**EPA REGISTRATION DIVISION -**  **COMPANY NOTICE OF FILING OF PESTICIDE**

**PETITION EPA Registration Division contact: Sidney Jackson (703) 305**  **- 7610**  **Interregional Research Project Number 4 (IR -**  **4) Pesticide Petition Number:**  **4 E8**  **239** EPA has received a pesticid e petition ( 4E8239 ) from the Interregional Research Project 4 ( IR - 4 ) , IR - 4 Headquarters, Rutgers, The State University of NJ, 500 College Road East, Suite 201 W, Princeton, NJ 08540 requesting, pursuant to section 408(d) of the Federal Food, Drug, and Cosm etic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 to establish tolerance s for combined residues of the herbicide sethox yd im, 2 - [1 - (ethox yimino)butyl] - 5 - [2 - (ethylthio)propyl] - 3 - hydroxy- 2 - cyclohexen - 1 - one (CAS Reg. No. 74051

– 80

–2), and its metabo lites containing the 2 - cyclohexen - 1 - one moiety (calculated as the herbicide) ] in or on the following raw agricultural commodit ies : Berry, low growing, subgroup 13 - 07H, except strawberry

at 2.5 parts per million (ppm) , Bushberry , subgroup 13 - 07B at 5.0 ppm; Caneberry subgroup 13 - 07A at 5.0 ppm, Fescue, forage at 6.0 ppm; Fescue , hay at 4.0 ppm; Fruit, citrus, group 10 - 10 at 0.5 ppm; Fruit, pome, group 11 - 10 at 0.2 ppm; Fruit, small, vine climbing, subgroup 13 - 07F, except fuzzy kiwifruit at 1.0 ppm; Rapeseed subgroup 20A at 35 ppm; Sunflower subgroup 20B, except safflower , seed at 7.0 ppm; Cottonseed subgroup 20C at 5.0; Vegetable, bulb, group 3 - 07 at 1.0 ppm; and Vegetable, fruiting, group 8 - 10 at 4.0 ppm . In addition, IR - 4 is proposing that upon approval of the above petitioned - for tolerances, established sethox yd im tolerances in or on the following commodities are removed , including: Blueberry at 4.0 ppm; B orage, seed at 6.0 ppm; Caneberry subgroup 13A at 5 .0 ppm; Canola, seed at 35.0 ppm; Cotton, undelinted seed at 5.0 ppm; Crambe, seed at 35.0 ppm; Cranberry at 2.5 ppm; Cuphea, seed at 35.0 ppm; Echium, seed at 35.0 ppm; Flax, seed at 5.0 ppm; Fruit, citrus, group 10 at 0 .5 ppm; Fruit, pom e , group 11 at 0.2 ppm ; Gold of pleasure, seed at 35.0 ppm; Grape at 1.0 ppm ; Hare’s ear mustard, seed at 35.0 ppm; Juneberry at 5.0 ppm; Lesquerella, seed at 35.0 ppm; L ingonberry

at 5.0 ppm; Lunaria, seed at 35.0 ppm; Meadowfoam, seed at 35.0 ppm; Milkweed, seed at 35.0 ppm; Mustard, seed at 35.0 ppm; Oil radish, seed at 35.0 ppm; Poppy , seed at 35.0 ppm; Rapeseed, seed at 35.0 ppm; Salal at 5.0 ppm; Sesame, seed at 35.0 ppm; Sunflower, seed at 7.0 ppm; Sweet rocket, seed at 35.0 ppm; Vegetable, bulb, group 3 at 1.0 ppm; and Vegetable, fruiting, group 8 at 4.0 ppm. EPA ha s determined that the petition contains data or information regarding the elements set forth in section 408 (d)(2) of FDDCA; however, EPA has not full y evaluated the sufficiency of the submitted data at this time or whether the data supports granting of th e petition. Additional data may

be needed before EPA rules on the petition. A. Residue Chemistry

1. Plant metabolism . The qualitative nature of the residues in plants and animalsis adequatel y understood for the purposes of registration. 2. Analytical method . Analy tical methods for detecting levels of sethoxydim and its metabolites in or on food with a limit of detection that allows monitoring of food with residues at or above the level in these tolerances we re submitted to EPA. The proposed anal yt ical method involves extraction, partition, and clean - up. Samples are then anal yz ed b y gas chromatograph y with sulfur - specific flame photometric detection. The limit of quantitation is 0.05 ppm. 3. Magnitude of residues . IR - 4 received a request from the Agricultural Experiment Stations of Oregon and Idaho for the minor use of sethox ydim on fine fescue (Creeping Red (

Festuca rubra ), Chewings (Festuca nigrescens ), and Hard Fescue ( Festuca ovina )) for the control of annual and perennial grasses in fine fescue grass grown for seed. The nature of the residues of sethox yd im is adequatel y understood and an acceptable anal yt ical method is available for enforcement purposes. The registration of this use would provide the growers with a safe and effective herbicide for the control of annual and perennial grasses, yet would not expose human beings or the environment to unreasonable adverse effects. Therefore, tolerances are proposed for fescue, forage at 6.0 ppm and fesc ue, hay at 4.0 ppm based on the OECD tolerance calculator. IR - 4 received a request from the Agricultural Experiment Station of Oregon and North Carolina for the minor use of sethox yd im on blueberry (highbush and lowbush) for the control of grass weeds and to reduce the pre - harvest interval from 30 day s to 1 day . The nature of the residues of sethox yd im is adequatel y understood and an acceptable anal yt ical method is available for enforcement purposes. The registration of this use would provide the growers with a safe and effective herbicide for the control of grasses, yet would not expose human beings or the environment to unreasonable adverse effects. There is an existing blueberry tolerance of 4.0 ppm for sethox ydim with a 30 day PHI. Based on the resu lts of that study , IR - 4 proposes the removal of the tolerance for blueberry (representative crop for the Bushberry subgroup 13 - 07B), Juneberry , Lingonberry

and Salal and the establishment of a subgroup tolerance for the Bushberry

subgroup 13 - 07B at 5.0 ppm . IR - 4 proposes to change the pre - harvest interval for highbush blueberry

to 1 day , while leaving the lowbush pre - harvest interval at 30 day s. In addition, IR - 4 proposes the establishment of tolerances for the following revised crop groups based on exist ing toleranc es that are shown in brackets:  Caneberry

subgroup 13 - 07A [Caneberry subgroup 13A at 5.0 ppm];  Berry , low growing, subgroup 13 - 07G [Strawberry at 10 ppm];  Berry , low growing, subgroup 13 - 07H, except strawberry [Cranberry

at 2.5 ppm];  Fruit, citr

us, group 10 - 10 [Fruit , citrus, group 10 at 0.5 ppm];  Fruit, pome, group 11 - 10 [Fruit, pome, group 11 at 0.2 ppm];  Fruit, small, vine climbing, subgroup 13 - 07F, except fuzzy kiwifruit [Grape at 1.0 ppm];  Rapeseed subgroup 20A [ Borage, seed at 6.0 ppm; Cano la, seed at 35 .0 ppm; Crambe, seed at 35.0 ppm; Cuphea, seed at 35.0 ppm; Echium, seed at 35.0 ppm; Flax, seed at 5.0ppm; Gold of pleasure, seed at 35.0 ppm; Hare’s ear mustard, seed at 35.0 ppm;

Lesquerella, seed at 35.0 ppm; Lunaria, seed at 35.0 ppm; M eadowfoam, seed at 35.0 ppm; Milkweed, seed at 35.0 ppm; Mustard, seed at 35.0 ppm; Oil radish, seed at 35.0 ppm; Poppy , seed at 35.0 ppm; Rapeseed, seed at 35.0 ppm; Sesame, seed at 35.0 ppm; and Sweet rocket, seed at 35.0 ppm] ;  Sunflower subgroup 20B, ex cept safflower [Sunflower, seed at 7.0 ppm] ;  Cottonseed subgroup 20C [Cotton, undelinted seed at 5.0];  Vegetable, bulb, group 3 - 07 [Vegetable, bulb, group 3 at 1.0 ppm]; and  Vegetable, fruiting, group 8 - 10 [Vegetable, fruiting, group 8 at 4.0 ppm]. **]** B. Toxicological Profile

1. Acute toxicity . Sethoxydim has favorable acute toxicity . The acute toxicity studies place technical sethoxydim in toxicity category I II for acute oral, dermal and inhalation toxicity . Sethoxydim is category I V for both ey e and skin irritation, and it is not a dermal sensitizer. 2. Genotoxicty . Sethoxydim was negative for inducing mutations in both an in vitro Ames test and an in vitro mammalian cell mutation assay . Sethoxydim also demonstrated no chromosomal effects in an i n vivo sister chromatid exchange (Chinese hamster bone marrow) assay . An additional in vitro study investigating unscheduled DNA sy nthesis showed no effects. In total, sethox ydim has been tested in five genetic toxicology assay s consisting of in vitro an d in vivo studies. It can be stated that sethoxydim did not show any mutagenic, clastogenic or other genotoxic activity

when tested under the conditions of the studies mentioned above. Therefore, sethox yd im does not pose a genotoxic hazard to humans.

3. Reproductive and developmental toxicity . The reproductive and developmental toxicity of sethox ydim was investigated in a 2 - generation rat reproduction study as well as in rat and rabbit developmental toxicity studies. In the reproduction study , a decre ased pup bod y weight and tail abnormalities were observed at the highest dose tested. There were no effects on reproduction or evidence of parental toxicity . The NOAEL is >150 mg/kg bw/day for reproductive toxicity

and 30 mg/kg bw/day

for developmental t oxicity . In the rat stud y, maternal toxicity observed at the two highest doses consisted of some clinical signs including irregular gait and decreased activity. Developmental changes were also noted at the two highest doses and consisted of decreased fet al weights, tail abnormalities and skeletal variations. The maternal and developmental NOAEL’s were 180 mg/kg bw/day . In the rabbit teratology

study , maternal toxicity

observed at high dose consisted of decreased food consumption and body weight gain. An increased incidence of incompletely ossified 6 th sternebrae was the only

sign of developmental toxicity . The NOAEL for both maternal and developmental toxicity

was 320 mg/kg bw.4. Subchronic toxicity . The subchronic toxicity of sethoxydim was inve stigated in 90 - day feeding studies with rats and mice, a six - month feeding study in dogs and a 21 - day dermal administration study in rats and a 4 - week inhalation study in rats. Generally , mild toxicity was observed. At high dose levels in feeding studies , general findings were decreased food consumption and body weight gain and liver changes indicative of an adaptive response to treatment. In addition, hemosiderosis of the spleen was observed at the highest dose tested in dogs. The lowest NOAEL in the s ubchronic feeding studies was 20 mg/kg bw/day in the 90 - day dog stud y. In the 21 - day

repeat dose dermal study , no s ys temic effects were noted up to the highest dose tested of 1000 mg/kg bw/day . The 4 - week inhalation toxicity study had a NOEC of 0.3 mg/l based on increased liver weight, clinical chemistry and liver histopathology

at 2.4 mg/l. 5. Chronic toxicity . The NOAEL in the chronic dog study was 17.5 mg/kg bw/day based on effects observed at the high dose consisting of increased hemosiderosis in the spleen and depressed m yeloid ery thropoiesis in the sternal bone marrow, increased absolute and relative liver weights and increased serum liver enzy mes. In a rat chronic/oncogenicity study , sethox ydim was administered at doses up to 143 mg/kg bw/day in males and 204 mg/kg bw/day in females. Body

weight gain decreases and liver toxicity in the form of hepatocellular hy pertrophy were observed at the higher doses tested. The NOAEL’s for the chronic/oncogenicit y study in rats were 12 mg/kg bw/day in mal es and 66 mg/kg bw/day

in females. There was no evidence of carcinogenicit y in rats. Sethoxydim was also tested for oncogenic potential in mice. Body weight gains were decreased in both sexes at the high dose. In addition, liver toxicity occurred at th e two highest doses tested in males. This included an earl y onset of liver effects including hepatocellular hypertroph y and fatty degeneration. The NOAEL’s are 13.8 mg/kg bw/day for males and 44 mg/kg bw/day for females. There was no evidence that setho xydim produced a carcinogenic effect in mice.

6. Animal metabolism . In a rat metabolism study with sethox yd im, excretion was shown to be extremely

rapid and tissue accumulation was negligible. Of the administered dose, 78% was excreted in urine and 20 .1% in feces. Sethoxydim is extensively metabolized with very little excretion of parent.

7. Metabolite toxicology . The most abundant plant metabolites for sethoxydim are hydrox y derivatives. Additional toxicology studies were conducted on 5 - OH - MSO2, as a surrogate for all h ydrox y metabolites. Based on these data, it was concluded that the toxicological potency

of the plant hydrox y m etabolites is likely to be equal to or less than that of the parent compound.

8. Endocrine disruption . No specific t ests have been conducted with sethoxydim to determine whether the chemical may have an effect in humans that is similar to an effect produced b y a naturall y occurring estrogen or other endocrine effects. However, there were nosignificant findings in othe r relevant toxicity studies (i.e., subchronic and chronic toxicity , teratology

and multi - generation reproductive studies) which would suggest that sethoxydim produces endocrine - related effects. C. Aggregate Exposure

1. Dietary exposure . A dietary asse ssment was conducted to evaluate the potential risk due to acute and chronic exposure. The sethoxydim chronic reference dose (cRfD) is 0.14 mg/kg bw/day

based on the NOAEL of 14 mg/kg bw/day and a 100X safet y factor. The acute reference dose (aRfD) is 1. 8 mg/kg bw/day for all populations including females of child bearing age, based on a NOAEL of 180 mg/kg bw/day and a 100X safet y factor. The anal ys is included all current tolerance values for sethoxydim listed in U.S. 40 CFR § 180.412 with the proposed c hanges in this notification. The proposed new tolerances are for Fescue, forage at 6.0 ppm and Fescue, hay. The proposed revised crop group tolerances based on existing tolerances are: 1) Bushberry

subgroup 13 - 07B at 5.0 ppm to replace blueberry , juneberry , lingonberry , and salal 2) Caneberry

subgroup 13 - 07A at 5.0 ppm to replace Caneberry subgroup 13A 3) Berry , low growing, subgroup 13 - 07G at 10 ppm to replace strawberry 4) Berry , low growing, subgroup 13 - 07H, except strawberry , at 2.5 ppm to replace Cranberry 5) Fruit , citrus, group 10 - 10 at 0.5 ppm to replace Fruit, citrus, group 10 6) Fruit, pome, group 11 - 10 at 0.2 ppm to replace Fruit, pome, group 11 7) Fruit, small, vine climbing, subgroup 13 - 07F, except fuzzy kiwifruit, at 1.0 ppm to replace Grape 8) Rapeseed subgroup 20A at 35 ppm to replace Borage, seed; Canola, seed; Crambe, seed; Cuphea, seed; Echium, seed; Flax, seed; Gold of pleasure, seed; Hare’s ear mustard, seed; Lesquerella, seed; Lunaria, seed; Meadowfoam, seed; Milkweed, seed; Mustard, seed; Oil radish, seed; P oppy , seed; Rapeseed, seed; Sesame, seed; and Sweet rocket, seed 9) Sunflower subgroup 20B, except safflower, seed at 7.0 ppm to replace Sunflower, seed 10) Cotton seed subgroup 20C at 5.0 ppm to replace Cotton, undelinted seed 11) Vegetable, bulb, group 3 - 07 at 1.0 ppm to replace Vegetable, bulb, group 3 12) Vegetable, fruiting, group 8 - 10 at 4.0 ppm to replace vegetable, fruiting, group 8.

i. Food . Acute Dietary

Exposure Assessment An acute dietary

assessment was conducted using tolerance level residues, 100% crop treatment factors, and default processing factors for all commodities. Using the exposure assumptions discussed above, the acute dietary exposure from food is 6.4% aPAD for the US population. The most highly exposed sub - population was children 1 - 2 y earsolds which utilized 14.4% of the aPAD. The results of the acute dietary assessment are presented in Table 1.

**Table 1. Results for Sethoxydim Acute Dietary Exposure Analysis Including both Food and Drinking Water.**  **Population Subgroups**  **95th Percentile**

**Ex posure Estimate**  **(mg/kg bw/day) %aPAD**  US Population 0.115813 6.4 All infants (< 1 year) 0.207434 11.5 Children 1 - 2 0.258563 14.4 Children 3 - 5 0.223652 12.4 Children 6 - 12 0.140949 7.8 Youth 13 - 19 0.085054 4.7 Adults 20 - 49 0.082702 4.6 Adults 50+ y

rs 0.078437 4.4 Females 13 - 49 y

rs 0.082104 4.6 Chronic Dietary

Exposure Assessment The chronic population adjusted dose (cPAD) used for US and all sub - populations is 0.14 mg/kg bw/day . Using the exposure assumptions discussed above, sethoxy dim chronic d ietary exposure from food for the US population was 31.9% of the cPAD. The most highl y exposure subpopulation was children 1 - 2 y ears old which utilized 94.4% cPAD. The results of the chronic dietary

assessment are presented in Table 2. **Table 2. Summ ary of Chronic Dietary Exposure**  **Assessment Considering Crops with Established and Proposed Tolerances for Sethoxydim and Drinking Water.**  **Population Subgroups**  **Exposure Estimate**

**(mg/kg bw/day) %cPAD**  US Population 0.044671 31.9 All infants (< 1 year) 0.093 969 67.1 Children 1 - 2 0.132143 94.4 Children 3 - 5 0.105162 75.1 Children 6 - 12 0.063504 45.4 Youth 13 - 19 0.036358 26.0 Adults 20 - 49 0.035444 25.3 Adults 50+ y

rs 0.035608 25.4 Females 13 - 49 y

rs 0.035204 25.1 **]**ii. Drinking water . The drinking wat er values used in this assessment were based

on the EPA document “Sethox yd im Drinking Water Assessment (Tier 1) for Reregistration Eligibility

Decision” February

7, 2005. The estimated drinking water concentrations (EDWCs) for total sethox yd im residues ar e 1.5 ppb for ground water and 130 ppb (acute) and 16 ppb (chronic) for surface water. These water concentration where included in the dietary assessment conducted above . Acute Aggregate Exposure and Risk (Food and water) The aggregate acute risk include s residues of sethoxydim from food and water. Exposures from residential uses are not included in the acute aggregate assessment. Table 1 above shows the aggregate assessment for sethoxydim. Chronic Aggregate Exposure and Risk (food and water) The aggr egate chronic risk includes residues of sethoxydim from food and water. Exposures from residential uses are not included in the chronic aggregate assessment. Table 2 above shows the aggregate exposure from food and water. Short - and Intermediate Term Ag gregate Exposure and Risk (Food, Water and Residential Exposure) Short - and intermediate - term aggregate exposure takes into account residential exposure plus chronic exposure from food and water. Sethoxydim is only used for spot treatment in residential e nvironments. The EPA has stated that exposure from spot treatment is negligible and a exposure risk assessment is not required. Therefore, the aggregate risk is the sum from chronic food and water. The chronic aggregate risk assessment has shown that th ere is no concern. Therefore, it is concluded with reasonable certainty that no harm will occur from short - term aggregate exposure of sethoxydim.

2. Non - dietary exposure . Sethoxydim is only used for spot treatment in gardens, flower beds, recreational areas, and around building and structures. The EPA has determined that for sethox ydim, the quantification of dermal exposure risk assessment is not required because of lack of dermal and prenatal toxicity in rabbits, and the low dermal absorption of setho xydim. The EPA has also stated that the residential post - application exposure from spot treatment is negligible. Therefore based on the lack of dermal toxicity and negligible exposure potential, a non - dietary

exposure assessment was not conducted. D. Cu mulative Effects

The EPA is currently

developing methodology to perform cumulative risk assessments. At this time, there is no available data to determine whether sethox yd im has a common mechanism of toxicity with other substances or how to include this pesticide in a cumulative risk assessment. Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity , sethox ydim does not appear to produce a toxic metabolite common to other substances. E. Saf ety Determination1. 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 sethoxydim residues.

2. Infants and children . Based on this risk assessment, BASF concludes that there is a reasonable certaint y that no harm will result to infants or children from the aggregate exposure to sethoxydim residues. F. International Tolerances

There are no CODEX maximum residue levels established or proposed for residues of sethox ydim.