EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER Interregional Research Project Number 4 (IR- 4) EPA Registration Division contact: Laura Nollen, (703) 305 - 7 390

Petition Number 0F7796 EPA has received a pesticide petition , PP # 0F7796, from Interregional Research Project Number 4 (IR - 4) , 500 College Road East, Suite 201 W, Princeton, NJ 08540 , 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 .142 to establish tolerance s for residues of 2,4 - D (2,4 - D dichlorophenoxyacetic acid), both free and conjugated, determined as the acid in or on the raw agricultural commodit ies t eff, bran at 4.0 parts per million (ppm); t eff, forage at 25.0 ppm; t eff, grain at 2.0 ppm ; and t eff, straw at 50.0 p pm. EPA has determined that the petition contains data or information regarding the elements set forth in sect ion 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. A. Residue Chemistry This petition for teff (a minor crop grain) builds on the existing registrati on of 2,4 - D for use in wheat . 1. Plant metabolism. Acceptable wheat, lemon, and potato metabolism studies have been submitted and reviewed as part of the 2005 EPA RED (EPA 73 8 - R - 05 - 002). 2. Analytical method. Per the 2005 EPA RED (EPA 738 - R - 05 - 002) page 98 , the 2,4 - D Task Force II submitted an adequate GC/ECD enforcement method for plants (designated as EN - CAS Method No. ENC - 2/93) which has been independently validated. A dequate radiovalidation data have been submitted and evaluated for the enforcement method using samples from the wheat metabolism study . 3. Magnitude of residues. IR - 4 submitted a proposal to US EPA ChemSAC to extrapolate to teff from wheat. Teff and other cereal grains including corn (sweet and field), rice, sorghum, wheat, barley , pearl and proso millet, oats, popcorn, rye, teosinte, and triticale have similar morphological, cultural practices, taxonomical characteristics, and share similar pest prob lems. Teff is scheduled for inclusion in the revised Cereal Grains Crop Group 15 t o be proposed b y IR - 4 and the International Crop Grouping Consulting Committee . IR - 4 proposed that the 2,4 - D tolerances for teff be based on the existing residue tolerances for 2,4 - D (40 CFR 180.142) on wheat, barley , oats, rye, and2

millet . US EPA ChemSAC in a meeting on October 29, 2008 agreed with the proposal, considering the low acreage of teff grown in the US and the similarity to other cereal grains . B. Toxicologic al Profile Per the 2005 RED (EPA 738 - R - 05 - 002) , the EPA stated that with very few exceptions, the effects and relative toxicities of the salt and ester forms of 2,4 - D are quite similar to those of the acid form. Thus, the acid form was selected as being representative of all members of the 2,4 - D reregistration case. The toxicological profile was reviewed and selected endpoints for 2,4 - D were previously published in the Federal Register of July

27, 2005 (Vol. 70, Number 143 , 43302 ) , per Table 2 . At that tim e, the EPA determined that the “toxicological database is sufficient for reregistration” but included a 10X database uncertainty factor in li eu of a DNT study . T he toxicity database is now augmented by a new F1 - extended one generation dietary toxicity stu dy in rats (MRID 47972101 ) which was recently s ubmitted by

the 2,4 - D task force and is currentl y under review at the EPA . Itis anticipated that the data base UF will be reduced in the future based on the new study . 1. Acute toxicity. Per Table 2 of Federal Register of July 27, 2005 (Vol. 70, Number 143, 43302), EPA has established acute endpoints from two different studies. For the general population including infants and children, the NOAEL of 67 mg/kg/day from the acute neurotoxicity study in rats is currently used in conjunction with a 1,000 X UF to arrive at an aRfD = aPAD of 0.067 mg/kg/day . For females 13 - 50 years of age the NOAEL of 25 mg/kd/day from the rat developmental toxicity study is currently used with a UF of 1000 to establish an aRfD = aPAD of 0.025 mg/kg/day for this subpopulation. 2. Genotoxicty . Per the 2005 RED (EPA 738 - R - 05 - 002) , b ased on the overall pattern of responses observed in both in vitro and in vivo genotoxicity tests, 2,4 - D was not mutagenic, although some cy togenic effects were observed. Per Table 1 of Federal Register of July

27, 2005 (Vol. 70, Number 143, 43302), several genotoxicity studies have been conducted. In the Ames test s, no evidence of bacterial mutation in S typhimurium . strains TA1535, TA1537, TA1538, TA98, TA100, with and without S9 were observed. No significant increase in bone marrow pol ychromatic ery throcy tes were found in the in vivo erythrocy te micro - nucleus assay . No evidence of increased chromosome aberrations in human ly mphocy tes in the in v itro chromosome aberration study with human ly

mphocy tes. Equivocal results (+ at top 2 doses, with results similar to dimethyl sulfoxide (DMSO control) were noted in the c yt ogenetics in vivo chromosome aberration study with rat bone marrow. No evidence of induction of unscheduled DNA sy

nthesis has been noted. 2,4 - D is considered “Not likely to pose a cancer risk” based on the lack of carcinogenicity in a rat carcinogenicity

study and a mouse carcinogenicity study. 3. Reproductive and developmental toxi city. Per the 2005 RED (EPA 738 - R - 05 - 002), the toxicity

database for 2,4 - D include s acceptable developmental and reproductive toxicity studies for use in risk assessment . However, the recentl y submitted F1 - extended one generation dietary

toxicity study in rats ( MRID 47972101 ) provides a new and detailed evaluation of the potential effects of 2,4 - dichlorophenoxyacetic acid (2,4 - D) on the reproductive function, a s well as potential effects on numerous endpoints in the first3

generation offspring, including survival, growth and the development of nervous, immune and reproductive sy stems . Across life stages, the 2,4 - D extended one generation study has established a no - observed adverse effect level (NOAEL) based on sy stemic toxicity of 100 ppm in males (5.5 mg/kg/day) and 300 ppm in females (20.6 mg/kg/day in non - pregnant P1 adults). Regarding reproductive effects, there was no indication of reproductive toxicity b y 2,4 - D in the new study . 2,4 - D had no effects on estrous cyclicity or reproductive indices, includi ng mating, fertility, time to mating, gestation length, pre - and post - implantation loss and corporalutea number. L itter sizes, pup survival, sperm parameters, ovarian follicle counts and reproductive organ histopathology were unaffected b y 2,4 - D. Pup growth was affected during lactation, but only at a dose causing parental toxicity and resulting in nonlinear renal clearance. Overall, 2,4 - D is not a reproductive toxin. There was no evidence of developmental neurotoxicity related to 2,4 - D exposure. There were no exposure - related effects on brain histopathology at an y age. Functional observational battery

(FOB) parameters (hand - held and open - field observations, grip performance, landing foot splay , rectal temperature), motor activity and acoustic startle re sponse (ASR) were assessed in these animals on post natal date (PND) 54 - 59. The offspring adults were perfused for central and peripheral nervous sy stem neuropathology . In addition, brain weights, gross brain measurements and morphometric measurements were evaluated. There were no exposure - related effects on FOB parameters, motor activity or ASR. Habituation (behavioral response to a stimulus) was not affected at any dose of 2,4 - D. Gross and morphometric brain measurements also were not affected. There was no exposure - related neuropathology in PND 22 or 60 animals, including no effects on brain m yelin (assessed b y special staining). Thus 2,4 - D exposure shows no evidence of DNT

. 4. Subchronic toxicity. Per Table 2 of Federal Register of July 27, 2005 (Vol . 70, Number 143, 43302), the short - term incidental oral and a short - term dermal endpoint s are currentl y established based on the rat developmental toxicity NOAEL = 25 mg/day

with an associated LOAEL of 75 based on decreased maternal body - weight gain and s keletal abnormalities . The intermediate - term incidental oral and dermal endpoint s are established based on the subchronic rat oral toxicity NOAEL of 15 mg/kg/day with an associated LOAEL = 1000 mg/kd/day based on decreased body weight/body - weight gain, al terations in some hematology (decreased platelets (both sexes)) and clinical chemistry (decreased T3 (females) and T4 (both sexes)) parameters, and cataract formation . The LOC for Residential MOEs is 1000. 5. Chronic toxicity. Inthe rat chronic toxic ity study , a LOAEL of 75 mg/kg/day was observed based on decreased body - weight gain (females) and food consumption(females), alterations in hematology (decreased RBC, HCT, and HGB (females),platelets (both sexes)) and clinical chemistry parameters (increase d creatinine (both sexes), alanine and aspartate aminotransferases (males), alkaline phosphatase (both sexes), decreased T4 (both sexes), glucose (females), cholesterol (both sexes), and trigl ycerides (females) . Per Table 2 of Federal Register of July 27, 2005 (Vol. 70, Number 143, 43302), the NOAEL = 5 mg/kg/day from this study

and a UF = 1000, EPA has currently established an cRfD = cPAD = 0.005 mg/kg/day for all populations. This4

NOAEL is also used for the long - term inhalation and dermal endpoints with a “ LOC for MOE ” of 1000. 6. Animal metabolism. The absorption, distribution, metabolism and exc retion of 2,4 - D has been studies in rats. Per Table 1 of Federal Register of July 27, 2005 (Vol. 70, Number 143, 43302), 2,4 - D e limination (85.5% - 93.7% ) is primarily via urine with 3.6% - 10.5% of dose eliminated via the feces . At the high - dose level, it appears that a nonlinear region (decreased clearance) is being reached in the disposition of 2,4 - D. Parent 2,4 - D was the major metabolite found in urine (72.9 % - 90.5% of the oral dose), with small amounts of uncharacterized compounds (0.6% - 1.3% and 0% - 0.7%) being found in the urine. P er the 2005 RED (EPA 738 - R - 05 - 002), EPA has noted that the mechanisms responsible for renal clearance of 2,4 - D have been invest ig ated in several species. 2,4 - D is actively secreted b y the proximal tubules. This mechanism of renal clearance is consistent with results seen with other phenox y acids. It has been suggested that observed dose dependent, non - linear, pharmacokinetics of 2,4 - D are primarily due to the saturation of this renal secretory

transport sy stem. Due to a limited capacity to excrete organic acids, the dog is more sensitive to the effects of 2,4 - D than the rat with respect to repeated dosing

. 7. Metabolite toxico logy . 2,4 - dichlorophenol (2,4 - DCP) is a known plant and animal metabolite is 2,4 - D . However, per the EPA RED (EPA 738 - R - 05 - 002), EPA has concluded that 2,4 - D alone is the residue of concern. 8. Endocrine disruption . T he recentl y submitted F1 - extended one generation dietary toxicity study in rats ( MRID 47972101 ) included numerous endpoints to assess for endocrine effects. Endocrine - sensitive endpoints included estrous cyclicity , reproductive indices, organ weights/pathology , and sperm parameters. Anogen ital distance, nipple retention, and puberty onset were assessed in offspring; quantitative ovarian follicle counts in a subset of offspring . 2,4 - D did not alter estrogen - or androgen sensitive endpoints. There were no effects on estrogen - sensitive endpoi nts including vaginal opening, estrous cyclicity , uterine weights or histopathology , or quantitative ovarian follicle counts. There were no significant, exposure - related changes in reproductive organ weights in offspring. Other androgen - sensitive endpoints , including anogenital distance (AGD) and nipple retention, which are considered very sensitive endpoints, sperm parameters and testicular and accessory sex gland histopathology , were not altered. Based on this data and other studies, 2,4 - D shows no eviden ce of being an endocrine disruptor interacting with either estrogen or androgen at doses at or below those resulting in nonlinear renal clearance . There were no th yr oid effects at low and mid dose levels and no biologically significant effects on thy

roid endpoints at all life stages examined. There were no adverse pathological alterations, thus, slight thy roid changes seen in a satellite group of pregnant females were considered adaptive , non - adverse responses. The onl y altered thy roid endpoints occurred at an exposure level that clearly resulted in nonlinear renal clearance .5

C. Aggregate Exposure This proposal is based on bridging uses and tolerances from wheat to teff. Wheat use is covered b y the exposure assessments within the EPA 2005 RED. The pro posed additional use of 2,4 - D on teff would not have changed the results of those assessments. 1. Dietary exposure. Tolerances for: Wh eat, bran at 4.0 ppm, Wh eat, forage at 25 ppm Wh eat, grain at 2.0 ppm are included in the EPA Final Rule (72 52017, Sept. 12, 2007). The exposure assessment supporting these tolerances values is found in the 2005 RED. The existing exposure assessment for wheat is sufficient to cover any teff exposure, because the exposure from the proposed use on teff is already covered by the existing EPA dietary

assessment for small grains. If the consumer switches to consumption of teff in place of traditional grains, the dietary exposure assessment is unchanged , hence the information from the 2005 RED is reiterated below . i. Fo od. Per the 2005 Reregistration Eligibility Decis ion for 2,4 - D (EPA738 - R 05 - 002) regarding acute food , exposure estimates to the general U.S. population w ere 18% and 17% of the aPAD using both DEEM and Lifeline, respectivel y. The most highl y exposed popul ation subgroup using both DEEM and L ifeline was children 1 - 2 ye ars of age; exposures were 33% and 32% of the aPAD, respectivel y. Calculated exposure to females 13 - 49 years of age was 31% of the aPAD using DEEM and 42% of the aPAD using Lifeline; these higher calculated percentages for women of child - bearing age are due to the 2.7x lower toxicological point of departure for developmental effects applicable to Females 13 - 49 years of age. These acute dietary (food) exposure estimates are all less than the Ag ency ’s level of concern (100% of aPAD). For chronic exposure the EPA RED concludes that exposures to the general U.S. population were 4.1% and 3.8% of the cPAD, using DEEM and Lifeline, respectivel y. Calculated food exposures to children 1 - 2 years of age , the most highl y exposed population subgroup, was 8.5% of the cPAD using DEEM and Lifeline . ii. Drinking water. Drinking water estimates were included in the previous DEEM model estimates listed in Federal Register of July 27, 2005 (Vol. 70, Number 14 3, page 43307 ). The resulting exposure estimates were 10% of the cPAD for the U.S. population, 24% of the cPAD for all Infants ( < 1 year old), and 18% of the cPAD for children 1

–2 ye ars old. 2. Non - dietary exposure . Per Federal Register of July 27, 20 05 (Vol. 70, Number 143, 43302), there are no residential uses for 2,4 - D that result in chronic residential exposure to2,4 - D. 2,4 - D is currentl y registered for use s that could result in short - term residential exposure. Short - term turf exposures were calcu lated onl y for females 13

–49 and children 1

– 6 , because these population subgroups have the highest exposure and are protective of the other subgroups. EPA published potential turf exposure values of 0.024 mg/kg/day

for females and 0.021 mg/kg/day for children 1 - 6 , respectivel y . D. Cumulative Effects . For the purposes of this tolerance action, it is not assumed that6

2,4 - D has a common mechanism of toxicity with other substances . E. Safety Determination 1. U.S. population. Per the Federal Register o f July 27, 2005 (Vol. 70, Number 143, 43302) aggregate risk assessments for the general population were conservativel y covered b y calculations for females 13

–49 and children 1

– 6, because these population subgroups have the highest exposure and are protecti ve of the other subgroups. EPA determined, the short - term aggregate MOEs which include turf exposure are not of concern because the MOEs equal or exceed the target MOE of 1,000. 2. Infants and children . In the Federal Register of July 27, 2005 (Vol. 7 0, Number 143, 43302) and after evaluating hazard and exposure data for 2,4 - D, EPA removed the default 10X FQPA safety factor , but retained a database uncertaint y factor (UFDB) of 10X in lieu of a developmental neurotoxicity (DNT) study

in rats for 2,4 - D . This FQPA decision was based on the existing toxicity database for 2,4 - D at that time which includes acceptable developmental and reproductive toxicity studies. The new extended F1 - generation study in rats is anticipated to result in the removal of the 1 0X UFDB in the future . F. International Tolerances There are no known tolerances specificall y for teff elsewhere in the world . According to Homologa (www.homologa.com ), there are man y international MRL s esta blished for wheat: Argentina, Australia and Brazil have established 0.2 ppm , Japan and Mexico list 0.5 ppm, CODEX and the US list 2 ppm and the EU , Russian Federation and Switzerland list 0.05 ppm .