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EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER EPA Registration Division contact: W. Cutchin, 703 - 305 - 7990 INSTRUCTIONS: Please utilize this outline in preparing the pesticide petition. In cases where the outline element does not apply, please insert “NA - Remove” and maintain the outline. Please do not change the margins, font, or format in your pesticide petition. Simply re place the instructions that appear in green , i.e., “ [ insert company name ] ,” with the information specific to your action. TEMPLATE: Dow AgroSciences, LLC 1E7949 EPA has received a pesticide petition 1E7949 from DowAgroSciences, LLC , 9330 Zionsville Rd., Indianapolis, IN, 46268 request ing, 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 to establish an exemption from the requirement of a tolerance for N

- Alkyl (C8

- C18) Dimethyl amidopropylamines (NADMAPA) where the alkyl group is linear and may be saturated and/or unsaturated under 40CFR 180.920 when used as an inert ingredient in a pesticide formulation with limits of up to 20% of a herbicide formulation. NADMAPA is a group of h ighly related materials that are all derived from the reaction of dimethylamidopropylamine (DMAPA) with linear C8

- C18 fatty acids. The following materials are proposed as being covered by the NADMAPA descriptor: CAS number PCCode Name 68140

- 01

- 2 800287 Amides, coco, N

- [3

- (dimethylamino)propyl] 146987

- 98

- 6 800288 Amides, C8

- C18 and C18

- unsatd., N

- [3

- (dimethylamino)propyl] 1147459

- 12

- 8 800289 N

- [3

- (dimethylamino)propyl]

- C12

- C18(even numbered)

- alkylamide 3179

- 80

- 4 800290 Dodecanamide, N

- [3

- (dimethylamino )propyl] 45267

- 19

- 4 800291 Tetradecanamide, N

- [3

- (dimethylamino)propyl] 39669

- 97

- 1 800292 Hexadecanamide, N

- [3

- (dimethylamino)propyl] 7651

- 02

- 7 800293 Octadecanamide, N

- [3

- (dimethylamino)propyl] 109

- 28

- 4 800294 9

- Octadecenamide, N

- [3

- (dimethylamino) propyl]

- ,(9Z)

- 22890

- 11

- 5 800295 Decanamide, N

- [3

- (dimethylamino)propyl] 22890

- 10

- 4 800296 Octanamide, N

- [3

- (dimethylamino)propyl]2 This petition is based on Coconut fatty acid, dimethylamidopropylamide (Coco APDMA; CAS 68140

- 01

- 2; Amides, coco, N

- [3

- (dimethylamino)propyl]) as the representative test material for NADMAPA materials. Coco APDMA is a blend and the chain length of the R group varies based on the natural origin of the coconut oil. The dominant components of the R chain are C12 and C14 at 52.47 and 15.72%, respectively, but the chain length ranges from C8 to C18. The petition is made in cooperation with and supported in part by proprietary informatio n owned in full or in part by AkzoNobel Surface Chemistry LLC. EPA h as 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. A. Residue Chemistry Specific residue information is not available for NADMAPA, but food residues are not expected to be significant. This information is not required for the e stablishment of a tolerance exemption. 1. Plant metabolism. NA - Remove 2. Analytical method. NA - Remove 3. Magnitude of residues. NA - Remove
B. Toxicological Profile The toxicity database for Coco APDMA contains several acute toxicity studies: in vitro genotoxicity assays and a repeat dose developmental/reproductive screening test (OECD 422) . The database is augmented by analogue information in the public domain and EPA’s High Production Volume (HPV) program. Historically , Coco APDMA is included in subcategory 3 of Category I amides within the 2004 HPV summary for Fatty Nitrogen Derived Amides class. 1. Acute toxicity. Coco APDMA has moderate acute oral toxicity with an LD 50 of 300 mg/kg/day and is corrosive and irritating to the skin and eye, respectively
. 2. Genotoxic i ty. Coco APDMA and its broader class of HPV analogues are negative for genotoxicity across a series of in vitro assays. 3. Reproductive and developmental toxicity. A combined repeated dose toxicity and reproduction and developmental toxicity screening test was conducted in rats with Coco APDMA via oral gavage under OECD 422 guidelines and in accordance to Good Laboratory Practices (GLP). No treatment

- relat ed effects were detected in the reproductive or developmental parameters examined. The no observed adverse effect level (NOAEL) for repeat dose toxicity was 15 mg/kg/day, and the no observed effect level (NOEL) for reproductive and developmental toxicity was the highest dose tested, 45 mg/kg/day. Coco APDMA is not a reproductive or developmental toxicant.3 4. Subchronic toxicity. A repeat dose NOAEL of 15 mg/kg/day has been established for Coco APDMA in an OECD 422 study, but the lowest observed adverse effect level (LOAEL) of 45 mg/kg/day was limited to localized gastric irritation due to the route of entry (oral gavage) and the c orrosive nature of the material, typical of surfactants. 5. Chronic toxicity. No chronic studies are available for Coco APDMA, but negative findings for genotoxicity and no preneoplastic lesions were observed in the OECD 422 study that would suggest pote ntial for carcinogenicity. Neither IARC nor other authoritative bodies have classified Coco APDMA or any other NADMAPA material as a carcinogen. 6. Animal metabolism. No direct information on animal metabolism is available for Coco APDMA. It is genera lly known that the amide linkage is often preserved in the metabolism of amide herbicides and that amines undergo oxidative amine metabolism followed by excretion. 7. Metabolite toxicology
. Specific information for the metabolites of Coco APDMA is not available. 8. Endocrine disruption
. The potential for Coco APDMA to interact with the endocrine system has not been specifically evaluated in a dedicated study; however, based on the available information, there is no indication of a concern for endocrin e disruption. There was no evidence of treatment

- related effects in reproductive or developmental parameters in an OECD 422 combined repeated dose toxicity and reproduction and developmental toxicity screening test. For analogues, there were no adverse e ff

ects from pre

- natal development (fetal NOAEL

- 1000 mg/kg/day for c oconut diethanolamide ( CAS 68603

- 42

- 9 ) ) nor were adverse effects on reproductive tissues and organs reported (dodecanamide,N,N

- bis(2

- hydroxyethyl)

- (CAS 120

- 40

- 1); coconut oil monoethanolam ide (CAS 68140

- 00

- 1)). C. Aggregate Exposure 1. Dietary exposure. The toxicity database supports a proposed endpoint for the chronic reference dose ( c RfD) and an equivalent chronic population adjusted dose (cPAD) of 0.15 mg/kg/day with the reduction of the 10X FQPA S afety F actor (FQPA SF) for children to 1X. An acute reference dose (a RfD ) is not considered warranted based on the corrosivity of the test material that resulted in direct tract/stomach irritation (when administered by oral gavage) that woul d not be relevant to humans. i. Food. Inert exposure predicted by the EPA Inert Ingredient Assessment Branch’s dietary model I

- DEEM is used. I

- DEEM uses a screening level dietary assessment of 57 of the most significant active ingredients as surrogates for inert ingredients within the Dietary Exposure Evaluation Model with the Food Commodity Intake Database (DEEM

- FCIDTM, Version 2.14) software. Exposure f rom food and drinking water are included. The EPA herbicide only I

- DEEM food and drinking water estimates of exposure are reduced to reflect the 20% formulation limitation and then4

assessed against the proposed cPAD of 0.15 mg/kg/day. ii. Drinking water . A conservative default drinking water estimate of 100 ppm is included in the I

- DEEM model. 2. Non

- dietary exposure
. No exposure to NADMAPA will occur via residential herbicidal products since the proposed pesticid e product uses are for crops only. For the general population, limited exposure to Coco APDMA may occur through use in cosmetics (at very low concentrations), but exposure is not expected for younger children. Other non

- dietary uses are limited to small percentages, a ssumed to be 5% or less, in the formulations of personal care soaps and shampoos. For the broader NADMAPA materials, some exposure to o ctadecanamide, N

- [3

- (dimethylamino)propyl] (CAS 7651

- 02

- 7) is possible from high

- end hair care dye kits and conditioners , primarily for adults. Coconut fatty acid, dimethylamidopropyl analogues have been reviewed by the Cosmetic Institute Review and deemed safe when used in rinse

- off products and known to display low dermal absorption. A dermal absorption estimate of 6% f or Coco APDMA is supported by a read

- across and quantitative structure

– activity relationship ( QSAR ) analysis within the petition. D. Cumulative Effects For the purposes of this tolerance action, it is not assumed that NADMAPA have common mechanisms of toxicity with other substances. E. Safety Determination The results of the exposure assessments coupled with the other information in the petition are sufficient to demonstrate that proposed use of NADMAPA based on data from Coco APDMA as an inert in herb icide formulations will not result in unreasonable adverse effects to humans. 1. U.S. population. Based on the proposed cRfD of 0.15 mg/kg/day and the 20% herbicide onl y formulation limitation, the estimated food and drinking water exposure id 17% of the c RfD. This result is analogous to a margin of exposure (MOE) of >600, the additional margin of safety above 100 is deemed adequate to cover any other potential aggregate exposure from non

- dietary uses. 2. Infants and children
. Reduction of the 10X FQPA SF to 1X is proposed given that no reproductive or developmental effects were observed in the OECD 422 study at the highest dose tested (NOAEL of 45 mg/kg/day), which is also higher than the proposed point of departure at 15 mg/kg/day. This 1X factor is fur ther supported by alkyl amides analogue information coupled with limited anticipated exposure from the crop

only herbicide use pattern. This information is proposed as adequate for the determination of a reasonable certainty of no harm. Compari son of the predicted exposure from the refined herbicide I

- DEEM analysis with the NOAEL of 15 mg/kg/day for Coco APDMA results in an estimated exposure for children 1

- 2 yrs old of 53% of th e proposed cPAD or an MOE of >1 9 0. MOE values for5

other subpopulations are higher. In general, the Agency is not concerned for MOEs greater than 100, when the FQPA SF is reduced to 1X. Because the MOE values from the dietary assessment are >180 for children and is considered to b e a conservative assessment, the additional margi n of safety above 100 is deemed adequate to cover any other potential aggregate exposure from non

- dietary uses. In 2005, t he EPA assumption fo r personal care chronic dermal exposure to the analogues of N,N

- dimethyloctamide (CAS 1118

- 92

- 9) and N,N

- dimethyl decanamide (CAS 14433

- 76

- 2) was 0.00032 mg/kg /day. If a similar level is ass umed for NADMAPA and then aggregated with the I

DEEM prediction of 0.08 mg/kg/day, the resulting MOE for children remains >190. F. International Tolerances There are no known international tolerances for NADMAPA.