2 EXECUTIVE SUMMARY

In December 2010 Monsanto submitted a petitio n to the Environmental Protection Agency, herein referred to as the Agency or EP A, to amend 40 CFR 180.910 by establishing an exemption from the requirement of a tolerance for the use of amides, C5-C9, N-[3- (dimethylamino) propyl]; CAS Reg. N o. 1044764-00-2 and amides, C6-C12, N-[3- (dimethylamino) propyl]; CAS Reg. No. 1044764-06-8 as inert ingredient s (surfactants) in pesticide products applied to growing crops and ra w agricultural commodities after harvest. The Agency is not aware of any curren t residential or pesticidal uses for these inert ingredients. For ease of reading the aforementioned chemicals will be referred to as alkyl amidodimethylpropyl amine (AADPA).

Acute studies revealed low oral and dermal toxi city, Toxicity Category III and IV, respectively. When tested on rabbits, the chemical was shown to be mildly irritating to the skin and severely irritating to the eyes, Toxicity Categories IV a nd I, respectively. Skin sensitization studies in guinea pigs showed that the chem ical was not a skin sensitizer.

Several repeat dose studies were conducted on amides, C5-C9, N-[3-(dim ethylamino) propyl]. A 28-day range finding study on rats showed no evid ence of toxicity at doses up to 300 mg/kg/day (No Observed Adverse Effect Level- (NOAEL)). Systemic toxicity (e.g., lower body weight gain, lower food consumption, and effects on red blood cells) were noted at 800 and 1000 mg/kg/day. Females in the 800 mg /kg/day group also had lower organ weights of the liver, spleen, and thymus.

A second range finding study administ ered the test substance to fe male rats on gestation days 6- 19. All females in the 1000 mg/kg/day group were found dead or euthanized in extremis by gestation day 8. In the 500 mg/kg/da y group, two females were euthanized in extremis . Females in this group exhibited clinical signs of toxicity (e.g., rales, incr eased respiration, gasping, dilated pupils, salivation, and body weight gain). There we re no test-substance related clinical findings noted up to150 mg/kg/day. In trauterine growth and survival we re unaffected at dose levels up to 500 mg/kg/day. No external malformations or deve lopmental variations we re noted in this study. The maternal and developmental NOAELs fo r this study were 150 and 500 mg/kg/day, respectively.

A dietary combined 90-day/Repr oductive and Developmental Toxic ity Screening Study in rats did not show evidence of toxicity at exposur es up to 175 mg/kg/day. At the high-dose (600 mg/kg/day), systemic toxicity was exhibited by clinical finding s, lower mean body weights, body weight gains, and food consumption for the male s, toxicology phase fe males, and reproductive phase females. Lower ovary, uterus, and pituita ry weights were noted for the 600 mg/kg/day reproductive phase females. In addition, lower li tter size, number of pups born, implantation sites, and mean pup body weights were noted in the 600 mg/kg/day group in the presence of excessive maternal toxicity. Therefore, the systemic, reproductive, and developmental NOAELs were considered to be 175 mg/kg/day. This st udy NOAEL was chosen as the Toxicity Endpoint used for all exposure scenarios in this risk assessment. An uncertainty factor of 100X was chosen base d on 10X interspecies ex trapolation and 10X for intraspecies variability. No acute endpoint of concern was identif ied in the available database.3 The EPA has determined that reliable data show the safety of infants and children would be adequately protected if the Food Quality Protection Act (FQPA) Safety Factor were reduced to 1X. Therefore, the chronic Reference dose (cRfD) is equal to chronic Population Adjusted Dose (cPAD).

No carcinogenicity studies are available on AADPA s. The Agency used a qualitative structure activity relationship (SAR) databa se, DEREK Version 11, to determin e if there were structural alerts suggestive of carcinogenic ity. No structural alerts were identified for the parent AADPAs nor its major metabolite dimethylaminopropylamin e (DMAPA). Based on these results and the negative findings in both the mutagenicity and cl astogenicity studies al ong with the lack of evidence of specific target organ toxicity, the Agency concluded that these inert ingredients have low potential to be carcinogenic.

Functional observational battery (home cage, handling, open field, neuromuscular, and physiological observations) and lo comotor activity (no remarkable shifts in the pattern of habituation) were recorded fo r Sprague-Dawley rats treated w ith 600 mg/kg/day of the test substance and no test relate d effects were observed.

The proposed initial primary route of metabolis m is believed to generate DMAPA. DMAPA has been recently evaluated by the Agency and an exemption from tolerance under 40 CFR 180.920 and 180.930 was established.

Exposure to AADPAs will be primarily through th e oral route of exposure when eating food treated with pesticides containi ng the chemical. Inhalation exposur e is not expected based on the physical/chemical properties which indicate that volat ilization is unlikely. Model estimates for oral exposure from the use of these inert ingred ients at 50% in formul ation (including exposure through drinking water) resulted in acceptable di etary exposure to all subpopulations. The most highly exposed subpopulation was children 1-2 years old at 35.7% of the cPAD. When residential and dietary exposures were combin ed the exposure did not exceed the acceptable level of risk.

Residential exposure to outdoor pesticide products were eval uated using Agency approved models to estimate the risk to residential handlers and post-ap plication exposures. All exposure scenarios resulted in acceptable levels of risk to all subpopu lations evaluated. Exposure to AADPA inert ingredients via paint, residentia l antimicrobials, pet pr oducts, and greenhouses were not evaluated in this risk assessment and therefore, should not be permitted in pesticide formulations intended for these uses.

Occupational exposure models showed that the us e of this inert ingred ient will result in exposures below the Agency’s level of concern (with the use of gloves in a few occupational exposure scenarios). Therefore, the Agency beli eves there is acceptable risk from the use of AADPAs as inert ingredients in pesticide formula tions (i.e., herbicides, fu ngicides, insecticides).

AADPAs are expected to bind to soil and degrad e rapidly; therefore, they have a very low potential to move to ground or drinking water. Acute ecological to xicity studies revealed that4 AADPA chemicals are slightly toxi c to aquatic invertebrates, ra inbow trout, and avian species. An avian dietary study indicated that AADPAs are practically nontoxi c to Northern Bobwhite.

Based on the findings in this risk assessment th e Agency is granting an exemption from the requirement of a tolerance under 40 CFR 180.91 0 for residues of amides, C5-C9, N-[3- (dimethylamino) propyl]; CAS Reg. N o. 1044764-00-2 and amides, C6-C12, N-[3- (dimethylamino) propyl]; CAS Reg. No. 1044764-06-8 as inert ingredient s (surfactants) in pesticide products applied to growing crops and raw agricultural commodities after harvest.5 I. BACKGROUND

In December 2010 Monsanto submitted a petition to the EPA to amend 40 CFR 180.910 by establishing an exemption from the requirement of a tolerance for the use of amides, C5-C9, N- [3-(dimethylamino) propyl]; CAS Reg. No. 1044764-00-2 and amides, C6-C12, N-[3- (dimethylamino) propyl]; CAS Reg. No. 1044764-06-8 as inert ingredient s (surfactants) in pesticide products applied to growing crops and ra w agricultural commodities after harvest. The Agency is not aware of any curr ent residential or agricultural uses for these inert ingredients.

II. PHYSICAL AND CHEMICAL PROPERTIES

Some of the physical and chemi cal characteristics of AADPAs are found in Table 1.

Table 1: Physical and Ch emical Properties of AADPA Parameter/OPPTS Test Guideline Value 1 Source

Generic Structure for AADPAs H

R= C 2 – C 11 saturated linear Petitioner-Monsanto

CAS Reg. No. 1044764-00-2 and 1044764-06-8 American Chemical Society

Common Names Amides, C5-C9, N-[3- (dimethylamino)propyl]; Amides, C6-C12, N-[3- (dimethylamino)propyl] American Chemical Society

Flammability Flame Extension 830.6315 Did not flash under test conditions MRID 48117101

Boiling Point (°C) 830.7220 323  with decomposition MRID 48117101
pH 830.7000 10.56 at 24  C (1% solution) MRID 48117101
Vapor Pressure 830.7950 <0.1 PSI MRID 48117101

Partition Coefficient (Kow)/Log P

830.7550 Mean 18.14 measured at 3 different ratios of octanol/water Log P- 1.26 MRID 48117101

Water Solubility 830.7840 3.19 g/L at 22  C MRID 48117101
Hydrolysis

835.2120 no hydrolysis noted at pH 4, pH 7, or pH 9 at 50  C MRID 48117103
Henry's Law Constant 8.85 E-11 EPI Suite

1 Values obtained for CAS Reg. No

. 1044764-00-26 III. HAZARD ASSESSMENT

Summary of Toxicity Data:

Monsanto has submitted studies on amides, C5 -C9, N-[3-(dimethylami no) propyl]; CAS Reg. No. 1044764-00-2 to represent both chemicals. The C5-C9 carboxylic acid amine content of the representative test compound CAS Reg. No. 1044764-00-2 represents 97% of the mass of compounds in the alternate C6 -C12 carbon chain length (i.e., CAS reg. No. 1044764-06-8). In addition, the two AADPA surfactants demonstrat e similar physiochemical properties (EPI SuiteTM) and metabolic pathways. The Agency agrees that data on amides, C5-C9, N-[3- (dimethylamino) propyl]; CAS Reg. No. 1044764-00-2 will accurately represent the risk from exposure to amides, C6-C12, N-[3-(dimethyl amino) propyl]; CA S Reg. No. 1044764-06-8.

Available toxicity data include an acute toxici ty battery (OPPTS Harmonized Test Guidelines 870.1100, 870.1200, 870.2400, 870.2500, and 870.2600 (acute inhala tion study not provided)), a 90-day Oral Reproductive and Developmenta l Toxicity Study (OPPTS 870.3650/3100), 2 range finding studies (OPPTS 870.3050 and 870.3700), a mu tagenicity study (OPPTS 870.5100) and a cytogenicity study (OPPTS 870.5395). In addition, suffi cient toxicity data are available on the metabolite dimethylaminopropylamine (CAS Reg. No. 109-55-7). This includes an acute oral, acute inhalation, skin sensitization, subchronic, mutagenicity studies , and an OECD 421 reproduction/developmental toxicity screening te st. (Federal Register , August 5, 2009 (74 FR 38924, FRL 8430-2)).

Toxicity Profile:

Acute Toxicity

Table 2: Acute Toxicity Profile of AADPA Inerts Guideline No. Study Type MRIDs # Results Toxicity Category 1

870.1100 Acute Oral- Rat 48117110 LD 50 3129 mg/kg III

870.1200 Acute Dermal- Rat 48117111 LD 50 >5000 mg/kg IV
870.2400 Primary Eye Irritation- Rabbit 48117112 Severely irritating I

870.2500 Primary Skin Irritation- Rabbit 48117113 Mildly irritating IV

870.2600 Dermal SensitizationGuinea Pig 48117114 Non-sensitizing NA

1 Toxicity Categories from EPA’s Label Review Manual, Chapter 7, updated August 2007 found at http://www.epa.gov/oppfead1/labeling/lrm7 Repeat Dose Toxicity

A 28-day range finding study (MRID 48117115) wa s conducted on Sprague-Dawley rats administered oral doses of 0, 10/800 (dose was increased to 800 mg/kg on study day 18), 50, 100, 300 or 1000 mg/kg/day. All rats were observed twice daily for morbidity and mortality and once daily for clinical observations. Individu al body weights were r ecorded approximately weekly, beginning at least one w eek prior to test substance ad ministration and ending on the day of the scheduled euthanasia. Individual food c onsumption was recorded weekly, beginning at least one week prior to test substance administration.

Blood samples for clinical pathology (hemat ology and serum chemistry) and urinalysis evaluations were collected from all surviving an imals just prior to the scheduled necropsies. Gross necropsies were conducted on all surviving anim als. Organ weights were taken for the following tissues: adrenals, brain, epididymides , heart, kidneys, liver, lung, ovaries with oviducts, pituitary, prostate, splee n, testes, thymus and thyroid w ith parathyroid. Note: uterus was not weighed; macroscopic examination only.

There was no evidence of toxicity noted at exposure levels of 10, 50, 100 or 300 mg/kg/day. Systemic toxicity was observed at 800 mg /kg/day (beginning on study day 18) and 1000 mg/kg/day as evidenced by lower body weight ga ins and lower food consumption. Decreases in liver, spleen and thymus weights (absolute and re lative to body and/or brain) were observed in the 800 mg/kg/day females.

A treatment related effect on red blood cells was noted in both the 800 and 1000 mg/kg/day groups. In the 800 mg/kg/day group, higher red blood cell count, hemoglobin, and hematocrit levels, and lower mean corpuscular volume (MCV) and reticulocyte counts were noted. In the 1000 mg/kg/day group, lower red blood cell coun t, hemoglobin, and hematocrit levels, and higher reticulocyte counts were noted. The chan ges in the 800 mg/kg/day group animals were considered secondary to dehydration or ma lnutrition, again correlating with lower food consumption noted in this group. The opposite eff ect on reticulocyte counts and red blood cell mass in the 1000 mg/kg/day group animals may be due to an over-compensation for an initial reduction in red blood cell counts. Additionally, lo wer eosinophil levels were noted for the 800 and 1000 mg/kg/day group animals.

Based on these finding the no-observed-adverse-eff ect level (NOAEL) was considered to be 300 mg/kg/day for males and females. The LOAEL is 800 mg/kg/day based on lower body weight gains; lower food consumption; higher red blood cell count, hem oglobin, and hematocrit levels; and lower MCV and reticulocyte counts in both sexes.

Developmental and Reproductive Toxicity

Study 1 An oral (gavage) range-finding prenatal developmental toxicity study was conducted on Sprague-Dawley rats (MRID 48117117). Female rats were given 0, 15, 50, 150, 500, or 1000 mg/kg/day on gestation days (GD) 6 through 19.8 All animals were observed twice daily for mo rtality and morbidity. Individual clinical observations were recorded from GD 0 to 20. Body weights and food consumption were recorded on GD 0 and 6-20 (daily). On GD 20 a laparohysterectomy wa s performed on each surviving female. The uteri, placenta, and ovaries were examined, and the numbers of fetuses, early and late resorptions, total implantations, an d corpora lutea were recorded. Gravid uterine weights were recorded, and net body weights an d net body weight changes were calculated. The fetuses were weighed, sexed, and examined fo r external malformations and developmental variations.

All eight females in the 1000 mg/kg/day group were found dead or euthanized in extremis by gestation day 8. These females were noted with rales, hypoactivit y, prostration, clonic convulsions, gasping, shallow resp iration, red and/or clear mate rial around nose and/or mouth, and dilated pupils at the daily examina tion or approximately 1 hour following dose administration 1 day prior to or on the day of death or euthanasia. Additionally, body weight losses and reduced food consumption prior to death or euthanasia were noted for these females. The mortality at 1000 mg/kg/day precluded the ev aluation of laprohysterectomy parameters and fetal morphology at this dose level.

In the 500 mg/kg/day group, two females were euthanized in extremis on gestation day 9 or 14. Females in these groups, including the two females that were euthanized in extremis , were noted with rales, increased respir ation, dilated pupils, gasping, decreased defecation, labored respiration, salivation, and/or clear and/or red material around th e nose, mouth, and/or forelimbs at the daily examinations or approximately 1 hour following dose administration. Additionally, reductions in mean maternal body weights, body we ight gains, and food consumption were noted in the 500 mg/kg/day group throughout the enti re treatment period (GD 6-20). There were no test-substance related clinical findings noted in the 15, 50, and 150 mg/kg/day groups.

At necropsy, two females in the 1000 mg/kg/da y group and one females in the 500 mg/kg/day group were noted with a distended stomach, a nd/or gas-filled distended stomach, duodenum, jejunum, ileum, cecum, and colon. One female in the 500 mg/kg/day group (euthanized in extremis on GD 14) was noted with thick brown contents in the vagina . Intrauterine growth and survival were unaffected at dose levels of 15, 50, 150, and 500 mg/kg/day. No external malformations or developmental vari ations were noted in this study.

The Agency has determined that the maternal NOAEL is 150 mg/kg/day and the LOAEL is 500 mg/kg/day based on decreased in body weight gain, lower food consumption and mortality The developmental NOAEL is 500 mg/kg/day, while the developmental LOAEL was not established.

Study 2 A dietary 90-day one generation Reproductive and Developmental Toxicity Screening Study (MRID 48117116; OPPTS 870.3100 and 870.3650) in Sprague-Dawley rats was conducted at dose levels of 0, 15, 50, 175, and 600 mg/kg/day.

All animals were observed twice daily for mortal ity and morbidity, and clinical observations were performed once daily. Physical examina tions, body weights, and food consumption were9 recorded at least weekly for the males, toxi cology phase females, and during the pre-mating period for the reproductive phase females. Th e reproductive phase female body weights were recorded on gestation days 0, 4, 7, 11, 14, 17, a nd 20 and on lactation days 1, 4, 7, 14, and 21. Food consumption was measured on gestation days 0-20 (daily) and lactation days 1-21 (daily) for the reproductive phase females.

Functional observational battery (FOB) and loco motor activity were recorded for males and toxicology phase females during the last week of test diet expo sure. Hematology, serum chemistry, and urinalysis parameters were eval uated for the males and toxicology phase females on the day of euthanasia. The study also looked at the effects on reproductive and developmental performance including gonadal function, estr ous cyclicity, mating behavior, conception, gestation, parturition, lactation, and on growth and development of the offspring. F1 pups were necropsied on postnatal day (PND) 21.

No evidence of toxicity was noted at exposur e levels of 15, 50, and 175 mg/kg/day. At the highdose (600 mg/kg/day), systemic toxicity was ex hibited by clinical findings, lower mean body weights, body weight gains, and lower food consumption for the males, toxicology phase females and reproductive phase females. Test substa nce-related clinical findings observed in the 600 mg/kg/day group reproductive phase females in cluded red material ar ound the nose observed predominantly during the gestation and/or lact ation periods and yellow material around the urogenital area which was occasionally noted du ring exposure for the 600 mg/kg/day males and reproductive phase females. Lower absolute and relative-to-brain ovary, uterus, and pituitary weights were noted for the 600 mg/kg/day reprod uctive phase females. In addition, lower litter size, number of pups born, implantation sites, and mean pup body weights were noted in the 600 mg/kg/day group in the presence of excessive maternal toxicity.

The parental systemic NOAEL is 175 mg/kg/ day and the LOAEL is 600 mg/kg/day based on lower mean body weights, body weight gains, an d food consumption for both sexes and lower absolute and relative-to-brain ovary, uterus, and pituitary weights for the reproductive phase females.

The reproductive/developmental NOAEL is 175 mg/kg/day and the LOAEL is 600 mg/kg/day, based on lower mean live litter size on PND 0, numb er of pups born and implantation sites, and lower mean pup weights. All repr oductive and developmental effect s were noted in the presence of maternal toxicity.

Neurotoxicity

A specific neurotoxicity study was not conducted on the supported chemicals. However, functional observational battery (home cage, handling, open field, neuromuscular, and physiological observations) and lo comotor activity (no remarkable shifts in the pattern of habituation) were recorded fo r Sprague-Dawley rats treated w ith 600 mg/kg/day of the test substance and no test related effects were observed. (MRID 48117116) Although evidence of neurotoxicity was observed in th e range-finding prenatal devel opmental toxicity study (MRID 48117117), as indicated in the 500 mg/kg/day gro up (dilated pupils) and the 1000 mg/kg/day group (dilated pupils and clonic con vulsions), these clinical signs we re considered to be due to10 generalized toxicity and not of neurologic origin. The Poin t of Departure (POD) of 175 mg/kg/day used in this risk assessment is protec tive of the effects seen at these dose levels.

Mutagenicity

Amides, C5-C9, N-[3-(dimethylamino) propyl] was evaluated in an Ames Assay (MRID 48117118) for their ability to induce reverse mutations at the histidine locus in multiple strains of Salmonella typhimurium (TA98, TA100, TA1535, and TA1537); a nd at the tryptophan locus of Escherichia coli (E. coli) strain WP2 uvr A in the presence or absence of an exogenous mammalian metabolic activation system (S9). Amides, C5-C9, N-[3-(dimethylamino) propyl] was evaluated in the initial mutagenicity assay, in all five tester strains, at doses of 0, 1.6, 5, 16, 50, 160, 500, 1600, or 5000 μ g/plate with and without S9. No positive increases were observed with any of the tester strains in the presence or absence of S9 mix.

Based on the results of the initial assay, amid es, C5-C9, N-[3-(dimethylamino) propyl] was reevaluated in the confirmatory mutagenici ty assay at doses of 0, 33.3, 100, 333, 1000, 2000, or 5000 μ g/plate with and without S9. No positive increases were obser ved with any of the tester strains in the presence or absence of S9 mix.

These results indicate amides, C5-C9, N-[3-(d imethylamino) propyl] we re negative in the Bacterial Reverse Mutation Assay with a C onfirmatory Assay under the conditions, and according to the criteria, of the test protocol. (OPPTS Test Guideline 870.5100)

Clastogenicity

An In Vivo Mouse Bone Marrow Micronucleus A ssay (OPPTS 870.5395) was conducted on IRC (CD-1) male mice with a dose level of 200, 400, or 800 mg/kg. Mortality was observed in 4 of 13 males at 800 mg/kg. Amides, C5-C9, N-[3-(dimet hylamino) propyl] induced signs of clinical toxicity in one male at 800 mg/kg, which incl uded squinted eyes a nd labored respiration. Amides, C5-C9, N-[3-(dimethylamino) propyl] did not induce statistically significant increases in micronucleated polychromatic erythrocytes (PCEs) at any dose level examined (200, 400, and 800 mg/kg). Additionally, amides, C5-C9, N-[3-(dim ethylamino) propyl] was not cytotoxic (i.e., no statistically significant decreas es in the PCE: normochromatic erythrocytes (NCE) ratios) to the bone marrow. Therefore, it is concluded that amides, C5-C9, N-[3 -(dimethylamino) propyl] is negative for clastogenicity.

Carcinogenicity

Although there are no animal carcinogenicity studi es available in the da tabase, amides, C5-C9, N-[3-(dimethylamino) propyl] tested negative in mutagenicity and clastogenicity assays and no evidence of specific target organ toxicity was observed in the O PPTS Harmonized Test Guideline 870.3650 study. A qualitativ e structure activity relations hip database, DEREK Version 11, was used to determine if there were structur al alerts suggestive of carcinogenicity. No structural alerts were identified for th e parent AADPAs nor its major metabolite dimethylaminopropylamine (DMAPA). Additiona lly, no evidence of carcinogenicity was observed in studies on the metabolite dime thylaminopropylamine. The Agency does not11 anticipate amides, C5-C9, N-[3-(dimethylam ino) propyl] or am ides, C6-C12, N-[3- (dimethylamino) propyl] to be carcinogenic; therefore, a car cinogenicity assessment was not performed.

Metabolism and Pharmacokinetics

According to the petitioner:

AADPA metabolism has been postulated ba sed upon well-characterized metabolic pathways that have been prev iously published in texts and peer-reviewed journal articles

. The initial primary route of metabolism is believed to be hydrolysis of the amide bond by amidases to generate the parent C 3 -C 12 carboxylic acid and dimethylaminopropylamine (DMAPA).

 The mixture of C 3 -C 12 fatty acids should enter the general metabolic pool of fatty acids in the body that are obtained primar ily from food sources. Fatty acids are metabolized primarily by beta-oxidation processes which result in successive releases of acetyl CoA (for even carbon chain aci ds) and propionyl CoA (for odd carbon chain acids) which enter into intermediary metabo lism and/or are metabolized ultimately to carbon dioxide and water.

 DMAPA is a dibasic amine and may unde rgo both primary and tertiary amine metabolism. Primary amine metabolism by monoamine oxidases to release ammonia would likely be the major route and shoul d predominate over alternative oxidative pathways such as N, N-demethylation or N-oxide formation.

DMAPA has been assessed by the Agency as an in ert ingredient and is exempt from tolerance under 40 CFR 180.920 and 180.930 (Federal Regi ster, August 5, 2009 (74 FR 38924-35).

Toxicity Endpoint Selection:

No acute endpoint of concern was identified in the avai lable database. The point of departure for this risk assessment for all durations and rout es of exposure was from the OPPTS Harmonized Test Guideline 870.3650 toxicity study in rats. The NOAEL is 175 mg/kg/day and the LOAEL is 600mg/kg/day based on body weight decreases and food consump tion for both sexes and lower absolute and relative-to-brain ovary, uterus, and pituitary weights for the reproductive phase females. A 100 fold uncertainty factor was used for the chronic exposure (10X interspecies extrapolation, 10X for intraspecies variability and 1X FQPA factor).

Although a NOAEL of 150 mg/kg/da y was observed in the 28-day range finding study, the Agency believes that this NOA EL was an artifact of the large dosing gap between the NOAEL of 150 and the LOAEL of 500 mg/kg/day. In the su bsequent 90-day study a dose of 175 mg/kg/day was found to be the NOAEL with the LOAEL of 600 mg/kg/day. In addition, a 28-day range finding study in rats resulted in a NOAEL of 300 mg/kg/day and a LO AEL of 800 mg/kg/day. The Agency feels that 175 mg/kg/day more accurately represents the true NOAEL.12 The NOAEL of 175 mg/kg/day was used as the e ndpoint for all exposure durations via oral, dermal, and inhalation routes of exposure. The re sidential, occupational, and aggregate level of concern (LOC) is for margins of exposure (MOE ) that are less than 100 and is based on 10X interspecies extrapolation, 10X for intraspeci es variability and 1X FQPA factor. Dermal absorption is estimated to be 25% based on the large molecular weight of the chemical and information available to the Agency regarding de rmal absorption from pesticidal chemicals. Due to the vapor pressure of the chemicals they are not expected to volatilize; however, in an effort to capture all potential exposures, in the absence of confirmatory data, the Agency has assumed a 100% inhalation exposure.

IV. FQPA SAFETY FACTOR

FFDCA section 408 provides that EPA shall appl y an additional tenfold margin of exposure (safety) for infants and children in the case of threshold effects to account for prenatal and postnatal toxicity and the comp leteness of the database on to xicity and exposure unless EPA determines that a different margin of exposure (saf ety) will be safe for infants and children. This additional margin of safety is commonly referred to as the FQPA Safety Factor (SF). In applying this provision, EPA either retains the default valu e of 10X, or uses a different additional safety factor when reliable data are available.

Reproductive and developmental effects were evaluated in a 90-day study conducted on Sprague-Dawley (CD) rats (MRID 48117116). No ev idence of toxicity was noted at exposure levels of 15, 50, and 175 mg/kg/day. Systemic t oxicity including lower mean body weights, body weight gains, and food consumption for both se xes and lower absolute and relative-to-brain ovary, uterus, and pituitary weights for the re productive phase female s was exhibited at 600 mg/kg/day. In addition, lower mean live litter size on PND 0, numb er of pups born and implantation sites, and lower mean pup wei ghts were noted in th e 600 mg/kg/day group. Therefore, the systemic, reproductive, and deve lopmental NOAELs were considered to be 175 mg/kg/day. All reproductive and developmental effects we re noted in the presence of maternal toxicity; therefore, there was no evidence of incr eased susceptibility in infants and children.

No evidence of neurotoxicity or imm unotoxicity was observed in the database. In addition, an OECD 421 reproduction and developmental toxic ity screening test using the metabolite dimethylaminopropylamine in Sprague-Dawley ra ts resulted in parental toxicity at 200 mg/kg/day based on decreased body weight gain and clinical si gns (respiratory sounds and piloerection). Reproductive and developmental to xicity were not observed at any dose level.

The FQPA factor can be reduced to 1X for the following reasons: • The toxicology database is adequate for asse ssing the sensitivity of infants and children to exposure from amides, C5-C9, N-[3-(dimet hylamino) propyl] and amides, C6-C12, N-[3- (dimethylamino) propyl] and its me tabolite, dimethylaminopropylamine. • No susceptibility was demonstrated in the offspring in the OECD 422 study following prenatal and potential post-natal exposure. • No susceptibility was demonstrated in th e offspring in the OECD 421 study with the metabolite, dimethylaminopropylamine, followi ng prenatal and post-natal exposure. • No evidence of neurotoxicity was demonstrat ed in the database a nd there is no need for a developmental neurotoxicity study or a dditional UFs to account for neurotoxicity.13 • Amides, C5-C9, N-[3-(dimethylamino) propyl] tested negative in mutagenicity and clastogenicity assays and no evidence of speci fic target organ toxici ty was observed in the OPPTS Harmonized Test Guideline 870.3650 study. No st ructural alerts for carcinogenicity were detected in the Derek model estimation. In addition, no evidence of carcinogenicity was observed in studies on the metabolite dimethylami nopropylamine. Therefore, there is no need to add additional uncertainty factors for the lack of carcinogenicity study. • Residue values used in the dietary risk assessment and exposure values used in the residential assessment are un likely to underestimate risk. The food exposure assessments are considered to be highly conservative as they ar e based on the use of the highest tolerance level from the surrogate pesticides for every food a nd 100% crop treated is assumed for all crops. EPA also made conservative (protective) assu mptions in the ground and surface water modeling used to assess exposure to AADPAs in drinking water

Based on the above weight of evidence EPA concluded that the FQPA factor could be reduced to 1X.

V. ENVIRONMENTA L FATE AND EFFECTS

In order to evaluate the environmental fate of amides, C5-C9, N-[3-(dimethylamino) propyl] and amides, C6-C12, N-[3-(dimethylamino) propyl] the Agency used experimental data submitted by the petitioner and, where data gaps were found, the EPISuiteTM Model was used.

Amides, C5-C9, N-[3-(dimethylamino) propyl] and amides, C6-C12, N-[3-(dimethylamino) propyl] are expected to have low mobility in soil, the preferre d media (Table 3). Adsorption/desorption studies (MRID 48117102) were c onducted in five soils and results further indicated that the chemical is considered to be non-mobile in soil and have a very low potential to move to groundwater. Although these chemicals ar e highly soluble in wate r (Table 1) they are unlikely to reach drinking water sources due to their strong soil binding and rapid degradation. Therefore, the Agency does not believe that ther e is an increased risk of exposure to AADPAs via drinking water from the intend ed use of these chemicals as inert ingredients in pesticide products.

The model predictions (e.g. Henry’ s Law constant and vapor pressu re, Table 1) indicate that AADPAs are unlikely to volatilize a nd therefore, inhalation exposur e is not expected. A closed bottle biodegradation study (MRID 48205701) was conduc ted on the test chemical and resulted in 84% biodegradation at day 28, indicating that the chemical is readily biodegradable. Based on the results of the modeled EPISuiteTM data (Tab le 3) these chemicals have a low potential for bioaccumulation. Study results indicate no evidence of hydrolysis at pH 4, pH7, or pH 9 at 50°C, (MRID 481171-03); therefore, aqueous abiotic hydrol ysis is not expected to be a significant route of elimination of AADPAs from the environment.14 Table 3: AADPA Environmen tal Fate Characteristics

Parameter Results Source Biodegradation readily biodegradable MRID 48117104 Fugacity (Level III Model) EPISuiteTM Air (%) 6.9 E -4 (e) Water (%) 13.6 (e) Soil (%) 86.2(e) Sediment (%) 0.22(e) Bioaccumulation (BCF) 8.9 L/kg wet wt EPISuiteTM U.S. EPA. 2009. Estimation Programs Interface SuiteTM for Microsoft® Windows, v 4.0. United St ates Environmental Protection Agency, Wash ington, DC, USA. http://www.epa.gov/opptintr /exposure/pubs/episuite.htm

VI. RESIDENTIAL (Non-Occupational) EXPOSURE

Dietary:

Exposure to amides, C5-C9, N-[3-(dimethylamino) propyl] and amides, C6-C12, N-[3- (dimethylamino) propyl] will be primarily throug h the oral route of exposure when eating food treated with pesticides containing the inert ingredient. In order to estimate the exposure from oral exposure to AADPAs the EPA’s I-DEEM model was used. See Table 4 for a summary of the results and Appendix A for the complete I-DEEM re sults. A complete description of the general approach taken to assess inert in gredient dietary risks in the abse nce of residue data is contained in the memorandum entitled “Alkyl Amines Po lyalkoxylates (Cluster 4): Acute and Chronic Aggregate (Food and Drinking Water) Dietary Expos ure and Risk Assessments for the Inerts.” (D361707, S. Piper, 2/25/09) and can be found at http://www.regulations.gov in docket ID number EPA-HQ-OPP-2008-0738.

The I-DEEM is a highly conservative model with the assumption that the residue level of the inert ingredient would be no higher than the high est tolerance for a given commodity. Implicit in this assumption is that there would be similar rates of degradation betw een the active and inert ingredient (if any) and that the concentration of inert ingredient in the scenarios leading to these highest of tolerances would be no higher than the concentration of the active i ngredient. The IDEEM assumes the inert ingredients will be 50% of the pesticide product.

The Agency believes the assumptions used to estimate dietary exposur es lead to a very conservative assessment of dietary risk for the following reasons:

 the highest tolerance level residues from the su rrogate pesticides for every food is used;

 100% crop treated (%CT) is assumed for all cr ops (every food eaten by a person each day has tolerance-level residues);

 many of these high tolerances are based on very short pre-harvest intervals where there is little time for degradation, whereas actual pesticide applications occur throughout the growing season;

 no consideration was given to potential de gradation between harvest and consumption (use of tolerance level residues which are typi cally one to two orders of magnitude higher than actual residues foun d in monitoring data);15  residue values were assigned to every co mmodity in DEEMTM with no consideration given to potential reduction in re sidues from washing or cooking.

Although sufficient information to quantify actual re sidue levels in food is not available, the compounding of these conservative assumptions w ill lead to a significant exaggeration of actual exposures. OPP does not believe that this appro ach underestimates exposure in the absence of residue data.

The dietary exposure for the US population was 10.9% of the RfD wh ich is within the Agency’s acceptable level of concern. The most highly ex posed subpopulation was children 1-2 years old at 35.7% of the cPAD. It is important to bear in mind that the I-DEEM model assumes a default value of 100 ppb for the concentratio n of the inert in all sources of drinking water. Based on the physical and chemical properties of these chem icals and the intended use pattern, exposure through drinking water is unlikely; therefore, these results are highl y conservative in regard to the exposure through drinking water.

Table 4: Summary of Dietary (Food and Dri nking Water) Exposure and Risk for AADPA

Population Subgroup Acute Dietar y (95 th Percentile) Chronic Dietary

Dietary Exposure (mg/kg/day) % aPAD Dietary Exposure (mg/kg/day) % cPAD

General U.S. Population

No acute endpoint selected 0.192 10.9

All Infants (< 1 year old) 0.397 22.7
Children 1-2 years old 0.624 35.7

Children 3-5 years old 0.462 26.4

Children 6-12 years old 0.255 14.6

Youth 13-19 years old 0.144 8.2

Adults 20-49 years old 0.144 8.3

Adults 50+ years old 0.152 8.7

Females 13-49 years old 0.145 8.3
The most highly exposed subgroup is bolded.

Residential Handler Exposure:

A screening level residential e xposure and risk assessment was completed for products that may contain AADPA inert ingredients in the future . Details of the assumptions informing the residential exposure and risk assessment can be found in “ JITF Inert Ingredients. Residential and Occupational Exposure Assessment Algorithms and Assumptions Appendix for the Human Health Risk Assessments to Support Proposed Ex emption from the Requirement of a Tolerance When Used as Inert Ingredient s in Pesticide Formulations”, D364751, 5/7/09. A summary of the residential exposure and risk as sessment is presented below.16 The Agency selected representative scenarios, based on end-use product application methods and labeled application rates. A lthough there are no known or anti cipated residential uses for AADPAs, in order to be protective of any future uses, a screening level exposure assessment was performed using high-end exposure scenarios fo r outdoor residential us es. These inerts may potentially be used in pesticide formulations th at are used around the hom e. Residential pesticide products are typically formulated as liquids in concentrates or as wettable powders. The Agency did not assess risk for residential antimicrobi al products, paint products, pet use products, or greenhouse uses. This assessment represents high -end outdoor residential exposure scenarios by assessing AADPA in pesticide form ulations (fungicides /insecticides/herbicide s) in outdoor use products.

The mixer/loader/applicator high exposure out door scenarios use data from the Outdoor Residential Exposure Task Force:

 Liquid products: Low Pressu re Handwand (ORETF data)

 Liquid products: Hose End Sprayer (ORETF data)

 Ready to Use (RTU): Trigger Pump Sprayer Applications (ORETF data)

The level of concern (LOC) for these risk assessments is an MOE of 100 based on the standard 10X inter-species and 10X intra-specie s extrapolation safety factors.

Exposure Data and Assumptions :

A series of assumptions and exposure factors serv ed as the basis for completing the residential handler risk assessments for the AADPA inerts. In addition to these factors, unit exposures were used to calculate risk estimates. The Agen cy used assumptions based on the Residential Exposure Assessment Standard Operating Procedur es (Residential SOPs). Key assumptions used in this assessment are summarized below.

 The maximum application rate for the inert based on its use in a class of pesticide (herbicide/insecticide/fungicide ) has been assessed for the short-term exposure duration.

 Residential risk assessments are based on hi gh-end estimates of what homeowners would typically treat. Per the Office of Pesticide’ s Health Effects Divisi on’s (HED) Residential SOPs (1997 & 2001 revision), residential pestic ide handlers are assumed to mix and use a volume of 5 gallons of product per day.

 For adult exposure, the mean bodyweight for US males and females was used to estimate exposure (70 kg).

 Only adults (age 18+) are e xpected to apply pesticides.

 For outdoor pesticide applicati ons, residential handlers are as sumed to use a total of 2.25 lbs AADPAs per day. This estimate is based on the following assumptions:

o Five (5) gallons of formulated pesticide solution are assumed to be used per day by a residential handler (Revised Resi dential SOPs Area Treated, February, 2001). Consistent with the residential SOPs, the density of the formulated pesticide solution is assumed to be 9 lb s/gallon. The amount of AADPA inert in the pesticide products is 50%. Therefor e 50% of any pesticidal product is17 5 gallons formulated pesticide solution*(9 lbs/gallon)*(50% AADPAs )*(1 part product concentrate/10 parts

w a t e r ) = 2.2 5 l bs AADPA s in f o rm u l a t ed pes ti c i de so l u ti o n s pe r day assumed to be AADPAs. Product concentrates are assumed to be diluted at a 1 to 10 ratio with water.

 Residential exposure is assesse d assuming clothing consisting of a short-sleeved shirt, short pants and no gloves or re spiratory protection, the typi cal clothing for a home-owner applicator

 A 25% dermal absorption value was used.

The duration of exposure for most homeowner a pplications of home garden and lawn care products is best represented by the short-term dur ation (1 to 30 days). These exposure scenarios include the application of herbic ides to lawns and insecticides/f ungicides to gardens, ornamental plants, or lawns. While these types of applicatio ns may be applied on consecutive days, they are not likely to exceed 30 consecutive application days.

Risk Summary :

For all the outdoor residential handl er scenarios, risk es timates are not of c oncern (i.e., MOEs are all greater than 100) for both th e route-specific (der mal or inhalation) assessment and for the total MOE (dermal and inhalation combined). A su mmary of the results ar e provided in Table 5 below. The Agency believes that the handler sc enarios assessed represen t worst-case exposures and risks resulting from use of outdoor pesticide products containing these inert ingredients in residential environments.

Table 5: Short-term Expo sure and Risks for Reside ntial Handlers for AADPA Exposure Scenario (Formulation/ Application) Application Rate 1 (lb

inert/ gallon) Quantity Handled/ Treated per day 2 Dermal Unit Exposure

(mg/lb inert) 3 Inhalation Unit Exposure (mg/ lb inert) 3 Dermal Dose (mg/kg /day) 4 Inhalation Dose (mg/kg/

day) 5 Baseline Dermal MOE 6 Baseline Inhalation

MOE 7 Total MOE 8

Outdoor Products Liquids/ Low Pressure Handwand (ST) (ORETF data) 0.45 lb/gal 5 gallons 38 0.003 0.305 9.6E-5 570 1,800,000 570

Liquids/ Hose End Sprayer, Lawn (ST) (ORETF data) 0.45 lb/gal 5 gallons 11 0.017 0.088 0.00055 2,000 320,000 2,000

Liquids/ Trigger Sprayer/ Home Garden (ST) (ORETF data) 0.45 lb/gal 5 gallons 54 0.0019 0.434 6.11E-5 400 2,900,000 400

1 Application rates are based on maximum application rates of products contai ning AADPA inerts multiplied by 50% for outdoor products to convert from product applicat ion rate to inert application rate.
2 Quantity treated daily values are back-calculated from 5 gallons of product used per day (Revised Residential SOPs 2001) for outdoor products.
3 Unit Exposure data sources are identified in the exposure scenario column. All exposure scenarios assess exposure reflecting applicators wearing short-sleeved shirts an d shorts and no respiratory protection.
4 Daily Dermal Dose = (Dermal Unit Exposure (mg inert /lb inert) * Application Rate (lb /gal) * Quantity handled (gallons/day))/ Body Weight (70 kg)
5 Daily Inhalation Dose = (Inhalation Unit Exposure (mg inert / lb inert) * Appli cation Rate (lb /gal) * Quantity handled (gallons/day)) / Body Weight (70 kg)
6 Dermal MOE = PoD (NOAEL of 175 mg/kg/day)/ Daily dermal dose (mg/kg/day) corrected for 25% dermal absorption.
7 Inhalation MOE = PoD (NOAEL of 175 mg/kg/ day) / Daily inhalation dose (mg/kg/day)
8 Total MOE = 1/ [(1/ Dermal MOE) + (1/ inhalation MOE)]18 Residential Post-application Exposure:

Residential post-application expos ures result when bystanders, such as children come in contact with the AADPA inerts in areas where end-use pr oducts have recently been applied (e.g., treated lawns and gardens). The Agency selected repr esentative scenarios, based on end-use product application methods and labeled application ra tes, and conducted an assessment to represent worst-case residential exposure by assessing post application expos ures and risks from AADPAs in pesticide formulations (fungicides/ insecticid es/ herbicides) used in outdoor scenarios. The following post-application high end outdoor exposure scenarios were assessed:

 Dermal exposure to treated lawns (adults/children)

 Hand-to-Mouth activity for toddler s on treated lawns (children)

 Object-to-Mouth activity for toddl ers on treated lawns (children)

 Soil ingestion from treated soil (children)

The exposures from these routes and scenarios were considered individually and were also added together, where appropriate, to determine a total dose for children exposure to treated lawns. Residential post-application expos ure is assessed on the day of a pplication, typically referred to as Day 0.

Inhalation exposures are not typically calcula ted for post-applicati on scenarios because inhalation exposures generally account for a neglig ible percentage of the overall body burden for most pesticide chemicals. Any inhalation exposu re through the post-application route will be less than the inhalation exposures assessed by residential handlers mentioned above.

For all post-application exposure scenarios, exposures are assesse d at short- and intermediateterm exposure durations because residues may be present on treated areas for lengths of time consistent with short- and in termediate-term exposure.

Exposure Data and Assumptions :

A series of assumptions and exposure factors serv ed as the basis for completing the residential post-application risk assessments. The assumptions and factors used in the risk calculations are consistent with current Agency policy for comp leting residential exposure assessments (i.e., SOPs for Residential Exposure Assessment [1997 and 2001 revision] ).

Exposures to adults/children after contact with treated lawns have been addressed using the latest approaches for this scenario including:

 For adult exposure, the mean bodyweight for US males and females was used to estimate exposure (70 kg). For child exposure, the mean of median values for male and female 3 year olds was used to estimate exposure (15 kg).

 HED has developed standard transfer coe fficient (TC) values for residential postapplication scenarios to ensure consistency in exposure assessments. For the short-term assessment, TC values of 14,500 cm 2 /hr (adults) and 5,200 cm 2 /hr (children) were used. For intermediate-term risk assessment, TC values of 7,300 cm 2 /hr (adults) and 2,600

cm 2 /hr (children) were used. These defau lt transfer coefficients, found in the 2001 Residential SOPs, were used to ca lculate post-application exposures.19  Based on HED’s Residential SOPs, it was assu med that the surface area used for each hand-to-mouth event is 20 cm 2 (based on the surface area of three fingers of a toddler’s hand). For short-term exposures, it is assu med that there were 20 events per hour (90 th percentile, according to the SOP) and for intermediate-term exposures, it was assumed that there were 9.5 event/hour (mean value).

 The exposure time used is 4 hours a day (USEPA, 2000 and 2001).

 The saliva extraction efficiency used is 50% (USEPA, 2000 and 2001).

 Pesticidal products are assumed to contain a maximum of 50% AADPAs by weight in the end use products.

 The relevant application rates for products containing these inerts are derived above.

 A 25% dermal absorption value was used.

Risk Summary :

A summary of the residential post- application exposure and risk es timates are presented in Table 6, below. Short- and intermediate-term post-appli cation risks for children are not of concern. The individual route-specific and combined non-di etary risks from dermal exposure and hand-tomouth exposure for the outdoor scenarios do not de monstrate risks of con cern for toddlers (i.e., the MOEs for the assessed scenarios are greater than 100) for both the short- and intermediateterm exposure durations.

Table 6: Residential Post-application Short- and Intermediate-term Exposures and Risks for AADPAs Exposure Scenario Application Rate 1 Exposed Population &

Exposure Duration 2 Daily Dose (mg/kg/day) 3 MOE 4

Outdoor Lawn Products

Dermal Exposure to Treated Lawns

2.25 lb/day Adult ST 0.131 1,300 Adult IT 0.0658 2,700 Child ST 0.219 800 Child IT 0.109 1,600 Hand-to-Mouth from Treated Lawn Child ST 0.037 5,200 Child IT 0.016 11,000 Object-to-Mouth from Treated Lawn Child ST 0.0084 21,000 Child IT
Soil Ingestion Child ST 0.000113 1,600,000 Child IT Total Lawn Combined Exposures* Child ST NA 690
Child IT NA 1,400

1 Application rates for outdoor products are derived in the “Residential Ha ndler” section above.
2 ST and IT indicate short- or in termediate-term exposure durations.
3 Daily Dose = Daily Dose algorit hms for various residential pos t-application scenarios outlined in “JITF Inert Ingredients

. Residential and Occupa tional Exposure Assessment Algorithms and Assump tions Appendix for the Human Health Risk Assessments to Support Proposed Exemption from the Requirement of a Tolerance When Used as Inert Ingredients in Pesticide Formulations”, D364751, 5/7/09.
4 Dermal MOE = PoD (NOAEL of 175 mg/kg/ day)/ Daily dermal dose (mg/ kg/day) corrected for 25% dermal absorption. Oral MOE = PoD (NOAEL of 175 mg/kg/ day) / Daily dose (mg/kg/day).
5 Combined exposures reflect the aggrega tion of dermal exposure to treated areas and HTM exposure from treated areas (for children). Total Combined Exposures = 1/ [(1 / Dermal MOE) + (1/ HTM MOE)]20 VII. AGGREGATE RISK ASSE SSMENTS AND CHARACTERIZATION

Although there is a potential for amides, C5-C9, N-[3-(dimethylamino) propyl] and amides, C6- C12, N-[3-(dimethylamino) propyl] to produ ce the metabolite dimethylaminopropylamine (DMAPA), which is currently approved under 40 CFR 180.920 and 180.930, EPA does not anticipate any risk concerns from aggregate exposure to DMAPA for the following reasons: i. Evidence from toxicology studies indicates that metabolization of amides, C5-C9, N- [3-(dimethylamino) propyl] and amides, C6-C 12, N-[3-(dimethylamino) propyl], to DMAPA does not occur in significant amounts. The pa rent chemicals (i.e., amides, C5-C9, N-[3- (dimethylamino) propyl] and amides, C6-C12, N-[3 -(dimethylamino) propyl]) have a larger and more complete toxicity database which resu lted in a higher NOAEL than the metabolite, DMAPA. The point of departure (NOAEL) select ed for all exposure scenarios for amides, C5- C9, N-[3-(dimethylamino) propyl] and amides , C6-C12, N-[3-(dimethylamino) propyl] is 175 mg/kg/day versus the NOAEL of 50 mg/kg/day for DMAPA. If DMAPA is a major metabolite of amides, C5-C9, N-[3-(dimethylamino) propyl ] and amides, C6-C12, N-[3-(dimethylamino) propyl] then the toxicity endpoints for amid es, C5-C9, N-[3-(dimethylamino) propyl] and amides, C6-C12, N-[3-(dimethylamino) propyl ] and DMAPA would be comparable. ii. The previous risk assessmen t of metabolite DMAPA (as inert ingredient) indicates that any marginal increase in DMAPA exposure as a result of the use of amides, C5-C9, N-[3- (dimethylamino) propyl] and amides, C6-C12, N -[3-(dimethylamino) propyl] would not alter the DMAPA risk significantly nor change EPA’s c onclusion regarding the safety of DMAPA. [Federal Register August 5, 2009 (74 FR 38924) (FRL-8430-2)]

Acute Aggregate Risk:

There was no hazard attributable to a single exposu re in the toxicity data base for the amides, C5- C9, N-[3-(dimethylamino) propyl] and amid es, C6-C12, N-[3-(dimethylamino) propyl]; therefore, an acute aggregate risk assessment is not required.

Short-Term/Intermediate-Term Aggregate Risk:

Short-term and intermediate-term aggregate ri sk assessments for the AADPA inert ingredients combine high end residential short- or interm ediate-term exposures with average food and drinking water exposures, and compar e this total to a short- or in termediate-term PoD. Short- and intermediate-term residential exposur es are summarized in Table 7.21 Table 7: Short- and Intermediate -Term Residential Risks for the AADPA Aggregate Risk Calculations Population Handler Risk (MOE) 1 Post-application Risk (MOE) Residential Risk (MOE) 2
Short-Term

Adult Male 400 Source: Table 5 Liquid/Trigger Sprayer/Home Garden (ST) 1,300 Source: Table 6 ST Dermal Exposure to Treated Lawns 300

Adult Female 400 Source: Table 5 Liquid/Trigger Sprayer/Home Garden (ST) 1,300 Source: Table 6 ST Dermal Exposure to Treated Lawns 300

Child N/A 690 Source: Table 6 ST Total Lawn Combined Exposures 690

Intermediate-Term

Adult Male N/A 2,700 Source: Table 6 IT Dermal Exposure to Treated Lawns 2,700

Adult Female N/A 2,700 Source: Table 6 IT Dermal Exposure to Treated Lawns 2,700

Child N/A 1,400 Source: Table 6 IT Total Lawn Combined Exposures 1,400

1 – Handler exposure combines high end de rmal and inhalation handler exposure, where the exposure duration is appropriate to

assess 2 - Residential exposure combines high end de rmal and inhalation handler exposure for short-term (Table 5) with high end post application dermal and incident al oral exposure (Table 6).22 Short- and intermediate-term aggregate ri sks are summarized in Table 8. Short- and intermediate-term aggregate risks are not of concern for adults or children

.

Table 8: Short-Term and In termediate-Term Aggregate Risk Calculations

Population LOC for Aggregate Risk 1 MOE food & water 2 MOE
residential 3 Aggregate MOE (food and residential) 4

Short-Term

Adult Male 100 1200 300 240

Adult Female 100 1200 300 240

Child 100 280 690 200

Intermediate-Term

Adult Male 100 1200 2,700 830

Adult Female 100 1200 2,700 830

Child 100 280 1400 230

1 The LOC is based on the standard 100X safety f actor for inter- and intra-species extrapolation

. 2 MOE food = [(short- or intermediate-term oral NOAEL)/(chroni c dietary exposure)]. Chroni c dietary exposure values from Table 4.
3 MOE residential from Table 7.
4 Aggregate MOE (food and residential) = 1

 [(1

 MOE food) + (1

 MOE residential)]

Long-Term Aggregate Risk:

For the AADPAs, the long-term aggregate risk in cludes dietary exposures to food and drinking water only. Long-Term (chronic) aggregate ri sks for the AADPAs are not of concern.

Cancer Risk:

The Agency has not identified any concerns for ca rcinogenicity; therefore, an aggregate cancer dietary exposure assessment was not performed.

VIII. OCCUPATIONAL EX POSURE/RISK PATHWAY

Occupational Handler Exposure:

Based on examination of product labels which could potentially contai n the AADPAs as inert ingredients, the Agency has determined that ex posure to handlers can occur in a variety of occupational environments. Details of the occupational exposure a ssessment for the AADPA inerts can be found in the document “ JITF Inert Ingredients. Residential and Occupational Exposure Assessment Algorithms and Assumpti ons Appendix for the Human Health Risk Assessments to Support Proposed Exemption from the Requirement of a Tolerance When Used as Inert Ingredients in Pestic ide Formulations”, D364751,” 5/7/09.

The representative occupational scenarios selected by the Agency for assessment were evaluated based on likely maximum application rates fo r products which may contain the AADPA inerts23 for the short-term exposure assessment and aver age application rates for products likely to contain AADPAs as inerts for the intermedia te- and long-term exposure durations. Active ingredient application ra tes were corrected for the maximum amount of AADPAs likely to be in the final formulations to determine exposure and risk from exposur e to AADPAs grouped by fungicide/insecticide or herbicide. A summary of the occupational asse ssment is presented below.

Exposure to pesticide handlers is likely during the occupational us e of pesticides containing the AADPA inert ingredients. Dermal and inhalati on exposure was estimated using the Occupational Pesticide Handler Unit Exposure Surrogate Reference Table published May 4, 2011. The quantitative exposure/risk assessment develo ped for occupational ha ndlers to support the requested exemption from the requirement of a tolerance for the AADPAs is based on the following scenarios. The Agency notes that th ese scenarios were selected to represent the scenarios with the highest potential exposure. 1) Mixer/Loader for aerial application- high acreage field crops (liquids) 2) Mixer/Loader for airblast application- tr ee nuts crops (both liquid and wettable powder) 3) Mixer/Loader for groundboom application- hi gh acreage field crops and turf (liquids and wettable powder) 4) Applicators for aerial application- high acreage field crops (liquid) 5) Applicators for airblast- tree nut crops 6) Applicators for groundboom- high ac reage field crops and turf 7) Mixer/Loader/Applicator- low pressure handwand (liquids and wettable powders) 8) Flagging- high acreage fi eld crops (liquids)

Risk estimates were calculated using the Marg in of Exposure (MOE) wh ich is a ratio of the toxicological PoD to the daily dos e. The level of concern (LOC) fo r these risk assessments is an MOE of 100 based on the standard 10X inter and 10X intra species uncertainty safety factors. Daily dose values are calculated by first calc ulating exposures by considering application parameters (i.e., rate and area treated) along with unit exposures. Exposures are then normalized by body weight to calculate dose levels. Dermal short- and intermediate-term exposure is compared to the dermal PoD of 175 mg/kg/da y. A 25% dermal absorp tion value was used. Inhalation short- and intermediate-term exposur e is compared to the inhalation PoD of 175 mg/kg/day (same PoD for short- and intermediate -term exposure durations). To assess handler risks, the Agency used surrogate unit exposure data from the Occupati onal Pesticide Handler Unit Reference Table.

Exposure Data and Assumptions:

The following assumptions and factors were used in order to complete the exposure and risk assessment for occupational handlers/applicators:

 All worker scenarios were assumed to be short- and intermediate-term in exposure durations (i.e., 1-30 days and 1-6 months) except the greenhouse/ hothouse scenario.

 For scenarios where greenhouse/ hothouse applications are pos sible, long-term exposure (6+ months) was assessed.

 The exposure assessment assumes an 8 hour work day.24  The maximum application rate per pesticide group (herbicide/insec ticide/fungicide) has been assessed for the short-term exposure duration.

 The average application rate per pesticid e group (herbicide/insect icide/fungicide) has been assessed for the intermediate-term exposure duration.

 For adult exposure, the mean for US male and female bodyweights was used to estimate exposure (70 kg).

 The baseline clothing level for occupational e xposure scenarios is c onsidered to be an individual wearing long pants, a long-sleeved shirt, shoes, socks, no chemical-resistant gloves, and no respiratory protection.

 For high acreage crops (e.g. corn, soybeans) where applicators can mix/load large quantities of pesticide, exposure assessments have also been completed for baseline dermal PPE (Personal Protective Equipment) plus chemical-resistant gloves, and no respiratory protection.

 There is no proposed limit to the amount of AADPA inerts in the pesticide products. Therefore 50% of any pesticidal product is assumed to be AADPAs (assuming that the inert ingredient would be in the formulation at a level equivalent to the active ingredient (50% active ingredient; 50% AADPA).

Risk Characterization:

The Agency initially assessed handler exposure and risks for the AADPA inerts in fungicides, herbicides and insecticid es at baseline PPE (long pants, a l ong-sleeved shirt, shoes, socks, no chemical-resistant gloves, and no respiratory protection) which the Office of Pesticides (OPP) considers to be standard agri cultural worker clothing. When th ese assessments indicated that there were potential risks of concern for s cenarios where workers w ould be handling large quantities of pesticide for high volume operations typically involving aerial applications to high acreage crops, we repeated the assessments and included additional PPE (i.e., chemical-resistant gloves for pesticide handlers). See Table 9A an d 9B for herbicide products, Table 10A and 10B for insecticide products, and Table 11A and 11B for fungicide products. The Agency has included an assessment for workers handling high volumes of chemicals, which includes gloves, as the Agency believes workers handling these vo lumes of pesticides will be wearing chemicalresistant gloves.

When handlers are wearing standard worker clothing (i.e., baseline PPE) the majority of occupational handler scenarios do not indicate ri sks of concern. For the occupational handler scenarios which involve the handling of large vo lumes of pesticides, those which EPA believes that handlers will be wearing chemical-resista nt gloves, occupational handler scenarios do not indicate risks of concern with the addition of chemical-resistan t gloves to baseline PPE (i.e., minimum dermal PPE).

Pesticide usage in greenhouses has not been eval uated in this assessment and therefore, these inert ingredients are not permitted in pestic ide formulations used in greenhouses.

For the mixer/loader/applicator scenarios describe d in the occupational ha ndler tables (below), the ORETF handler studies have no data for ba seline dermal exposure be cause the handlers in the study wore gloves and no resp iratory protection. HED believes baseline exposure is relevant25 to assess for these exposure scen arios (i.e., baseline dermal PPE and no respiratory protection). Therefore, both ORETF and PHED scenarios are shown in the mixe r/loader/applicator section of the occupational handler tables. Baseline inhala tion MOEs are reported “as is” because ORETF study participants did not wear respiratory pr otection. Additional explanation of the ORETF studies, as well as additional information c oncerning the exposure s cenarios assessed, is available in “ JITF Inert Ingredients. Residential and Occupational Exposure Assessment Algorithms and Assumptions Appendix for the Human Health Risk Assessments to Support Proposed Exemption from the Requirement of a To lerance When Used as Inert Ingredients in Pesticide Formulations”, D364751,” 5/7/09.

Table 9A: Exposure and Risks for Occupational Handlers of AADPAs in Herbicide Products (All Exposure Durations) at Baseline Dermal PPE

Exposure Scenario

(Formulation/ Application/ Crop) Application Rate 1 (lb inert/ A) Area Treated Daily 2 (acres) Dermal Unit Exposure

(mg/lb inert) 3 Inhalation Unit Exposure

(ug/ lb inert) 3 Baseline Dermal Dose (mg/kg /day) 4 Baseline Inhalation

Dose (mg/kg/

day) 5 Baseline Dermal MOE 6 Baseline Inhalation

MOE 7 Total MOE 8

Mixer/Loader Scenarios Liquids/ Aerial Application/ High Acreage Crops (ST) 5.2 1200

0.22 0.219 19.611 0.0195 36 9000 36

Liquids/ Aerial Application/ High Acreage Crops (IT) 1 3.771 0.00375 190 47000 180

Liquids/ Airblast/ Nut Tree (ST) 3.6 40 0.453 0.00045 1500 390000 1500
Liquids/ Airblast/ Nut Tree (IT) 1.6 0.201 0.0002 3500 870000 3500
Liquids/ Groundboom/ High Acreage Crops (ST) 5.2 200 3.269 0.00325 210 54000 210
Liquids/ Groundboom/ High Acreage Crops (IT) 1 0.629 0.00063 1100 280000 1100
Liquids/ Groundboom/ Turf (ST) 5.2 40 0.654 0.00065 1100 270000 1100
Liquids/ Groundboom/ Turf (IT) 1 0.126 0.00013 5600 1400000 5500
Liquids/ Low Pressure Handwand/ Turf (ST) 3.6 5 0.0566 0.00006 12000 3100000 12000
Liquids/ Low Pressure Handwand/ Turf (IT) 3.6 0.0566 0.00006 12000 3100000 12000

Wettable Powder/ Airblast/ Nut Tree (ST) 0.8 40

3.7 43 1.69 0.0197 410 8,900 400

Wettable Powder/ Airblast/ Nut Tree (IT) 0.8 1.69 0.0197 410 8,900 400

Wettable Powder/ Groundboom/ High Acreage Crops (ST) 0.8 200 8.457 0.0983 83 1800 79

Wettable Powder/ Groundboom/ High Acreage Crops (IT) 0.5 5.286 0.0614 130 2,800 130

Wettable Powder/ Groundboom/ Turf (ST) 0.8 40 1.69 0.0197 410 8,900 4000

Wettable Powder/ Groundboom/ Turf (IT) 0.5 1.057 0.0123 660 14,000 630
Wettable powder/ Low Pressure Handwand/ Turf (ST) 3.6 5 0.951 0.011 740 16,000 700

Wettable powder/ Low Pressure Handwand/ Turf (IT) 3.6 0.951 0.011 740 16,000 700
Applicator Scenarios Liquid/ Aerial Application/ High Acreage Crops (ST) 9 5.2 1200 Eng control only: 0.0055 Eng control only: 0.068 0.49 0.0061 1,400 29,000 1,400

Liquid/ Aerial Application/ High Acreage Crops (IT) 9 1 0.094 0.0012 7,400 150,000 7,100

Airblast/ Nut Tree (ST) 0.8 40 0.36 4.5 0.1646 0.0021 4,300 85,000 4,10026 Table 9A: Exposure and Risks for Occupational Handlers of AADPAs in Herbicide Products (All Exposure Durations) at Baseline Dermal PPE

Exposure Scenario

(Formulation/ Application/ Crop) Application Rate 1 (lb inert/ A) Area Treated Daily 2 (acres) Dermal Unit Exposure

(mg/lb inert) 3 Inhalation Unit Exposure

(ug/ lb inert) 3 Baseline Dermal Dose (mg/kg /day) 4 Baseline Inhalation

Dose (mg/kg/

day) 5 Baseline Dermal MOE 6 Baseline Inhalation

MOE 7 Total MOE 8

Airblast/ Nut Tree (IT) 0.8 0.1646 0.0021 4,300 85,000 4,100

Groundboom/ High Acreage Crops (ST) 5.2 200 0.014 0.74 0.208 0.011 3,400 16,000 2,800
Groundboom/ High Acreage Crops (IT) 1 0.04 0.0021 18,000 83,000 14,000

Groundboom/ Turf (ST) 5.2 40 0.042 0.0022 17,000 80,000 14,000

Groundboom/ Turf (IT) 1 0.008 0.00042 88,000 410,000 72,000 Mixer/Loader/Applicator Scenarios

Low Pressure Handwand/ Turf (ORETF data) (ST) 10 3.6 5 No Data 6.6 NA 0.0017 NA 100,000 NA

Low Pressure Handwand/ Turf (ORETF data) (IT) 10 3.6 NA 0.0017 NA 100,000 NA

Wettable Powder/ Low Pressure Handwand/ Ornamentals (ST) 10 3.6

5 No Data 1100 NA 0.2829 NA 620 NA

Wettable Powder/ Low Pressure Handwand/ Ornamentals (IT) 10 3.6 NA 0.2829 NA 620 NA

Wettable Powder/ Low Pressure Handwand/ Ornamentals (LT) 10 3.6 NA 0.2829 NA 620 NA
Flagger Scenarios Liquid/ Flagger/ High Acreage Crops (ST) 5.2 1200 0.011 0.35 0.981 0.0312 710 5,600 630
Liquid/ Flagger/ High Acreage Crops (IT) 1 0.189 0.006 3,700 29,000 3,300

1 Application rates are based on maximum application rates of pr oducts that may contain these inerts multiplied by 50% to convert to application rate of just inert in a product (Pesticide products assumed to contain a maximum of 50% inert AADPAs). Application rates for Short-term (ST) expos ure risk estimates are based on maximum a pplication rates. Application rates for Intermediate-term (IT) and long-te rm (LT) exposures are based on average applic ation rates. Baseline Dermal PPE is single layer clothing, no gloves.
2 Area treated daily values are from the EP A HED estimates of acreage tr eated in a single day for each exposure scenario of

concern. 3 Unit Exposure values are reported in EPA’s Occupational Pe sticide Handler Unit Exposur e Surrogate Reference Table (OPHUE) dated May 4, 2011. All exposure sc enarios assess baseline dermal PPE plus baseline inhalation exposure except for aerial applicator scenarios, which assess inhalation and dermal exposures with engineering controls.
4 Daily Dermal Dose = (Dermal Unit Exposure (mg inert /lb inert) * Application Rate (lb inert /A) * Area Treated (A /day))/ Body Weight (70 kg)
5 Daily Inhalation Dose = (Inhalation Unit Exposure (μg inert / lb inert) * Conversion Factor (1 mg /1000 μg) * Application Rate (lb inert /A) * Area Treated (A /day)) / Body Weight (70 kg)
6 Dermal MOE = PoD (NOAEL of 175mg/kg/day)/ Daily dermal dose (mg/kg/day) corrected for 25% dermal absorption.
7 Inhalation MOE = PoD (NOAEL of 175 mg/kg/ day) / Daily inhalation dose (mg/kg/day)
8 Total Combined MOE = 1/ [(1/ De rmal MOE) + (1/ inhalation MOE)]
9 Aerial applicators do not have baseline exposure: only engineering control e xposure can be assessed. All other exposure scenarios assess baseline dermal (no gl oves) plus baseline inhalation exposure.
10 These scenarios have baseline inhalation unit exposures , but not baseline dermal unit expos ures. The M/L/A scenario assessed has a higher unit exposure at baseline dermal exposure than either of the two scenarios shown at baseline PPE plus gloves derma l
exposure.27 Table 9B: Exposure and Risks for Occupational Handlers of AADPAs in Herbicide Products (All Exposure Durations) with Baseline Dermal PPE and Gloves for High Acreage Mixer/ Loader Scenarios

Exposure Scenario

(Formulation/ Application/ Crop) Application Rate 1 (lb inert/ A) Area Treated Daily 2 (acres) Dermal Unit Exposure

(mg/lb inert) 3 Inhalation Unit Exposure

(ug/ lb inert) 3 Min PPE Dermal Dose (mg/kg /day) 4 Baseline Inhalation

Dose (mg/kg/

day) 5 Min PPE Dermal MOE 6 Baseline Inhalation

MOE 7 Total MOE 8

Mixer/Loader Scenarios Liquids/ Aerial Application/ High Acreage Crops (ST) 9 5.2 1200 0.0376 0.219 3.352 0.0195 210 9000 200

Wettable Powder/ Groundboom/ High Acreage Crops (ST) 0.8 200 0.17 43 0.389 0.0983 1,800 1,800 900

1 Application rates are based on maximum application rates of potential produc ts containing AADPAs multiplied by 50% to convert to application rate of just inert in a product (Pesticide products assumed to contain a maximum of 50% inert AADPAs). Application rates for Short-term (ST) expos ure risk estimates are based on maximum a pplication rates. Application rates for Intermediate-term (IT) and long-te rm (LT) exposures are based on average applic ation rates. Scenarios shown are with Baseline Dermal PPE plus gloves.
2 Area treated daily values are from the EP A HED estimates of acreage tr eated in a single day for each exposure scenario of

concern. 3 Unit Exposure values are reported in OPHUE dated May 4, 2011. All exposure scenarios asse ss minimum dermal PPE (with gloves) plus baseline inhalation exposure.
4

, 5

, 6

, 7, 8 See Table 9A
9 Exposure scenarios assess minimum derm al PPE (baseline PPE plus gloves) plus baseline inhalation exposure.28 Table 10A: Exposure and Risks for Occupational Handlers of AADPAs in Insecticid e Products (All Exposure Durations) at Baseline Dermal PPE

Exposure Scenario

(Formulation/ Application/ Crop) Application Rate 1 (lb inert/ A) Area Treated Daily 2 (acres) Dermal Unit Exposure

(mg/lb inert) 3 Inhalation Unit Exposure

(ug/ lb inert) 3 Baseline Dermal Dose (mg/kg /day) 4 Baseline Inhalation

Dose (mg/kg/

day) 5 Baseline Dermal MOE 6 Baseline Inhalation

MOE 7 Total MOE 8

Mixer/Loader Scenarios Liquids/ Aerial Application/ High Acreage Crops (ST) 1 1200

0.22 0.219 3.771 0.00375 190 47000 180

Liquids/ Aerial Application/ High Acreage Crops (IT) 0.35 1.32 0.00131 530 130000 530

Liquids/ Airblast/ Nut Tree (ST) 4.5 40 0.566 0.00056 1200 310000 1200
Liquids/ Airblast/ Nut Tree (IT) 1.25 0.157 0.00016 4500 1100000 4400
Liquids/ Groundboom/ High Acreage Crops (ST) 1 200 0.629 0.00063 1100 280000 1100
Liquids/ Groundboom/ High Acreage Crops (IT) 0.35 0.22 0.055 3200 800000 3200
Liquids/ Groundboom/ Turf (ST) 1 40 0.126 0.00013 5600 1400000 5500
Liquids/ Groundboom/ Turf (IT) 0.35 0.044 0.00004 16000 4000000 16000
Liquids/ Low Pressure Handwand/ Turf (ST) 3.6 5 0.0566 0.00006 12000 3100000 12000
Liquids/ Low Pressure Handwand/ Turf (IT) 3.6 0.0566 0.00006 12000 3100000 12000

Wettable Powder/ Airblast/ Nut Tree (ST) 3 40

3.7 43 6.34 0.0737 110 2,400 110

Wettable Powder/ Airblast/ Nut Tree (IT) 1.5 3.17 0.037 210 4,700 210

Wettable Powder/ Groundboom/ High Acreage Crops (ST) 0.8 200 8.457 0.098 83 1,800 79

Wettable Powder/ Groundboom/ High Acreage Crops (IT) 0.35 3.7 0.043 190 4,100 180

Wettable Powder/ Groundboom/ Turf (ST) 0.8 40 1.69 0.0197 410 8,900 400

Wettable Powder/ Groundboom/ Turf (IT) 0.35 0.74 0.0086 950 20,000 900
Wettable powder/ Low Pressure Handwand/ Turf (ST) 3.6 5 0.951 0.011 740 160,000 700

Wettable powder/ Low Pressure Handwand/ Turf (IT) 3.6 0.951 0.011 740 160,000 740
Applicator Scenarios Liquid/ Aerial Application/ High Acreage Crops (ST) 9 1 1200 Eng control only: 0.0055 Eng control only: 0.068 0.094 0.0012 7,400 150,000 7,100

Liquid/ Aerial Application/ High Acreage Crops (IT) 9 0.35 0.033 0.0004 21,000 430,000 20,000

Airblast/ Nut Tree (ST) 4.5 40 0.36 4.5 0.9257 0.0116 760 15,000 720
Airblast/ Nut Tree (IT) 1.25 0.257 0.0032 2,700 54,000 2,600

Groundboom/ High Acreage Crops (ST) 1 200 0.014 0.74 0.04 0.00211 18,000 83,000 14,000
Groundboom/ High Acreage Crops (IT) 0.35 0.014 0.00074 50,000 240,000 41,000

Groundboom/ Turf (ST) 1 40 0.008 0.00042 88,000 410,000 72,000

Groundboom/ Turf (IT) 0.35 0.0028 0.00015 250,000 1,200,000 210,000 Mixer/Loader/Applicator Scenarios

Low Pressure Handwand/

Turf (ORETF data) (ST) 10 3.6 5 NA 6.6 NA 0.0017 NA 100,000 NA

Low Pressure Handwand/ Turf (ORETF data) (IT) 10 3.6 NA 0.0017 NA 100,000 NA

Wettable Powder/ Low 3.6 5 NA 1100 NA 0.2829 NA 620 NA29 Table 10A: Exposure and Risks for Occupational Handlers of AADPAs in Insecticid e Products (All Exposure Durations) at Baseline Dermal PPE

Exposure Scenario

(Formulation/ Application/ Crop) Application Rate 1 (lb inert/ A) Area Treated Daily 2 (acres) Dermal Unit Exposure

(mg/lb inert) 3 Inhalation Unit Exposure

(ug/ lb inert) 3 Baseline Dermal Dose (mg/kg /day) 4 Baseline Inhalation

Dose (mg/kg/

day) 5 Baseline Dermal MOE 6 Baseline Inhalation

MOE 7 Total MOE 8

Pressure Handwand/ Ornamentals (ST) 10
Wettable Powder/ Low Pressure Handwand/ Ornamentals (IT) 10 3.6 NA 0.2829 NA 620 NA

Wettable Powder/ Low Pressure Handwand/ Ornamentals (LT) 10 3.6 NA 0.2829 NA 620 NA
Flagger Scenarios Liquid/ Flagger/ High Acreage Crops (ST) 1 1200 0.011 0.35 0.1886 0.006 3,700 29,000 3,300
Liquid/ Flagger/ High Acreage Crops (IT) 0.35 0.066 0.0021 11,000 83,000 9,400

1 Application rates are based on maximum application rates of products contai ning inerts in AADPAs multiplied by 50% to convert to application rate of just inert in a product (Pesticide products assumed to contain a maximum of 50% inert AADPAs). Application rates for Short-term (ST) expos ure risk estimates are based on maximum a pplication rates. Application rates for Intermediate-term (IT) and long-te rm (LT) exposures are based on average applic ation rates. Baseline Dermal PPE is single layer clothing, no gloves.
2 Area treated daily values are from the EP A HED estimates of acreage tr eated in a single day for each exposure scenario of

concern. 3 Unit Exposure values are reported in OPHUE dated May 4, 2011. All exposure scenarios asse ss baseline dermal PPE plus baseline inhalation exposure except for ae rial applicator scenarios, which asse ss inhalation and dermal exposures with engineering controls.
4 Daily Dermal Dose = (Dermal Unit Exposure (mg inert /lb inert) * Application Rate (lb inert /A) * Area Treated (A /day))/ Body Weight (70 kg)
5 Daily Inhalation Dose = (Inhalation Unit Exposure (μg inert / lb inert) * Conversion Factor (1 mg /1000 μg) * Application Rate (lb inert /A) * Area Treated (A /day)) / Body Weight (70 kg)
6 Dermal MOE = PoD (NOAEL of 175 mg/kg/day)/ Daily dermal dose (mg/kg/day) corrected fo r 25% dermal absorption.
7 ST Inhalation MOE = PoD (NOAEL of 175 mg/kg/ day) / Daily inhala tion dose (mg/kg/day)
8 Total Combined MOE = 1/ [(1/ De rmal MOE) + (1/ inhalation MOE)]
9 Aerial applicators do not have baseline exposure: only engineering control e xposure can be assessed. All other exposure scenarios assess baseline dermal (no gl oves) plus baseline inhalation exposure.
10 These scenarios have baseline inhalation unit exposures , but not baseline dermal unit expos ures. The M/L/A scenario assessed has a higher unit exposure at baseline dermal exposure than either of the two scenarios shown at baseline PPE plus gloves derma l
exposure.
Table 10B: Exposure and Risks for Occupational Handlers of AADPAs in Insecticide Products (All Exposure Durations) with Baseline Dermal PPE and Gloves for High Acreage Mixer/ Loader Scenarios

Exposure Scenario

(Formulation/ Application/ Crop) Application Rate 1 (lb inert/ A) Area Treated Daily 2 (acres) Dermal Unit Exposure

(mg/lb inert) 3 Inhalatio n Unit Exposure

(ug/ lb inert) 3 Min PPE Dermal

Dose (mg/kg /day) 4 Baseline Inhalation

Dose (mg/kg/

day) 5 Min PPE Dermal MOE 6 Baseline Inhalation

MOE 7 Total MOE 8

Mixer/Loader Scenarios
Wettable Powder/ Groundboom/ High Acreage Crops (ST) 0.8 200 0.17 43 0.389 0.098 1,800 1,800 900

1 Application rates are based on maximum application rates of potential produc ts containing AADPAs multiplied by 50% to convert to application rate of just inert in an insecticide product (Insectic ide products assumed to contain maximum of 50% AADPA inert). Application rates for Shor t-term (ST) exposure risk estimates are based on maximum application rates. Application rates for Intermediate-term (IT) and long-term (LT) exposures ar e based on average application rates.
2 Area treated daily are from the EPA HED estimates of acreage treated in a single day for each exposure scenario of concern.
3 Unit Exposure values are reported in OPHUE dated May 4, 2011. All exposure scenarios asse ss minimum dermal PPE plus baseline inhalation exposure except for ae rial applicator scenarios, which asse ss inhalation and dermal exposures with engineering controls.
4

, 5

, 6

, 7
, 8 See Table 10A
9 Exposure scenarios assess minimum derm al PPE (baseline PPE plus gloves) plus baseline inhalation exposure.30 Table 11A: Exposure and Risks for Occupational Handlers of AADPAs in Fungicide Products (All Exposure Durations) at Baseline Dermal PPE

Exposure Scenario

(Formulation/ Application/ Crop) Application Rate 1 (lb inert/ A) Area Treated Daily 2 (acres) Dermal Unit Exposure

(mg/lb inert) 3 Inhalation Unit Exposure

(ug/ lb inert) 3 Baseline Dermal Dose (mg/kg /day) 4 Baseline Inhalation

Dose (mg/kg/

day) 5 Baseline Dermal MOE 6 Baseline Inhalation

MOE 7 Total MOE 8

Mixer/Loader Scenarios Liquids/ Aerial Application/ High Acreage Crops (ST) 2.5 1200

0.22 0.219 9.429 0.0094 74 190000 74

Liquids/ Aerial Application/ High Acreage Crops (IT) 0.35 1.32 0.0013 530 130000 530

Liquids/ Airblast/ Nut Tree (ST) 5.5 40 0.691 0.00069 1000 250000 1000
Liquids/ Airblast/ Nut Tree (IT) 1.5 0.189 0.00019 3700 930000 3700
Liquids/ Groundboom/ High Acreage Crops (ST) 2.5 200 1.571 0.00156 450 110000 440
Liquids/ Groundboom/ High Acreage Crops (IT) 0.35 0.22 0.00022 3200 800000 3200
Liquids/ Groundboom/ Turf (ST) 2.5 40 0.314 0.00031 2200 560000 2200
Liquids/ Groundboom/ Turf (IT) 0.35 0.044 0.00004 16000 4000000 16000
Liquids/ Low Pressure Handwand/ Turf (ST) 3.6 5 0.0566 0.00006 12000 3100000 12000
Liquids/ Low Pressure Handwand/ Turf (IT) 3.6 0.0566 0.00006 12000 3100000 12000

Wettable Powder/ Airblast/ Nut Tree (ST) 3.5 40

3.7 43 7.4 0.086 95 2,000 90

Wettable Powder/ Airblast/ Nut Tree (IT) 1 2.11 0.025 330 7,100 320

Wettable Powder/ Groundboom/ High Acreage Crops (ST) 0.5 200 5.29 0.0614 130 2,800 125

Wettable Powder/ Groundboom/ High Acreage Crops (IT) 0.3 3.17 0.0369 220 4,700 210

Wettable Powder/ Groundboom/ Turf (ST) 0.5 40 1.057 0.0123 660 14,000 630

Wettable Powder/ Groundboom/ Turf (IT) 0.3 0.634 0.0074 1,100 24,000 1,100
Wettable powder/ Low Pressure Handwand/ Turf (ST) 3.6 5 0.95 0.011 740 16,000 700

Wettable powder/ Low Pressure Handwand/ Turf (IT) 3.6 0.95 0.011 740 16,000 700
Applicator Scenarios Liquid/ Aerial Application/ High Acreage Crops (ST) 9 2.5 1200 Eng control only: 0.0055 Eng control only: 0.068 0.236 0.0029 3,000 60,000 2,800

Liquid/ Aerial Application/ High Acreage Crops (IT) 9 0.35 0.033 0.0004 21,00 430,000 20,000

Airblast/ Nut Tree (ST) 3.5 40 0.36 4.5 0.72 0.009 970 19,000 930
Airblast/ Nut Tree (IT) 1.5 0.309 0.0039 2,300 45,000 2,200

Groundboom/ High Acreage Crops (ST) 2.5 200 0.014 0.74 0.1 0.0053 7,000 33,000 5,800
Groundboom/ High Acreage Crops (IT) 0.35 0.014 0.0007 50,000 240,000 41,000

Groundboom/ Turf (ST) 2.5 40 0.02 0.0011 35,000 170,000 29,000

Groundboom/ Turf (IT) 0.35 0.0028 0.00015 250,000 1,200,000 210,000 Mixer/Loader/Applicator Scenarios

Low Pressure Handwand/ Turf (ORETF data) (ST) 10 3.6 5 No Data 6.6 NA 0.0017 NA 100,000 NA

Low Pressure Handwand/ Turf (ORETF data) (IT) 10 3.6 NA 0.0017 NA 100,000 NA

Wettable Powder/ Low Pressure Handwand/ 3.6 5 No Data 1100 NA 0.2829 NA 620 NA31 Table 11A: Exposure and Risks for Occupational Handlers of AADPAs in Fungicide Products (All Exposure Durations) at Baseline Dermal PPE

Exposure Scenario

(Formulation/ Application/ Crop) Application Rate 1 (lb inert/ A) Area Treated Daily 2 (acres) Dermal Unit Exposure

(mg/lb inert) 3 Inhalation Unit Exposure

(ug/ lb inert) 3 Baseline Dermal Dose (mg/kg /day) 4 Baseline Inhalation

Dose (mg/kg/

day) 5 Baseline Dermal MOE 6 Baseline Inhalation

MOE 7 Total MOE 8

Ornamentals (ST) 10
Wettable Powder/ Low Pressure Handwand/ Ornamentals (IT) 10 3.6 NA 0.2829 NA 620 NA

Wettable Powder/ Low Pressure Handwand/ Ornamentals (LT) 10 3.6 NA 0.2829 NA 620 NA
Flagger Scenarios Liquid/ Flagger/ High Acreage Crops (ST) 2.5 1200 0.011 0.35 0.47 0.015 1,500 12,000 1,300
Liquid/ Flagger/ High Acreage Crops (IT) 0.35 0.066 0.0021 11,000 83,000 9,400

1 Application rates are based on maximum application rates of potential produc ts containing AADPAs multiplied by 50% to convert to application rate of just inert in a product (Pesticide products assumed to contain a maximum of 50% inert AADPA). Application rates for Short-term (ST) expos ure risk estimates are based on maximum a pplication rates. Application rates for Intermediate-term (IT) and long-te rm (LT) exposures are based on average applic ation rates. Baseline Dermal PPE is single layer clothing, no gloves.
2 Area treated daily values are from the EP A HED estimates of acreage tr eated in a single day for each exposure scenario of

concern. 3 Unit Exposure values are reported in OPHUE dated May 4, 2011. All exposure scenarios asse ss baseline dermal PPE plus baseline inhalation exposure except for ae rial applicator scenarios, which asse ss inhalation and dermal exposures with engineering controls.
4 Daily Dermal Dose = (Dermal Unit Exposure (mg inert /lb inert) * Application Rate (lb inert /A) * Area Treated (A /day))/ Body Weight (70 kg)
5 Daily Inhalation Dose = (Inhalation Unit Exposure (μg inert / lb inert) * Conversion Factor (1 mg /1000 μg) * Application Rate (lb inert /A) * Area Treated (A /day)) / Body Weight (70 kg)
6 Dermal MOE = PoD (NOAEL of 175 mg/kg/day)/ Daily dermal dose (mg/kg/day) corrected fo r 25% dermal absorption.
7 Inhalation MOE = PoD (NOAEL of 175 mg/kg/ day) / Daily inhalation dose (mg/kg/day)
8 Total Combined MOE = 1/ [(1/ De rmal MOE) + (1/ inhalation MOE)]
9 Aerial applicators do not have baseline exposure: only engineering control e xposure can be assessed. All other exposure scenarios assess baseline dermal (no gl oves) plus baseline inhalation exposure.
10 These scenarios have baseline inhalation unit exposures , but not baseline dermal unit expos ures. The M/L/A scenario assessed has a higher unit exposure at baseline dermal exposure than either of the two scenarios shown at baseline PPE plus gloves derma l
exposure.32 Table 11B: Exposure and Risks for Occupational Handlers of AADPAs in Fungicide Products (All Exposure Durations) with Baseline Dermal PPE and Gloves for High Acreage Mixer/ Loader Scenarios

Exposure Scenario

(Formulation/ Application/ Crop) Application Rate 1 (lb inert/ A) Area Treated Daily 2 (acres) Dermal Unit Exposure

(mg/lb inert) 3 Inhalation Unit Exposure

(ug/ lb inert) 3 Min PPE Dermal Dose (mg/kg /day) 4 Baseline Inhalation

Dose (mg/kg/

day) 5 Min PPE Dermal MOE 6 Baseline Inhalation

MOE 7 Total MOE 8

Mixer/Loader Scenarios Liquids/ Aerial Application/ High Acreage Crops (ST) 9 2.5 1200 0.0376 0.219 0.226 0.00131 430 190000 420

Wettable Powder/ Airblast/ Nut Tree (ST) 3.5 40 0.17 43 0.34 0.086 2,100 2,000 1,000

1 Application rates are based on maximum application rates of potential produc ts containing AADPAs multiplied by 50% to convert to application rate of just inert in a fungicide product (Fungicide pr oducts assumed to contain maximum of 50% inert from the AADPAs). Application rates for S hort-term (ST) exposure risk estimates are based on maxi mum application rates. Application rates for Intermediate-term (IT) exposures are based on average application rates.
2 Area treated daily values are from the EP A HED estimates of acreage tr eated in a single day for each exposure scenario of

concern. 3 Unit Exposure values are reported in OPHUE dated May 4, 2011. All exposure scenarios asse ss minimum dermal PPE plus baseline inhalation exposure except for ae rial applicator scenarios, which asse ss inhalation and dermal exposures with engineering controls.
4

, 5,
, 6

, 7
, 8 See Table 11A
9 Exposure scenarios assess minimum derm al PPE (baseline PPE plus gloves) plus baseline inhalation exposure.
Post-application Occupational Risk:

The Agency uses the term post-application to desc ribe exposures that occu r when individuals are present in an environment that has been previously treated with a pe sticide (also referred to as reentry exposure). Such exposures may occur when workers enter previously treated areas to perform job functions, including ac tivities related to crop producti on, such as scouting for pests or harvesting. Post-application e xposure levels vary over time and depend on such things as the type of activity, the nature of the crop or target that was trea ted, the type of pesticide application, and the chemical’s degradation properties. In addition, the timing of pe sticide applications, relative to harvest activities, can greatly reduce the potential for post-application exposure.

This assessment is considered to be a screeni ng level estimate, demonstrating that there are minimal potential risks to workers re-entering fi elds treated with pes ticides containing the AADPAs as inert ingredients. Risks were cal culated using the Margin of Exposure (MOE) approach, which is a ratio of the body burden to the toxicological PoD. The three occupational post-application scenarios assessed are for post-application activities associated with:

 Tall field/row crops (including scouti ng, weeding, hand harvesting sweet corn)

 Turf (golf course/sod farm) (includi ng mowing, transplant ing, hand weeding)

 Vine/Trellis crops (including scouting, training, tying, thinni ng, and grape girding and cane turning)

Inhalation exposures are not typically calcula ted for post-applicati on scenarios because inhalation exposures generally account for a neglig ible percentage of the overall body burden for most pesticide chemicals. This is particularly tr ue for chemicals with a low vapor pressure such as AADPAs.33 Exposure Data and Assumptions :

Key assumptions used in the post-application risk assessment calculations are detailed as follows:

 The average occupational workday is assumed to be 8 hours.

 For adult exposure, the mean for US male and female bodyweights was used to estimate exposure (70 kg).

 HED has developed standard transfer coeffici ent values for occupa tional post-application scenarios to ensure consistency in exposure assessments. These standard values were used to calculate post -application exposures.

 Anticipated post-application activities and thei r respective dermal transfer coefficients (TCs) are summarized in Table 12. The TC info rmation is based on the Science Advisory Council for Exposure Policy Number 3.1.

 TC for sod transplanting, hand weeding is fr om data using Agriculture Re-entry Task Force (ARF) Study ARF-035 (MRID 45432303).

 Calculations of post-appli cation exposures are complete d using maximum application rates of the products of that type of pestic ide (herbicide, insectic ide, or fungicide) for short-term exposures and aver age application rates of pr oducts for intermediate-term
exposures.

 Herbicides/insecticides/fungicides assessed can contain a maximum of 50% AADPAs in any product formulation.

 No post-application data were submitted fo r the AADPAs cluster; a default 20% of the application rate (for agricultu ral crops) and 5% (for turf) is considered available as a transferrable residue with a 10% default daily dissipation rate.

 A 25% dermal absorption value was used.

“ JITF Inert Ingredients. Residential and Occupational Expo sure Assessment Algorithms and Assumptions Appendix for the Human Health Risk Assessments to Support Proposed Exemption from the Requirement of a Tolerance When Used as Inert Ingredients in Pesticide Formulations”, D364751, 5/7/09 contains additional information about the exposure scenarios assessed in this document.

A variety of pesticide formulati ons may potentially contain AADPAs as inert ingredients. PPE is usually not required for worker re -entry, and therefore these post- application risk estimates are based on baseline PPE (no gloves). Typically, the Agency characterizes the risk estimate in relation to the restricted entry interval (REI) for a particular active ingredient. However, since this assessment is to support an exemption fr om the requirement of a tolerance without a requirement for an REI, MOEs have been calcu lated on the day of application (Day 0).

Risk Summary :

Occupational post-applicati on risk estimates are presented in Table 12. The risk estimates for a number of the scenarios assessed demonstrate risk s of concern (i.e., MOEs < 100) for any of the assessed scenarios on Day 0. Those scenarios include: 1) The short-term worker pos t-application activ ities involving herbicides on corn, specifically the hand-harvesting / detassling scen ario. That scenario resulted in an MOE34 of 31 on the day of application (Day 0). A ssuming an herbicide application at the maximum application rate, the MOE would exceed 100 for this scenario at day 11 after application. The Agency notes th at it is not expected to be typical agricultural practice to apply herbicides on the same day worker s would be conducting hand harvesting and detassling activities. As noted earlier in this assessment, herbicides are typically applied relatively early in a growing season. 2) The short-term worker post- application activit ies involving insecticides on corn, specifically the hand-harvesting / detassling scen ario. That scenario resulted in an MOE of 32 on the day of application (Day 0). A ssuming an insecticide application at the maximum application rate, the MOE would exceed 100 for this scenario at day 11 after application. The Agency notes that it is not ex pected to be typical agricultural practice to apply insecticides on the same day work ers would be conducting hand harvesting and detassling activities. 3) The short-term worker post- application activitie s involving insecticides on grapes, specifically the cane turning/girdle. That scenario resulted in an MOE of 78 on the day of application (Day 0). Assuming an insecticide application at the maximum application rate, the MOE would exceed 100 for this scenario at day 3 after application. The Agency notes that it is not expected to be typical agricultural practice to apply insecticides on the same day workers would be conducting cane turning/girdle. 4) The short-term worker pos t-application activ ities involving fungicides on corn, specifically the hand-harvesting / detassling scen ario. That scenario resulted in an MOE of 64 on the day of application (Day 0). A ssuming an insecticide application at the maximum application rate, the MOE would exceed 100 for this scenario at day 5 after application. The Agency notes that it is not ex pected to be typical agricultural practice to apply insecticides on the same day work ers would be conducting hand harvesting and detassling activities.35 Table 12: Short- and Intermediate-Term Occupational Post-application Dermal Exposures and Risks for MOTs

Crop & Exposure Duration Application Rate (lb inert /A) Work Activity Transfer Coefficient 1

(cm 2 /hr) Day after Treatment 2 DFR t (μg/cm 2 ) 3 Daily Dose (mg/kg/day) 4 MOE 5
Herbicide Products

Corn (ST) 5.2 Scout, weed low foliage 100 0

11.668 0.0333 5200
Scout, weed high foliage 400 0 0.1333 1300 Scout, irrigate,

weed high

foliage 1,000 0 0.3334 520

Harvesting/ detassling 17,000 0 5.6672 31 Days after Treatment where MOE > 100 11

Corn (IT) 0.6 Scout, weed low foliage 100 0

1.346 0.0038 45000
Scout, weed high foliage 400 0 0.0154 11000 Scout, irrigate,

weed high

foliage 1,000 0 0.0385 4500

Harvesting/ detassling 17,000 0 0.6539 270

Grapes (Table) (ST) 2.4 Hedge, irrigate, weed, scout,

train, tie 500 0

5.385 0.0769 2300

Scout, train, tie 1,000 0 0.1539 1100 Harvest, pull,

thin, prune,

train, tie 5,000 0 0.7693 230

Cane turning, girdle 10,000 0 1.5386 110

Grapes (Table)

(IT) 1.4 Hedge, irrigate, weed, scout,

train, tie 500 0

3.141 0.0449 3900

Scout, train, tie 1,000 0 0.0898 1900 Harvest, pull,

thin, prune,

train, tie 5,000 0 0.4488 390

Cane turning, girdle 10,000 0 0.8975 190

Turf/ sod

(ST) 5.2 Mowing 500 0 2.917 0.042 4200 Transplant, weed, harvest 6,800 0 0.567 310

Turf/ Sod (IT) 0.6 Mowing 500 0 0.337 0.005 36000 Transplant, weed, harvest 6,800 0 0.065 2700

Insecticide Product

Corn (ST) 5 Scout, weed low foliage 100 0

11.219 0.0321 5500
Scout, weed high foliage 400 0 0.1282 1400 Scout, irrigate,

weed high 1,000 0 0.3205 55036 Table 12: Short- and Intermediate-Term Occupational Post-application Dermal Exposures and Risks for MOTs

Crop & Exposure Duration Application Rate (lb inert /A) Work Activity Transfer Coefficient 1

(cm 2 /hr) Day after Treatment 2 DFR t (μg/cm 2 ) 3 Daily Dose (mg/kg/day) 4 MOE 5 foliage Harvesting/ detassling 17,000 0 5.4492 32 Days after treatment when MOE > 100 11

Corn (IT) 0.5 Scout, weed low foliage 100 0

1.122 0.0032 55000
Scout, weed high foliage 400 0 0.0128 14000 Scout, irrigate,

weed high

foliage 1,000 0 0.0321 5500

Harvesting/ detassling 17,000 0 0.5449 320

Grapes (Table) (ST) 3.5 Hedge, irrigate, weed, scout,

train, tie 500 0

7.853 0.1122 1600

Scout, train, tie 1,000 0 0.2244 780 Harvest, pull,

thin, prune,

train, tie 5,000 0 1.1219 160

Cane turning, girdle 10,000 0 2.2438 78 Days after treatment when MOE > 100 3

Grapes (Table)

(IT) 1.5 Hedge, irrigate, weed, scout,

train, tie 500 0

3.366 0.0481 3600

Scout, train, tie 1,000 0 0.0962 1800 Harvest, pull,

thin, prune,

train, tie 5,000 0 0.4808 360

Cane turning, girdle 10,000 0 0.9616 180

Turf/ sod

(ST) 5 Mowing 500 0 2.805 0.040 4400 Transplant, weed, harvest 6,800 0 0.545 320

Turf/ Sod (IT) 0.5 Mowing 500 0 0.28 0.004 44000
Transplant, weed, harvest 6,800 0 0.054 3200 Fungicide Products

Corn (ST) 2.5 Scout, weed low foliage 100 0

5.609 0.016 11000
Scout, weed high foliage 400 0 0.0641 2700 Scout, irrigate,

weed high

foliage 1,000 0 0.1603 1100

Harvesting/ detassling 17,000 0 2.7246 64 Days after treatment when MOE > 100 537 Table 12: Short- and Intermediate-Term Occupational Post-application Dermal Exposures and Risks for MOTs

Crop & Exposure Duration Application Rate (lb inert /A) Work Activity Transfer Coefficient 1

(cm 2 /hr) Day after Treatment 2 DFR t (μg/cm 2 ) 3 Daily Dose (mg/kg/day) 4 MOE 5

Corn (IT) 0.5 Scout, weed low foliage 100 0

1.122 0.0032 55000
Scout, weed high foliage 400 0 0.0128 14000 Scout, irrigate,

weed high

foliage 1,000 0 0.0321 5500

Harvesting/ detassling 17,000 0 0.5449 320

Grapes (Table) (ST) 2.5 Hedge, irrigate, weed, scout,

train, tie 500 0

5.609 0.0801 2200

Scout, train, tie 1,000 0 0.1603 1100 Harvest, pull,

thin, prune,

train, tie 5,000 0 0.8014 220

Cane turning, girdle 10,000 0 1.6027 120

Grapes (Table)

(IT) 1 Hedge, irrigate, weed, scout,

train, tie 500 0

2.244 0.0321 5500

Scout, train, tie 1,000 0 0.0641 2700 Harvest, pull,

thin, prune,

train, tie 5,000 0 0.3205 550

Cane turning, girdle 10,000 0 0.6411 270

Turf/ sod

(ST) 2.5 Mowing 500 0 1.402 0.020 8700
Transplant, weed, harvest 6,800 0 0.272 640

Turf/ Sod (IT) 0.5 Mowing 500 0 0.28 0.004 44000
Transplant, weed, harvest 6,800 0 0.054 3200

1 Transfer coefficient from Science Advisory Council for Expos ure: Policy Memo #003 “Agricu ltural Transfer Coefficients” 05/07/98. 2 DAT = Day After Treatment
3 DFR = Application rate (lbs in ert/acre) * fraction of active ingredient that remains on foliage (0.2 for crop, 0.05 for turf)* (1- D(10% dissipation)) (t= 0) * 4.54 μg/lb * 24.7 x10-9 acre/cm 2

4 Daily Dose = DFR (μg/cm 2 ) * Tc (cm 2 /hr) * (1 mg/1000 μg) * ET (8 hrs/day) * 25% Dermal Absorption/ body weight (70 kg)
5 Dermal MOE = PoD (NOAEL of 175 mg/kg/ day)/ Daily dermal dose (mg/kg/day).

IX. ENVIRONMENTAL JUSTICE

Potential areas of environmental ju stice concerns, to the extent possi ble, were considered in this human health risk assessment, in accordance w ith U.S. Executive Order 12898, "Federal Actions to Address Environmental Just ice in Minority Populations an d Low-Income Populations," http://www.eh.doe.gov/oepa/ guidance/justice/eo12898.pdf

.38 As a part of every pesticide risk assessment , OPP considers a large variety of consumer subgroups according to well-estab lished procedures when applicab le. In line with OPP policy, ARIA/HED estimates risks to popul ation subgroups from pesticid e exposures that are based on patterns of that subgroup’s food and water c onsumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intakes by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups base d on age, season of the year, ethnic group, and region of the country. Additionally, OPP is ab le to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate , non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for childre n (three to less than six years old), youths, and adults entering or playing on treated areas post-application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and mode ls that consider exposure to bystanders and farm workers as well as lifesty le and traditional dietary patterns among specific subgroups.

X. RISK CHARACTERIZATION

The Agency is unaware of any current residentia l or pesticidal uses for AADPA chemicals.

Acute studies revealed low acute and dermal toxi city for AADPAs, Toxicity Category III and IV, respectively. When tested on rabbits, the chemical was shown to be moderately irritating to the skin and severely irritating to the eyes. Skin se nsitization studies in guinea pigs showed that AADPAs were not skin sensitizers.

Several repeat dose studies were conducted on amides, C5-C9, N-[3-(dim ethylamino) propyl]. A 28-day range finding study in rats showed no evidence of toxicity at doses up to 300 mg/kg/day (NOAEL). Systemic toxicity (e.g., lower body wei ght gain and food consumption, and effects on red blood cells) were noted at 800 and 1000 mg/ kg/day. Females in the 800 mg/kg/day group also had lower organ weights of the liver, spleen, and thymus.

A second range finding study admini stered AADPA to female rats on gestation days 6-19. All females in the 1000 mg/kg/day group were found dead or euthanized in extremis by gestation day 8. In the 500 mg/kg/day group, two females were euthanized in extremis on gestation day 9 or 14. Females in this group, including th e two females that were euthanized in extremis
, exhibited clinical signs of toxi city (e.g., rales, increased resp iration, gasping, dilated pupils, salivation and body weight gains and food consumption). There we re no test-substance related clinical findings noted up t o150 mg/kg/day groups. Intrauterine growth and survival were unaffected by test substance administration at dose levels up to 500 mg/kg/day. No external malformations or developmental variations were noted in this study. The maternal and developmental NOAELs for this study we re 150 and 500 mg/kg/day, respectively.

A dietary combined 90-day/Repr oductive and Developmental Toxic ity Screening study in rats showed no evidence of toxicity at exposur e up to 175 mg/kg/day. At the high-dose (60039 mg/kg/day), systemic toxicity was exhibited by clinical finding s, lower mean body weights, body weight gains, and food consumption for the ma les, toxicology phase females and reproductive phase females. Lower absolute and relative-to-b rain ovary, uterus, and pituitary weights were noted for the 600 mg/kg/day reproductive phase female s. In addition, lower litter size, number of pups born, implantation sites, and mean pup body weights were noted in the 600 mg/kg/day group in the presence of excessive maternal toxi city. Therefore, the systemic, reproductive, and developmental NOAELs were considered to be 175 mg/kg/day. This study NOAEL was chosen as the Toxicity Endpoint used for all expos ure scenarios in this risk assessment.

Based on the negative findings in both the mutage nicity and clastogenicity studies, the lack of evidence of specific target organ t oxicity, and the lack of structur al alerts in DEREK the Agency concluded that AADPAs have low potential to be carcinogenic. F unctional observational battery (home cage, handling, open field, neuromuscular, and physiological observations) and locomotor activity (no remarkable shifts in the pattern of habituation) were recorded for Sprague-Dawley rats treated with 600 mg/kg/day of the test substance and no test related effects were observed. (MRID 48117116) Although evidence of neurotoxi city was observed in MRID 48117117 as indicated in the 500 mg/kg/day treatment gr oup (dilated pupils) and the 1000 mg/kg/day treatment group (dilated pupils a nd clonic convulsions), these clin ical signs were considered secondary to severe systemic t oxicity and not a neurologic origi n. The Point of Departure (POD) of 175 mg/kg/day used in this risk assessment is protective of the eff ects seen at these dose levels.

The primary route of metabolism is believed to be hydrolysis of the amide bond by amidases to generate the parent C 3 -C 12 carboxylic acid and dimethylami nopropylamine (DMAPA). DMAPA has been recently evaluated by the Agency and a Final Rule published in the Federal Register on August 5, 2009 gave DMAPA an exemption from tolerance under 40 CFR 180.920 and 180.930. Although there is a potential to produce the metabolite DMAPA, EPA does not anticipate any risk concerns from aggregate exposure to DMAPA because evidence from toxicology studies indicates that metabolization to DMAPA does no t occur in significant am ounts and the previous risk assessment of the metabolite DMAPA (as inert ingredient) indicates that any marginal increase in DMAPA exposure as a result of th e use of amides, C5-C9, N-[3-(dimethylamino) propyl] and amides, C6-C12, N-[3-(dimethylamino) propyl] would not alter the DMAPA risk significantly nor change EPA’s conclusi on regarding the safety of DMAPA.

Exposure to AADPAs will be primarily through th e oral route of exposure when eating food treated with pesticides contai ning the chemical. In order to estimate the exposure from oral exposure to AADPAs the EPA’s highly conservative I-DEEM mode l, which incorporates a default drinking water concentra tion of 100 ppb, was used. These chemicals are expected to bind tightly to soil and rapidly degrade and are theref ore, unlikely to reach ground or surface water. The use of the I-DEEM will lead to an even more conservative estimate of exposure than what would be expected from the use of AADPAs as in ert ingredients in pestic ide formulations. They are unlikely to volatilize so inha lation exposure is not expected

The I-DEEM showed the exposure from the use of this inert ingredient at 50% in formulation (including exposure through drinking water) would result in acceptable risk to all40 subpopulations. The most highly exposed subpopulat ion was children 1-2 y ears old at 35.7% of the cPAD.

Residential exposure to outdoor pesticide products were eval uated using Agency approved models to estimate the risk to residential handlers and post-ap plication exposures. All exposure scenarios resulted in acceptable levels of risk (i.e., MOEs >100 based on 10X interspecies extrapolation, 10X for intraspe cies variability and 1X FQPA factor) to all subpopulations evaluated. Exposure to AADPA inert ingredients vi a paint, residential an timicrobials, and pet products were not evaluated in this risk asse ssment and therefore, should not be permitted in pesticide formulations intended for these uses. When residential and dietary exposures were combined exposure did not exceed the acceptable level of risk.

Occupational exposure models showed that the us e of this inert ingred ient will result in exposures below the Agency’s level of concern (with the use of gloves in a few occupational exposure scenarios). Therefore, the Agency believ es there is acceptable risk from the use of AADPAs as inert ingredients in pesticide form ulations applied to growing crops and raw agricultural commodities after harvest.

XI. ECOLOGICAL EFFECTS

Daphnia magna were exposed for 48-hours under static conditions to five mean measured concentrations of amides, C5-C9, N-[3-(dimet hylamino) propyl] ranging from 2.9 to 48 mg/L. The 48-hour EC 50 value was 15 mg/L with a 95% confid ence interval of 12 to 17 mg/L. The slope of the concentration-response curve wa s 8.202. The no-immobility concentration and the NOEC were both 6.0 mg/L. This study indicates th at AADPAs are slightly toxic to fresh water daphnids based on acute toxicity (MRID 48117105).

A 96-hour static acute toxicity test with Rainbow Trout ( Oncorhynchus mykiss ) (OPPTS Test Guideline 850.1075) was conducted on amides, C5 -C9, N-[3-(dimethylami no) propyl]. Rainbow trout were exposed under static conditions for 96- hours to five mean measured concentrations of amides, C5-C9, N-[3-(dimethylamino) propyl] ranging from 9.5 to 50 mg/L. The 96-hour LC 50 value was empirically derived to be 50 mg/L w ith a 95% confidence interval of 34 mg/L and above. The no-mortality concentration and NOE C were 34 mg/L. This study indicates that AADPAs are slightly toxic to rainbow trout based on acute toxicity (MRID 48117106).

An acute oral toxicity study was conducted on the Northern Bobwhite (OPPTS 850.2100) at doses of 0, 175, 292, 486, 810, or1350 mg/kg. The acute oral LD 50 value for northern bobwhite was calculated to be 561 mg/kg with a 95% c onfidence interval of 441 to 716 mg/kg. The slope of the dose response curve was 5.516 with a Chi-square value of 0.704. The no-mortality level was 175 mg/kg. This study indicates that AADPAs ar e slightly toxic to Northern Bobwhite based on acute toxicity (MRID 48117107).

A dietary LC 50 study (OPPTS 850.2200) was conducted on the Northern Bobwhite at doses of 0, 562, 1000, 1780, 3160 or 5620 ppm. The dietary LC 50 value for Northern Bobwhite exposed to amides,, C5-C9, N-[3-(dimethylamino) propyl] was determined to be greater than 5620 ppm (1130 mg/kg/day), the highest c oncentration tested. The no mo rtality concentration was 5620 ppm. The no observed effect concentration, base d on a body weight effect at the 5620 ppm test41 concentration, was 3160 ppm (623 mg/kg/day). This study indicates that AADPAs are practically non-toxic to Northern Bobwhite (MRID 48117108).

Pseudokirchneriella subcapitata were exposed to seven concentr ations of amides, C5-C9, N-[3- (dimethylamino) propyl] and eval uated for effects on cell density, area under the growth curve (biomass) and growth rate (OPPTS 850.5400). The 96-hour EC 50 , based on cell density, was estimated to be 1.25 mg/L with a 95% confid ence interval of 1.17 to 1.32 mg/L. The EbC 50 , based on area under the growth curve, was 1.15 mg /L, with the 95% confidence intervals of 1.01 to 1.30 mg/L. The ErC 50 , based on growth rate, was 2.13 mg/L with the 95% confidence intervals of 2.08 to 2.18 mg/L. At 96-hours, Dunnett’ s test indicated that cell density and growth rate were significantly reduced (p<0.05) in the 1.3 and 2.7 mg amides, C5-C9, N-[3- (dimethylamino) propyl]/L trea tment groups relative to the ne gative control. Area under the growth curve was significantly reduced in the 0.64, 1.3, and 2.7 mg amides, C5-C9, N-[3- (dimethylamino) propyl]/L treatment groups wh en compared to the negative control. EC 20 values, calculated as a 96-hour NOAEC es timate, were 0.92, 0.77, and 1.48 mg/L for cell density, biomass and growth rate, respectively (MRID 48117109).

The algal species used in this st udy is not one of the four that is listed in the study guideline; therefore, the optimal concentrations or environm ental conditions are not listed for this species. However, all the environmental factors for the stu dy are within the range of the species that are mentioned in the guideline.42 REFERENCES

MRID 48117110: Oley SD (2009) Acut e Oral Toxicity Up And Down Procedure In Rats. Project Number: 26611. Unpublished report prepared by Euro fins/Product Safety Laboratories. July 16, 2009.

MRID 48117111: Oley SD (2009) Acute Dermal T oxicity Study in Rats. Project Number 26612. Unpublished study prepared by Eurofins/Pr oduct Safety Laboratories. July 16, 2009.

MRID 48117112: Oley SD (2009) Primary Eye Irri tation Study in Rabbits. Project Number: 26613. Unpublished study prepared by Eurofins/Pr oduct Safety Laboratories. July 16, 2009.

MRID 48117113: Oley SD (2009) Primary Skin Irritation Study in Rabbits. Project Number 26614. Unpublished study prepared by Eurofins/Pr oduct Safety Laboratories. July 16, 2009.

MRID 48117114: Oley SD (2009) Dermal Sensitizati on Study in Guinea Pigs (Buehler Method). Project Number 26615. Unpublished study prepared by Eurofins/Product Safety Laboratories. July 17, 2009.

MRID 48117115: Haas MC (2010) A 28-Day Oral (dietary) Dose Range Finding Study in Rats with MON 51803. Unpublished study prepared by WIL Research Laboratories. April 15, 2010.

MRID 48117116: Edwards TL (2010) A dietary combined 90-day/Reproductive and Developmental Toxicity Screening Study of MON 51803 in rats. Unpublished study prepared by WIL Research Laboratories. May 20, 2010.

MRID 48117117: Edwards TL (2010) An Oral (gavage) Range-finding Prenatal Developmental Toxicity Study of MON 51803 in Rats. Unpublished study prepared by WIL Research Laboratories. February 26, 2010.

MRID 48117118: Farabaugh CS (2009) Bacterial Reve rse Mutation Assay with a Confirmatory Assay. Unpublished study prepared by C ovance Laboratories Inc. August 21, 2009.

MRID 48117119: Xu Y (2009) In Vivo Mouse B one Marrow Micronucleus Assay. Unpublished study prepared by Covance Laboratories Inc. August 13, 2009.

MRID 48205701: Van Ginkel CG (2009) Biodegradabil ity of Cross Reference 1 in the Closed Bottle Test. Study Number T09040C. Unpublished study prepared by Akzo Nobel Technology & Engineering, Arnhem, Netherlands. November 3, 2009

MRID 48117101: Prost D (2010). Substance Char acterization for MON 51803, a Surfactant to be used in XXX Formulations. Unpublished st udy prepared by Monsanto Company. June 24, 2010.

MRID 48117102: Walsh K (2010). Adsorption/Desorption of [ 14 C] for MON 51803 in Five Soils. Unpublished study prepared by Ricerca Biosciences, LLC. June 10, 2010.43 MRID 48117103: Grommes S and DiFrances co D (2010). Hydrolysis of [ 14 C]MON 51803 in pH 4, pH 7 and pH 9 Buffered Water. Unpublishe d study prepared by Ricerca Biosciences, LLC. June 4, 2010.

MRID 48117104: Herczog KJS (2010). Rate of Degradation of [ 14 C]MON 51803 in Three Soils Under Aerobic Conditions. Unpublished study pr epared by Ricerca Biosciences, LLC. June 4, 2010.

MRID 48117105: Minderhout T, Kendall TZ, and Krueger HO (2010). A 48-Hour Static Acute Toxicity Test with the Cladoceran ( Daphnia magna ) . Unpublished study prepared by Wildlife International, Ltd . June 14, 2010.

MRID 48117106: Minderhout T, Kendall TZ, and Krueger HO (2010). MON 51803: A 96-Hour Static Acute Toxicity Test with the Rainbow Trout ( Oncorhynchus mykiss ) . Unpublished study prepared by Wildlife International, Ltd . June 14, 2010.

MRID 48117107: Hubbard PM and Beavers JB (2010). MON 51803: An Acute Oral Toxicity Study with the Northern Bobwhite . Unpublished study prepared by Wildlife International, Ltd . May 4, 2010.

MRID 48117108: Hubbard PM, Martin KH, and Beavers JB (2010). MON 51803: A Dietary LC50 Study with the Northern Bobwhite . Unpublished study prepared by Wildlife International, Ltd . May 4, 2010.

MRID 48117109: Cartee TL, Kendall TZ, Krueger HO, and Porch JR(2010). MON 51803: A 96- Hour Toxicity Test with the Freshwater Alga ( Pseudokirchneriella subcapitata ) . Unpublished study prepared by Wildlife International, Ltd . June 9, 2010.

US Environmental Protection Agency (2011) Occupational Pesticide Handler Unit Exposure Surrogate Reference Table. (May 4, 2011) retrieved from http://www.epa.gov/pesticides/sci ence/handler-exposure-table.pdf44 Appendix A

U.S. Environmental Protection Agency Ver. 2.00 DEEM-FCID Chronic analysis for INERTS (1994-98 data) Residue file name: C:\DEEMFCID\Inerts_57active_100ppbH2Orev.R98 Adjustment factor #2 NOT used. Analysis Date 03-17-2011/12:04:37 Residue file dated: 03-03-2009/12:17:18/8 Reference dose (RfD, Chronic) = 1.75 mg/kg bw/day NOEL (Chronic) = 175 mg/kg bw/day COMMENT 1: Inert 57 active ingredients + drinking water (100ppb)

=============================================================================== Total exposure by population subgroup

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Total Exposure

----------------------------------- Population mg/kg Margin of Percent Subgroup body wt/day Exposure 1/ of RfD

-------------------------------------- ------------- ---------- --------- U.S. Population (total) 0.191509 914 10.9%

U.S. Population (spring season) 0.195512 895 11.2% U.S. Population (summer season) 0.193733 903 11.1% U.S. Population (autumn season) 0.188144 930 10.8% U.S. Population (winter season) 0.188739 927 10.8%

Northeast region 0.208249 840 11.9% Midwest region 0.190460 919 10.9% Southern region 0.171478 1,021 9.8% Western region 0.209414 836 12.0%

Hispanics 0.201698 868 11.5% Non-hispanic whites 0.187723 932 10.7% Non-hispanic blacks 0.185288 944 10.6% Non-hisp/non-white/non-black 0.246967 709 14.1%

All infants (< 1 year) 0.397082 441 22.7% Nursing infants 0.212711 823 12.2% Non-nursing infants 0.467077 375 26.7% Children 1-6 yrs 0.495834 353 28.3% Children 7-12 yrs 0.239839 730 13.7%

Females 13-19 (not preg or nursing) 0.138939 1,260 7.9% Females 20+ (not preg or nursing) 0.149292 1,172 8.5% Females 13-50 yrs 0.154523 1,133 8.8% Females 13+ (preg/not nursing) 0.163842 1,068 9.4% Females 13+ (nursing) 0.192592 909 11.0%

Males 13-19 yrs 0.148194 1,181 8.5% Males 20+ yrs 0.144142 1,214 8.2% Seniors 55+ 0.152430 1,148 8.7%

Children 1-2 yrs 0.624005 280 35.7% Children 3-5 yrs 0.461958 379 26.4% Children 6-12 yrs 0.255310 685 14.6% Youth 13-19 yrs 0.144122 1,214 8.2% Adults 20-49 yrs 0.144401 1,212 8.3% Adults 50+ yrs 0.152076 1,151 8.7% Females 13-49 yrs 0.145389 1,204 8.3%

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