20 44038201 Acetamiprid (neonicotinoid) <12.5 44651874 Trichlorfon (organophosphate) 59.83 00036935 Chlorantraniliprole (anthranilic diamide) >100 46889120

Methoxyfenozide (diacyhydrazine) >100 44144429

Flubendiamide (phthalic acid diamide) >200 46817009

Spirotetramat (tetramic acid) 1073 46904461 *Note that the cyantraniliprole-thiamethoxam TEP is less toxic than thiamethoxam alone.8 Table 5. Comparison of Acute Oral Toxicity to Honeybees for Cyantraniliprole and Other Insecticides Chemical (Class) Oral LD 50 (μg ai/bee) MRID Clothianidin (ne onicotinoid) 0.0037 45422426 Imidacloprid (neonicotinoid) 0.0038 42273003 Thiamethoxam (neonicotinoid) 0.005 44714927 Cyantraniliprole/Thiamethoxam TEP (diamide/neonicotinoid)* 0.0062 48432530

Dinotefuran (neonicotinoid) 0.0076 45639727 Chlorantraniliprole (anthranilic diamide) 0.0274 46979602

Cyantraniliprole (diamide) 0.116 48432416 Cypermethrin (pyrethroid) 0.172 260647 (accession number) Methomyl (carbamate) 0.2900 45093001 Oxydemeton-methyl (organophosphate) 0.31 05001991

Malathion (organophosphate) 0.3800 05004151 Lambda -cyhalothrin (pyrethroid) 0.909 40052409 Acetamiprid (neonicotinoid) >10.21 44651874 Methoxyfenozide (diacyhydrazine) >100 44617717

Spirotetramat (tetramic acid) 607 46904461 *Note that the cyantraniliprole-thiamethoxam TEP is less toxic than thiamethoxam alone.

References Baer, C.A., T.N. Davis-Cannon, and T.I. McPherson. 2011. Reduced risk rationale for use of cyantraniliprole on bushberries, citrus, cotton, oil seeds, pome fr uit, stone fruit, tree nuts, vegetables (bulb, corm and tuberous, cucu rbit, fruiting, leafy br assica, and leafy nonbrassica), and professional pr oducts (fly bait, indoor & outdo or insect control for public health pests such as cockroaches, ants, f lies and termites and nuisance insect pests, turfgrass & ornamentals, tree injecti on and production greenhouse & nursery ornamentals). E.I. du Pont de Ne mours and Company, Newark, Delaware.

USEPA, 2011. Reduced Risk Analysis for Cyan traniliprole Use on Bushberries, Citrus, Cotton, Oil Seeds, Pome Fruit, Stone Fruit, Tree Nuts, Vegetables (Bulb, Corm and Tuberous, Cucurbit, Fruiting, Leafy Brassica, and Leaf y Non-Brassica), and Professional Products (Fly Bait, Indoor and Outdoor Insect Cont rol for Public Health Pests such as Cockroaches, Ants, Flies, and Termites a nd Nuisance Insect Pests, Turfgrass and Ornamentals, Tree Injection, and Producti on Greenhouse and Nursery Ornamentals). Environmental Fate and Eff ects Division, Office of Pestic ide Programs, Environmental Protection Agency.