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EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: [insert name and telephone number with area code]

TEMPLATE:

[ PP 0E7815 ]

EPA has received a pesticide petition ( [ PP 0E7815 ] ) from the Monsanto Company , [ 1300 I Street, NW Suite 450 East Washington, DC 20005 ] proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to establis h an exemption from the requirement of a tolerance for [ the surfactants referred to as Alkyl Amidodimethylpropyl Amines (AADPA) under 40 CFR §180.910 pre

- and post

- harvest uses , including;

Chemical Abstract Services Registry Numbers (CAS RNs) supported un der the following the following tolerance exemption descriptor:

“C 3 - C 12 Alkyl Amidodimethylpropyl Amines (AADPA)”

CAS RN Chemical Name 1044764

- 00

- 2 Amides, C 5 - C 9 , N

- 3

- [(dimethylamino)propyl] 1044754

- 06

- 8 Amides C 6 - C 12 , N

- 3

- [(dimethylamino)propyl]

MON 5180 3 is the Monsanto code for the surfactant id entified by CAS RN 1044764

- 00

- 2 and the chemical name Amides, C5

- C9, N

- 3

- [(dimethylamine)propyl]. MON 51803 is a representative of the surfactants meeting the descript ion of “C3

- C12 Alkyl Amidodimethylpropyl Amines (AADPA)” and wa s the test substance used in the studies conducted to obtain the data to support this petition.]

A. Residue Chemistry

1. Plant metabolism. [N ot applicable or required for the establishment of a tolerance exemption for inert ingredients

. ]

2. Analytical method. [ Not applicable or required for the est a blishment of a tolerance exemption for inert ingredients. ]3. Magnitude of residues. [ There are no specific crop residue data available

for AADPA surfactant s. This information is not typically required for the establishment of a tolerance exemption. The potential residues in or on food or feed commodities were assessed based on the EPI Suite TM 4.0 physicochemical properties modeling and environmental fate laboratory data. This information indicated that AADPA surfactants are :

E xtensively degraded/mineralized through microbial processes. R apidly and tightly adsorbed to the soil and should not under desor p tion. S table to hydrolysis in sterile buffers at pH 4, 7 and 9 at 50 o C

.
Accordingly, AADPA surfactants should be classified as readily biodegradable and not persist ent in the environm ent and are not expected to bioaccumulate

. The composite o f the all available physicochemical properties and environmental fate studies provide strong evidence that crop residues would be minimal ]

B. Toxicological Profile

1. Acute toxicity. [ The AADPA pesti cide inert ingredients exhibit EPA C ategory III acute oral toxicity, C ategory IV acute dermal toxicity, severe eye irritation, and moderate skin irritation. The representative test compound, MON 51803 , was slightly toxic to rats after acute oral administration and practically non

toxic afte r acute dermal administration. M ON 51803 was severely irritating to rabbit eyes and moderately irritating to rabbit skin, but did not induce dermal sensitization in guinea pigs

. ]

2. Genotoxi ci ty and Mutagenicity

. [ The representative test compound MON 51803 demonstrated no ev idence of genotoxicity in bacterial mutagenicity assays with S. typhimurium and E. coli and no mutagenicity in the in vivo mouse micronucleus assay .]

3. Reproductive and developmental toxicity. [MON 51803 was evaluated in the Pilot Rat Developmental Toxicity Study (OPPTS 870.3700) and the Combined 90

- Day/One

- Generation Rat Reproduction Study (OPPTS 870.3100 and 870.3650). The systemic chronic NOAEL, 175 mg/kg/day resulting from the Combined 90

- Day/One

- Generation Rat Reproducti on Study was chosen as the relevant endpoint to evaluate I

- DEEM dietary exposure and for FQPA risk assessment.

The maternal NO A EL in the pilot rat developmental toxicity study was 150 mg/kg/day due to decreased maternal weight and weight gain as well as food consumption in the 500 mg/kg/day test group. There was no effect on fetal growth, survival, or morphology in this pilot study. The reproductive toxicity study resulted in NOAEL of 175 mg/kg/day for the maternal and pup reproductive and developmental endpoints. The reproductive and developmental findings in this study were not considered to be of significant concern, or indicative of a specific reproductive or developmental toxicant, since they occurred only in the presence of severe malnutrition and excessively decreased maternal weight gain. Furthermore,no evidence of developmental toxicity was observed in the pilot rat developmental

toxicity study, even at a dose level (500 mg/kg/day) which caused 25% maternal mortality. ]

4. Subchronic toxicit

y. [ The Combined 90

- Day/One

- Generation Rat Reproduction Study (OPPTS 870.3100 and 870.3650) demonstrated maternal systemic toxicity at 600 mg/kg/day . The NOAEL was 175 mg/kg/day.]

5. Chronic toxicity. [ No chronic toxicity data are available for AADPA surfactants. ]

6. Animal metabolism. [ AADPA metabolism has been postulated based up on well

- characterized metabolic pathways that have been previously 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 dimethyl aminopropyl amine (DMAPA)

.

The mixture of C 3 - C 12 fatty acids should enter the general metabolic pool of fatty acids in the body that are obt ained primarily from food sources. Fatty acids are metabolized primarily by beta

- oxidation processes which result in successive releases of acetyl CoA (for even carbon chain acids) and propionyl CoA (for odd carbon chain acids) which enter into intermediar y metabolism and/or are metabolized ultimately to carbon dioxide and water.

D M A PA is a dibasic amine and may undergo both primary and tertiary amine metabolism. Primary amine metabolism by monoamine oxidase s to release ammonia would likely be the major route and should predominate over alternative oxidative pathways such as N, N

- demethylation or N

- oxide formation. ]

7. Metabolite toxicology

. [ No metabolites of toxicological concern are expected based up on the proposed animal metabolic pathway. EPA has recently r eviewed and accepted proposed D M A PA mammalian metabolism and granted a tolerance exemption for its use as an amine counter ion for the Alkyl (C 8 - C 24 ) Benzenesulfonic Acid Amine Salts (ABAAS) inert i ngredients in food use pesticide formulations (PP8E7472) that was published as a final rule on August 5, 2009 (Vol

. 74, No

. 149 pages 38924

- 38935)

. ]8. Endocrine disruption

. [ The AADPA surfactants do not belong to a class of

chemicals known or suspected of having adverse effects on the estrogen receptor or endocrine system and have been evaluated in acute, repeated oral dose toxicity, developmental and reproductive studies capable of detecting effects on endocrine mediated events. The representative test compound MON 51803 did not exhibit toxicity related to endocrine disruption in the repeat ed

- dose Combined 90

- Day/One

Generation Rat Reproduction Study (OPPTS 870.3100 and 870.3650 ) and other repeated

- dose pilot studies , 28

- Day Dietary range finding (OPPTS 870.3050 ) and Pilot Rat Developmental Toxicity Study (OPPTS 870.3700 ). ]

C. Aggregate Exposure

1. Dietary exposure. [ The dietary (food plus drinking water) exposures for AADPA surfactants are expressed as a percentage of the proposed chronic population adjusted dose (cPAD) for the general US population and children 1

- 2 years old, the subpopulation with the highest potential
exposures.

Based on I

- DEEM screening level calculations, the chro nic dietary exposures for the AA DPA surfactants are estimated to be 10.9 % of the cPAD for the general U.S. population and 35.7 % of the cPAD for children 1

- 2 years old.

The toxicological data for the representative test compound MON 51803 do not suggest a ny qualitative or quantitative evidence or concern for increased susceptibility of infants and children from the use of the AADPA inert ingredients in pesticide formulations. Therefore, the default 10X FQPA safety factor may be reduced to 1X, and the cRfD is therefore equivalent to the chronic population adjusted dose (cPAD).

CHRONIC DIETARY SAFE TY ASSESSMENT, % CPA D

Study Chronic

Systemic NOAEL 1 mg/kg bw/day cPAD 2

mg/kg bw/day Percent

cPAD 3
Children 1

- 2 years of age Percent

cPAD 3
U.S. Gen Populatio

n Combined OPPTS 870.3100 870.3650 90

- Day/One

Generation Rat Reproduction Study 175 1.75 35.7 % 10.9%

Note: 1 NOAEL

– No observed adverse effect level 2 cPAD

– Chronic population adjusted dose, defined as: chronic NOAEL / (safety factors FQPA factor) 3 Refer to Petition Appendix IV. Table IV 3. ]i. Food. [The available information demonstrate s that the I

- DEEM

screening level chronic dietary (food and drinking water) exposures are well below 100% of the cPAD, and are therefore below EPA’s established level of concern for all U.S. subpopulations.]

ii. Drinking water. [Drinking water is included in the I

- DEEM exposure assessment. Exposure to AA DP A surfactants via drinking water is expected to be negligible .]

2. Non

- dietary exposure

. [ The AADPA surfactants will not be formulated for use in either non

- crop residential pesticide or consumer product formulations. The AADPA surfactants supported by way of the Monsanto tolerance exemption petition are proposed only for use in pesticide f ormulation according to 40 CFR § 180.910
pre - and post

- harvest applications. ]

D. Cumulative Effects

[ For the establishment of the tolerance exemption proposed herein, the AA DP A surfactants will not have a common mechanism of toxicity with other surfacta nt substances. It is therefore appropriate to consider only the potential risks of the compounds included in the exposure assessment provided herein. ]

E. Safety Determination

1. U.S. population. [ A dietary exposure assessment using current EPA inert screening level methodology (I

- DEEM) was conducted. Based on the conservative I

- DEEM dietary exposure estimates, there is a reasonable certainty that no harm will result to the US population from the ag gregate exposure to AADPA surfactants included in to 40 CFR § 180.910 pre

- and post

- harvest use pesticide formulations

. ]

2. Infants and children

. [ The FFDCA Section 408 requires an additional tenfold margin of safety for the protection of infants and chi ldren in case of threshold effects to account for prenatal and postnatal toxicity, or an inadequate toxicity database. Where an adequate and reliable database is available and there is a lack of evidence for increased susceptibility, the FQPA safety facto r may be reduced or removed. An evaluation of susceptibility and uncertainty issues has been performed for the AADPA surfactants. The evaluation, with key points summarized below, support that the FQPA safety factor be reduced from the default 10X to 1X.

Additionally, under these circumstances the chronic Population Adjusted Dose, cPAD, is the same as the Chronic Reference Dose (cRfD) cited above; cPAD = cRfD = 1.75 mg/kg/day.A scientifically sound mammalian toxicology database, which includes acute ,

repeat ed

- dose oral toxicity, reproductive, and developmental toxicity study data, found no adverse effects to sensitive populations. There was also no consistent evidence of effects on the nervous system in the acute, repeat ed

- dose oral toxicity or reproduction study. The AADPA surfactants do not belong to a class of chemicals known or suspected of having adverse effects on the estrogen receptor or endocrine system. The Combined OPPTS 870.3100/ 870.3650 90

- Day/One

- Generation Rat Reproduction Study and other repeat ed

- dose testing provided no evidence of endocrine disruption

. ]

F. International Tolerances

[There are currently no international tolerances for the AADPA surfactants supported herein .]