UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY
AND POLLUTION PREVENTION

November 2, 2012

MEMORANDUM

SUBJECT: Petition No.: 1E7949; PC Code 800287; N-Alkyl (C8-C18) Dimethylamidopropylamines. Human Health Risk Assessment and Ecological Effects Assessment to S upport Proposed Exemption from the Requirement of a Tolerance When Used as an Inert Ingredient in Pesticide
Formulations.

Petition No: 1E7949 DP Barcode: N/A
Decision No.: 458130 Regulatory Action: Inert Tolerance Exemption;

40 CFR180.920 Inert Tracking No: N/A

CAS Reg. No. PC Code Name

68140-01-2 800287 Amides, coco, N-[3-(dimethylamino)propyl] 146987-98-6 800288 Amides, C8-C18 and C18-unsatd., N-[3-(dimethylamino)propyl] 1147459-12-8 800289 N-[3-(dimethylamino)propyl]-C12-C18(even numbered)-alkylamide 3179-80-4 800290 Dodecanamide, N-[3-(dimethylamino)propyl] 45267-19-4 800291 Tetradecanamide, N-[3-(dimethylamino)propyl] 39669-97-1 800292 Hexadecanamide, N-[3-(dimethylamino)propyl] 7651-02-7 800293 Octadecanamide, N-[3-(dimethylamino)propyl] 109-28-4 800294 9-Octadecenamide, N-[3-(dimethylamino)propyl]-,(9Z)-

22890-11-5 800295 D ecanamide, N-[3-(dime thylamino)propyl] 22890-10-4 800296 Octanamide, N-[3-(dimethylamino)propyl]

FROM: W. Cutchin, Chemist Inert Ingredient Assessment Branch (IIAB) Registration Division (RD; 7505P)

TO: PV Shah, Chief IIAB/RD (7505P)2 EXECUTIVE SUMMARY

Introduction : In October 2011 Dow AgroSciences, LLC submitted a petition to the Environmental Protection Agency, herein referred to as the Agency or EPA, to amend 40 CFR 180.920 by establishing an exemption from the require ment of a tolerance for the use of N-Alkyl (C8-C18) dimethylamidopropylamines (NADMAPA), where the alkyl group is linear and may
be saturated and/or unsaturated
, as inert ingredients in pesticides formulations at no more than 20% of formulation in herbicidal pesticide pr oducts. The request covers several CAS numbers for a group of related materials that are all derived from the reaction of dimethylamidopropylamine (DMAPA, CAS Reg N o. 109-55-7) with linear C8-C18 alkyl fatty acids. The Agency is not aware of any current re sidential or pesticidal uses for these inert ingredients.

Summary of Toxicology: The toxicity database for NADMAPA includes acute toxicity studies, in vitro genotoxicity assays and a repeat dose developmental/reproduc tive screening test (OECD 422) toxicity studies on a representative member of the group (Coco ADPMA; (CAS Reg. No. 68140-01-2). The database is augmented by analogue information in the public domain and EPA’s High Production Volume (HPV) program . Coco APDMA is included in subcategory 3 of Category I amides within the 2004 HPV s ubmission for Fatty Nitrogen Derived Amides class. Coco APDMA has moderate acute oral toxicity with an LD 50 of 300 mg/kg/day and is corrosive and irritating to the sk in and eye, respectively. Coco APDMA and its broader class of HPV analogues are negative for geno toxicity across a series of in vitro assays. A combined repeated dose toxicity and reproduction and develo pmental toxicity screen ing test was conducted in rats with Coco APDMA via oral gavage und er OECD 422 guidelines. No treatment-related effects were detected in the reproductive or developmental parameters examined. The no
observed adverse effect level (NOAEL) for repeat dose toxic ity was 15 mg/kg/day, and the NOAEL for reproductive and developmental toxicity was the highest dose tested, 45 mg/kg/day. Based on results of this study, Coco APDMA is not a reproductive or developmental toxicant.

A repeat dose NOAEL of 15 mg/kg/day has been es tablished for Coco APDMA in an OECD 422 study, but the lowest observed a dverse effect level (LOAEL) of 45 mg/kg/day was limited to localized gastric irritation due to the route of entry (oral gavage) and the corrosive nature of the material, typical of surfactants.

No chronic studies are availa ble for NADMAPA but negative fi ndings for genotoxicity and no preneoplastic lesions were observed in th e OECD 422 study on Coco APDMA that would suggest no potential for carcinogenicity for NAD MAPA. 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 NADMAPA. Neither
IARC nor other authoritative bodies have cla ssified any of the NADMAPA chemicals as a carcinogen. Although the duration of exposure was 90 days, there is no need for an additional uncertainty factor because the effects do not seem to increase in severity over time (4 weeks to 13 weeks). Based on the lack of progression of severity of effects with time along with the3 considerable similarities of ef fects across the specie s tested and the observation that the vast majority of the effects observed were related to local irritation and corrosive effects, the ToxSAC
concluded that an additional uncer tainty factor (UF) for extra polation from subchronic toxicity study to a chronic exposure scenar io would not be needed. As a result, the ToxSAC concluded that the typical 100-fold uncertainty factor w ould be sufficiently prot ective since it is not expected that humans’ response to local irr itation/corrosiveness effects would be markedly
different from animals.

No acute endpoint of concern wa s identified in the av ailable database. An acute reference dose (aRfD) is not considered warranted based on the co rrosivity of the test material that resulted in direct tract/stomach irritation (w hen administered by oral gavage). The toxicity database supports a proposed endpoint for the chronic reference dose (cRfD) and with an uncertainty factor of 100X (based on 10X interspecies extrapolation and 10X for in traspecies variability) an equivalent chronic population adjusted dose (cPAD) of 0.15 mg/kg/day for NADMAPA. IIAB
has determined that reliable data show the safety of infants a nd children would be adequately protected if the Food Quality Protection Act Sa fety Factor (FQPA SF) were reduced to 1X. Therefore, the cRfD is equal to cPAD.

No carcinogenicity studies are available on NADMA PA. 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 NADMAPA. Based on these results and the negative findings in both the mutagenicity and clastogenicity studies along with the lack of evidence of specific target organ toxicity, the Agency concluded that these inert ingredients have low pot ential to be carcinogenic.

Endpoints for short and intermedia te term incidental oral and inhalation assessments for all durations of exposure were taken from the same study. Although rout e-specific inhalation toxicity studies are available, the NOAEL for the oral and inhalation studie s are consistent when dose spacing is considered, and the endpoints from the oral study are more robust. Since common endpoints were selected for the oral and inhalation routes of exposure, an aggregate risk assessment can be performed.

Although dermal absorption data for un-ionized amines are available in the li terature, data for the salt forms are not. Since dermal exposure to these amines will be to the ionized forms which are likely to have minimal potential for dermal abso rption and the ionized forms are not likely to exist in any significant concentrations, dermal risks are expected to be insignificant. A quantitative dermal risk a ssessment is not required.

The residential, occupational and aggregate risk le vel of concern (LOC) is for MOEs that are less than 100 and is based on 10X for interspecies ex trapolation from animals to humans and 10X for variation in sensitivity among hu mans. These LOCs are applicable to all populations, including individuals exposed in a re sidential setting and occupa tionally exposed workers.

Exposure: Exposure to NADAMPA will be primarily through the oral route of exposure when eating food treated with pesticid es containing the chemical. Inha lation exposure is not expected based on the physical/chemical properties which indicate that volatili zation is unlikely.4 NADAMPA is expected to bind to soil and degrade rapidly; therefor e, it has a very low potential to move to ground or drinking water.

Dietary Exposure: Model estimates for oral e xposure from the use of NADAMPA at 20% in herbicidal formulations (including exposure th rough drinking water) resu lted in acceptable dietary exposure to all subpopul ations. The most highly expose d subpopulation was children 1-2 years old at 53.4% of the cPAD.

Non-Dietary Exposure: Residential exposure to outdoor pestic ide products were evaluated using Agency approved models to estimate the risk to residential handler s and post-application exposures. All exposure scenarios resulted in ac ceptable levels of risk to all subpopulations
evaluated.

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 NADAMPA as inert ingredients in herbicides formulations.

FQPA Conclusions: There was no evidence of increased su sceptibility of infants and children due to exposure to Coco APDMA in the OECD 422 study. The reproductive and development NOAEL in the OECD 422 study is 45 mg/kg, whic h is higher than the proposed point of departure (POD) for Coco APDMA at 15 mg/ kg, and supports a lower FQPA SF. The alkyl amides analogue information coupled with lim ited anticipated exposure from the crop-only herbicide use pattern also supports a lower FQPA SF. The FQPA safety factor can be reduced to 1x for this group of chemicals since regulation ba sed on the forestomach lesions in rats, a very conservative hazard endpoint, coupled with the highly conservative expos ure assessment and an absence of evidence of increased sensitivity, or ne urotoxicity, supports the finding that the use of
the standard 100X inter- and intra- species uncertainty facts are ad equate to protect infants and
children.

Using a 100X uncertainty factor is very conserva tive since we are regulat ing based on portal of entry effects for which inter-species differences as well as variability among humans are likely to be relatively small. This class of compounds is hi ghly irritating and the toxicity was enhanced by the gavage dosing. Furthermore, hu mans lack a forestomach which serves as a storage reservoir in rodents. Based on the weight of evidence, IIAB has reduced the 10X FQPA safety factor to 1X
for NADMAPA.

Aggregate Exposure: No exposure to NADMAPA will occur via residential herbicidal products, because all planned pesticide products uses are for crops only. For the general population some exposure to NADMAPA could occur via cosmetic use (at very low concentrations), but not for younger children

. A review of general information indicates there is also potential for exposure to NADMAPA mate rials through personal soaps and shampoos. For Coco APDMA exposure at low percentages is cons ervatively assumed to be 5% or less of the overall formulation based on the ingredient lis t rankings of 19th or lower. For the broader NADMAPA materials, some exposure to CAS 7651- 02-7 is possible via hi gh-end hair care dye5 kits and conditioners, primarily for adults. There is no reliable data for this exposure to adults; however, such uses are not expected to result in si gnificant exposures.

There was no hazard attributable to a single exposure in the toxicity database for NADMAPA; therefore, an acute aggregate risk assessment is not required.

Since there are no residential or commercial us es on lawns or ornamentals for NADMAPA, there are no aggregate short- or intermediate term risks.

For NADMAPA, the long-term aggregate risk in cludes dietary exposures to food and drinking water only, which do not exceed IIAB’s level of concern. Chronic aggregate risks are not of

concern.

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

Ecological and Environmental Effects: Acute ecological toxicity studies revealed that NADMAPA is slightly toxic to aquatic invertebrate s, rainbow trout, and avian species. An avian dietary study indicated NADMAPA is prac tically nontoxic to Northern Bobwhite.

Environmental Justice Statement: Potential areas of environm ental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to A ddress Environmental Justice in Minority Populations and Low-Income Populations," http://www.eh.doe.gov/oepa/ guidance/justice/eo12898.pdf

.

Occupational Exposure: Results indicate accep table MOE values (great er than 100) for all occupational scenarios when gloves are worn. HED has previously indicated that the assumption
that mixer/loaders will w ear gloves is reasonable.

Final Conclusions : Based on the findings in this risk assessment the Agency is granting an exemption from the requirement of a tole rance under 40 CFR 180.920 by establishing an exemption from the requirement of a tole rance for the use of N-Alkyl (C8-C18) dimethylamidopropylamines (NADMAPA), where the alkyl group is linear and may be saturated
and/or unsaturated
, as inert ingredients in herbicide products not to exceed maximum amount of
20% in the end use formulation.

I. BACKGROUND

In October 2011 Dow AgroSciences, LLC submitted a petition to the Environmental Protection Agency, herein referred to as the Agency or EPA, to amend 40 CFR 180.920 by establishing an exemption from the requirement of a tolerance for the use of NADMAPA, where the alkyl group is linear and may be saturated a nd/or unsaturated, as inert ingr edients not to exceed 20% in herbicide products. The request covers several CAS numbers for a group of highly related
materials that are all derived from the reaction of DMAPA with linear C8-C18 alkyl fatty acids. This petition is focused on Coco APDMA as the representative test material for NADMAPA6 materials. The Agency is not aware of any current residential or pesticid al uses for these inert ingredients

II. Inert Ingredient Profile

A. Summary of Uses

Dow AgroSciences is requesting to establish an exemption from the requirement of a tolerance for NADMAPA when used as an inert ingredient in herbicide formulations with limits of up to
20% in the final formulation.

B. Physical Chemical Properties

Some of the physical and ch emical characteristics of Coco APDMA, a substance representative of the physical and chemical properties of th e NADMAPA group, along with its structure and nomenclature, are found in Tables 1 and 2

.

Table 1. Coco APDMA Nomenclature and Structure. Common Name Coco amidopropyldimethylamine CAS Reg No. : 68140-01-2 IUPAC Name, proposed (1): N-[3-(dimethylamino)propyl]-Dodecanamide + N-[3- (dimethylamino)propyl]- Tetradecanamide, Molecular Formula (4): ~ C17H36N2O1 EINECS Number (2): 268-771-8 Molecular Weight (g/mol) (4,3): ~ 285 to 315 (estimated); 308 from AkzoNobel (1) Synonyms (2,5, 6,7): Coco APDMA
Alkamide CAP Amida CHF (KAO) Coco amidopropyl Dimethyl Amine Coco amides, N-[3-(di methylamine)propyl]Coconut fatty acid, dimethylamidopropylamide 1-(N,NDimethylamino)-3-(Coconut Oil Amido)Propan e Amides,coco, N-[3-(dimethylamino)propyl]7 Structure (3):

1. USEPA. Office of Pollution Prevention and Toxics, EPI SuiteTM v4.1 with DERMWINTM v2.01, http://www.epa.gov/opptintr/exposure/pubs/episuite.htm ; accessed on August 8, 2011a. 2. National Library of Medicine. ChemIDplus®, http://chem.sis.nlm.nih.gov/ chemidplus/; accessed on August 8,

2011. 3. B. M. Magnusson, Y. G. Anissimov, S. E. Cross, and M. S. Roberts. Molecular Size as the Main Determinant of Solute Maximum Flux Across the Skin. J Invest Dermatol 122:993– 999, 2004. 4. T. Bouwman, M.T.D. Cronin, J.G.M. Bessems, and J.J. M. van de Sandt. Improving the Applicability of (Q)SARs for Percutaneous Penetration in Regulatory Risk Assessment. Human & Experimental Toxicology, Vol. 27, No. 4, 269-276, 2008 5. Organisation for Economic Co-Operation and Developmen t (OECD). Draft Guidance Notes for the Estimation of Dermal Absorption Values, Environmental Directorate, H ealth and Safety Publications Series on Testing and Assessment, at http://www.oecd.org/dataoecd/51/19/40736824.pdf ; accessed August 8, 2011. 6. USEPA. Hazard Characterization Document for Fatty Nitrogen Derived Amides Category, http://www.epa.gov/hpv/pubs/ summaries/amines/c14171tc.htm; accessed on August 8, 2011c. 7. USEPA. Dermal Exposure Assessment: Principles and Applications, Exposure Assessment Group, EPA/600/8- 91/011B, 1992.

Table 2. Coco APDMA Physical-Chemical Properties Physical state (1) Yellow, liquid Melting point (2) 150.12°C

Boiling point (2, 3) 407.12 °C (Adapted Stein & Brown method); reported as > 200 °C in IUCLID (3) Average Log Kow (2) 4.4 (estimated) Density (3) 1.06 g/mL at 20°C Flash Point (3) > 100°C

Reactivity (1) Product is stable; Reactive with OXIDIZING AGENTS, acids; Hazardous polyermerization will not occur.

Water solubility (2, 3) 2.623 (mg/L) at 25°C (WSKOW v1.41); reported as < 10 g/L °C in IUCLID (3) Vapor pressure (2) 2.97E-007 (mm Hg,25°C Modified Grain method) Henry’s Law Constant (2) 4.238E-008 atm-m3/mol (via VP/Wsol estimates) Log Koc (2) 3.3 to 3.8 L/kg OH Reaction Rate (2) 107.4 E-12 cm 3/molecule-sec (half-life = 1.2 hrs) Log BCF (2) 1.198 L/kg; EPI Suite algorithm8 Level III Fugacity Model (2) Mass Amount Half-Life Emissions (percent) (hr) (kg/hr) Air 0.00297 2.4
1000 Water 10.9 900 1000 Soil 85.5 1.8e+003 1000 Sediment 3.62

8.1e+003 0 Persistence Time: 1.87e+003 h r 1. MSDS for ARMEEN* APA C-1, AkzoNobel, MSDS # 15-14630, http://www.surfactants.akzonobel.com/msds_eu_2.cfm ?Region=1&Product=2067 , accessed May 17, 2010. 2. US EPA, Estimation Programs Interface SuiteTM for Microsoft® Windows v 4.10 http://www.epa.gov/oppt/exposure/pubs/episuite.htm ; United States Environmental Protection Agency, Washington, DC, USA, downloaded on August 1, 2011. 3. Amides, coco, N-[3-(dimethylamine)propyl], IUCLID , 19-Feb-2000, http://ecb.jrc.ec.europa.eu/IUCLIDDataSheets/68140012.pdf , accessed on May 3, 2010.

III. Hazard ASSESSMENT

A. Summary of Toxicity Data.

Table 3. Toxicology Data Summary for Coco APDMA
Study Value Comments Reference Acute oral (rat) LD 50 = >2000 mg/kg Directive
84/449/EEC Henkel KGaA, unpublished data, Archive-No. TBD 850340, reference 8 within the IUCLID Ref. (6), 2000. Acute oral (rat) LD 50 = 300 mg/kg OECD 423 guidelines, minimal long
terms effects were
observed at the
low dose of 50 mg/kg. Acute Oral Toxicity in Rats “Acute Toxic Class Method”, CIT/Study No. 36059 TAR, Coco APDMA/CECA S.A, MRID 48556303.

Acute dermal irritation (rabbit) Corrosive, when applied topically to
rabbits OECD 404 guidelines; listed
as corrosive to skin on MSDS (1) Acute Dermal Irritation in Rabbits, CIT/Study No. 36060 TAL, Coco APDMA/CECA S.A, AkzoNobel Study, April 28, 2010, MRID

48556304 Eye irritation irritating OECD 405 guideline, listed as corrosive to eyes on MSDS (1) Henkel KGaA, unpublished data, Archive-No. TBD 850340, reference 9 within the IUCLID Ref. (6), 2000.

Dermal sensitization (LLNA) 75% Coco APDMA
in formulation Positive OECD 429 and

OPPTS 870.2600 guidelines Adsee C80W And Ammononyx Lo: Reduced Local Lymph Node Assess in CBA/J Mice, Internal Report of Dow Chemical Co. Study ID 100272, April 25, 2011.
Dermal sensitization (Buehler) Not a sensitizer Contact Hypersensitivity in Albino Guinea Pigs, Buehler Test, Harlan Laboratories Study C83737, ARMAK 2096, MRID 48621603.

I n vitro bacterial reverse gene mutation Negative, not mutagenic OECD 471 guidelines Bacterial Reverse Mutation Test, CIT/Study No. 36057 MMO, Coco APDMA/CECA S.A, AkzoNobel Study, August 20, 2010, MRID
48556301

In vitro Mammalian
Chromosome Aberration in Human Lymphocytes Negative, not genotoxic OECD 473 guidelines In Vitro Mammalian Chromosome
Aberration Test in Cultured Human Lymphocytes, CIT/Study No. 36058 MLH, Coco APDMA/CECA S.A,9 B. Toxicity Profile

B.1. Acute Oral Toxicity

An acute oral toxicity study of Coco APDMA, female rats were administered 50, 300 or 2000 mg/kg via a single oral ad ministration and evaluated for 15 days post dosing. At the dose-level of 2000 mg/kg three females were found dead on da y 2. Hypoactivity or sedation, piloerection, dyspnea and/or soft feces were observed prior to their deaths. At necropsy, no apparent abnormalities were observed in any animal. At th e dose-level of 300 mg/kg three females were found dead on day 2 or 3. Hypoactivity or seda tion, piloerection, dyspnea, hypersalivation, loud breathing and/or tonic-clonic c onvulsions were noted prior to their deaths. Hypoactivity, piloerection, dyspnea and hypersaliv ation were observed in three out of six surviving females on day 1. Loud breathing was noted in two out of th ree surviving females on day 2 and from day 8 until the end of the observation period (day 15). Dyspnea and abdominal swelling in one female was observed on days 13 and 15, respectively. A body weight loss was noted in one surviving animal between day 8 and day 15 (-19%). Additi onally, when compared to historical control data, a lower body weight gain was noted in one surviving female between day 1 and day 8 (returning to normal thereafter). At necropsy, no apparent abnormalities were observed in any animal. At the dose-level of 50 mg/kg no mortal ity or clinical signs were noted during the observation period. When compared to historical control data, a lower body weight gain was noted in two out of six females (between day 1 and day 8 returning to normal thereafter). At necropsy, no apparent abnormalities were observed in any animal. Under the experimental conditions of this study, the oral LD 50 in rats is 300 mg/kg of the test item, Coco APDMA.

B.2. Acute Dermal Irritation

The objective of this study was to evaluate the potential of Coco APDMA to induce skin irritation in rabbits according to OECD 404. The petitioner reported that the test item was
considered non-corrosi ve in a previous in vitro skin corrosion study (Study No. 2983/0001).
Therefore for this in vivo corrosion study, the test item was eval uated in a stepwise fashion in
rabbits.

The day before treatment, areas of skin (3.5 cm x 5 cm) were closely clipped using electric clippers on the flanks of the animal (two areas, on the anterior and posterior parts of each flank). Care was taken to avoid damaging the skin. Clip ping was repeated thereafter on day 2. A single AkzoNobel Study, January 19, 2011,

MRID 48556302. Developmental/Reproductive Repeat Dose Screening Test Reproductive and developmental

NOEL = 45 mg/kg/day

NOAEL = 15 mg/kg/day OECD 422 guidelines ARMAK 2096: Oral (Gavage) Combined Repeat Dose Toxicity Study with Reproduction/Developmental Toxicity Screening Test in the Rat (OECD 422), Project Number 3076-0007, 2011, MRID 48621602. Acute oral (rat) LD 50 = >2000 mg/kg Directive
84/449/EEC Henkel KGaA , unpublished data, Archive-No. TBD 850340 , reference 8 within the IUCLID Ref. (6), 2000.10 dose of 0.5 mL of the test item in its origin al form was placed on a dry gauze pad, which was then applied to the anterior left flank of the animal for 3 minutes. The gauze pad was held in contact with the skin by mean s of a non-irritating semi-occlus ive dressing and a restraining bandage. During the 3-minute exposure time, a dry gauze pad was applied to the opposite untreated flank, in order to check that no alterati on of the skin is induced by the semi-occlusive dressing and restraining bandage. After removal of the dressing, any residual test item was wiped off by means of a moistened cott on pad. Since the test item show ed corrosive properties on this animal, the study was considered complete a nd no other exposure times were performed.

The study reported that a very sl ight erythema was noted on day 1, 1 hour after removal of the dressing. On day 2, severe erythema and edema and scabs were observed on the treated flank. Additionally, a brownish area wa s noted during the obs ervation. According to these severe cutaneous reactions, the study was considered complete and the animal was prematurely sacrificed for ethical reasons on day 2. The study concluded that under the experimental conditions of this study
, Coco APDMA was corrosive when applied topically to rabbits.

B.3. Skin Sensitization

It should be noted that strong irritants may pr oduce false positive respons es in the Local Lymph Node Assay (LLNA) by triggering an immunological reaction that is unrelated to sensitization. While no systemic toxicity (as observed by no ch ange in body weight) or local irritation (as evidenced by the absence of erythema) was observed in the LLNA at the concentrations tested, the Buehler assay was found to be negative. For this reason, both sets of data are presented.

B.3.a Buehler Assay

The purpose of this skin sensitizing study was to assess the possible allergenic potential of Coco APDMA when administered topically to albino Dunkin Hartley guinea pigs (Contact Hypersensitivity in Albino Guinea Pigs, Buehler Test, Harlan Laboratories Study C83737, ARMAK 2096, MRID 48621603). For this purpose the “Buehler Test” modified by Ritz, H.L. and Buehler, E.V. (1980) was used.

Twenty male animals of the test group were trea ted topically with Coco APDMA at 0.5% in corn oil once a week for a 3-week induction phase. Tw o weeks after the final induction the animals were challenged with the test item at 0.05 and 0.01%. The ten animals of the control group were not treated during the induction. They were ch allenged with the test item at 0.05 and 0.01%, identical to the test group animals. None of the test or control animals were observed with skin
reactions after the chal lenge with both test item concentrations.

No clinical signs were recorded in the test or control animals during th e course of the study. The body weights were within the range commonly reco rded for this strain and age. Based on the above mentioned findings and in accordan ce with Regulation (EC) No 1272/2008, Coco
APDMA does not have to be cl assified as skin sensitizer

B.3.b. Local Lymph Node Assay

A LLNA was conducted to assess th e potential of a blend with concentration of >75% Coco11 APDMA along with 5 to 15% pr opylene glycol to cause contact sensitization by measuring lymphocyte proliferative responses from auricu lar lymph nodes following topical application of test material to the mouse ear (Adsee C80W And Ammononyx Lo: Reduced Local Lymph Node Assess in CBA/J Mice, Internal Report of Dow Chem ical Co. Study ID 100272, April 25, 2011). This study is a non-GLP investigativ e study that was conducted to evaluate potential sensitization of form ulation components for Dow Agro Sciences. Note, a second test
material was included in this study (Ammonyx LO which has 30% lauramine oxide), but this
is unrelated to Coco AP DMA and this petition.

Five female mice/group received 0.98% or 3.84% of test material, vehicle (1% L92) or 30% α

hexylcinnamaldehyde (HCA; positive control) on days 1-3. On day 6, uptake of 3H-thymidine into the auricular lymph nodes dr aining the site of chemical application was measured five hours post administration. Proper conduct of th e LLNA was confirmed via a positive response using 30% HCA, a moderate cont act sensitizer, which elicited a stimulation index (SI) that was 3.8 in comparison to vehicle-treated mice. Erythema was absent and body weights were unaffected in all dose groups. Test material at concentrations of 0.98% and 3.84% elicited proliferative responses with stimulation indi ces (SI) that were respectively 1.0, and 5.7 in comparison to vehicle-treated mice. The associated EC3 value for test material was 2.2%. As the test material elicited a stimulation index gr eater than 3, it is considered positive for dermal sensitization potential in the LLNA.

B.4. Genotoxicity/Mutagenicity

B.4.a. Bacterial Reverse Mutation Test

The objective of this study was to evaluate the potential of Coco APDMA to induce reverse
mutation in Salmonella typhimurium according to OECD 471 guideline in compliance with the principles of Good Laboratory Practice Re gulations (Bacterial Reverse Mutation Test, CIT/Study No. 36057 MMO, Coco amidopropyldime thylamine/CECA S.A, AkzoNobel Study, August 20, 2010, MRID 48556301).

In an initial toxicity-mutation assay, the test substa nce was found to be toxic. Therefore, the highest dose level selected for the confirmatory mutagenicity assay was based on the level of toxicity, according to the criteria spec ified in the international guidelines.

The vehicle controls and positive controls in th e initial toxicity-mutation and confirmatory mutagenicity assays were within the acceptable hi storical ranges and fulfilled the requirements for a valid assay. Under the experimental condi tions, Coco APDMA did not show any mutagenic activity in the bacterial reverse mutation test with Salmonella typhimurium with or without S9.

B.4.a.1. Experiments without S9

The selected treatment-levels were:

● 3.13, 6.25, 12.5, 25, 50 and 100 μ g/plate for all the strains in the first experiment,

● 1.56, 3.13, 6.25, 12.5, 25 and 50 μ g/plate for all the strains in the second experiment,

● 6.25, 12.5, 18.8, 25, 37.5 and 50 μ g/plate for the TA 1537 strain in the third experiment.12 No precipitate was observed in the plates when scoring the revertants at any dose-levels. A moderate to strong toxicity was noted at dose-levels ≥ 25 μ g/plate in the TA 100 and TA 102
strains and ≥ 50 μ g/plate in the TA 1535, TA 1537 and TA 98 strains. The test item did not induce any increase in the number of revertants , which could be considered as biologically relevant, in any of the five strains.

B.4.a.2. Experiments with S9

The selected treatment-levels were:

● 15.6, 31.3, 62.5, 125, 250 and 500 μ g/plate for all the strains in the first experiment,

● 7.81, 15.6, 31.3, 62.5, 125 and 250 μ g/plate for all the strains in the second experiment.

No precipitate was observed in the plates when scoring the revertants at any dose-levels. A moderate to strong toxicity was noted at dose-levels ≥ 62.5 μ g/plate in the TA 102 strain,

≥ 125 μ g/plate in the TA 1537, TA 98 and TA 100 strains and ≥ 250 μ g/plate in the TA
1535 strain. The test item did not induce any noteworthy in crease in the number of revertants, in any of the five strains.

B.4.b. Chromosome Aberration Test

Coco APDMA was evaluated in an in vitro mammalian chromosome abe rration test in cultured human lymphocytes to determine its potential to induce chromoso me aberrations according to OECD 473 guidelines.

The dose-level of 5000 μ g/mL showed no precipitate, and the pH and osmolality were approximately 7.6 (7.4 for the vehicle contro l) and 400 mOsm/kg H2O (465 for the vehicle control), respectively. Therefore, the in itial treatment-levels were 39.06, 78.13, 156.3, 312.5, 625, 1250, 2500 and 5000 μ g/mL, both with and without S9 mix were selected. Severe cytotoxicity was induced at all dose-levels, ther efore the metaphases analysis was not performed and a new treatment was undertaken using a lo wer range of dose-lev els as follows: 0.39, 0.78, 1.56, 3.13, 6.25, 12.5, 25 and 50 μ g/mL both with and without S9 mix.

The frequency of cells with structural chromo some aberrations of th e vehicle and positive controls was as specified in acceptance criteria, and the study was considered valid. Under the experimental conditions, Coco APDMA did not induce chromosome aberrations in cultured human lymphocytes with or without S9.

B.4.b.1. Experiments without S9

Cytotoxicity: Following the 3-hour treatment, a slight to severe decrease in the mitotic index was noted mainly at dose-levels ≥ 3.13 μ g/mL (up to 100% decrease). After the 20-hour treatment, a slight to severe decrease in the m itotic index was noted at dose-levels ≥ 6.25 μ g/mL (31 to 93% decrease). With the 44-hour treatment, a slight to severe decrease in the mitotic index was noted
at dose-levels ≥ 12.5 μ g/mL (26 to 100% decrease).

Metaphase Analysis : Dose-levels selected for metaphase analysis were: a) 3.13, 6.25 and

12.5 μ g/mL for the 3-hour and the 20-hour trea tments, the latter inducing a 79% and 49%13 decrease in the mitotic in dex, respectively, and b) 12.5 μ g/mL, for the 44-hour treatment,
which induced a 26% decrease in the mitotic index; the higher dos e-level was too cytotoxic.

In the 3-hour treatment, the dose-level of 12.5 μ g/mL, was incorrectly selected for the metaphase analysis. This dose-level showed a decrease in the mitotic index indi cating a high level of cytotoxicity, which may lead to false positive results. Nevertheless, in the present study, no significant increase in the frequency of cells with structural chromosomal aberrations was observed at this dose-level (despite the high level of toxicity) or at the two other analyzed doselevels. After the 20 and 44-hour treatments, no signi ficant increase in the fr equency of cells with
structural chromosomal aberrations was noted.

B.4.b.2. Experiments with S9

Cytotoxicity: At the 20-hour harvest time in the firs t experiment, a 29-100% decrease in the
mitotic index was noted at dose-levels ≥ 6.25 μ g/mL. At the 20-hour harvest time in the second experiment, a 99% decrease in th e mitotic index was noted at 25 μ g/mL. At the 44-hour harvest time (second experiment), a 100% decrease in the mitotic index was noted at 25 μ g/mL.

Metaphase Analysis: The dose-levels selected for metapha se analysis were as follows: 1.56,
3.13 and 6.25 μ g/mL for the 20-hour harvest time in the first experiment, the latter inducing a
29% decrease in the mitotic inde x; the higher dose-levels were too cytotoxic. Levels of 3.13,
6.25 and 12.5 μ g/mL were used for the 20-hour harvest time in the second experiment, the higher dose-level being too cytotoxic. A level of12.5 μ g/mL was used for the 44 -hour harvest time, the higher dose-level being too cytotoxic. No signifi cant increase in the fr equency of cells with
structural chromosomal aberrations was noted in e ither experiment and at either harvest time.

B.5. Reproductive and Developmen tal Toxicity for Coco APDMA

A combined repeated dose toxicity and reproduc tion and developmental to xicity screening test
was conducted in rats administered Coco APDMA via oral gavage under OECD 422 guidelines (MRID 48621602). The study was designed to investigate the syst emic toxicity and potential adverse effects of the test item on reproduction (including o ffspring development). This study is also supported by a 14- day range-finding study (MRID 48621601).

The oral administration of Coco APDMA to rats by gavage at dose levels of 5, 15 and 45 mg/kg/day resulted in treatment-related t oxicity of 45 mg/kg/day in both sexes. The microscopic changes identified in the stomach are attributed to the irritant/corrosive effects of the test material. No systemic t oxicity was observed. It would not be possible to show significant clinical reactions to treatment at higher dose levels without inducing intolerable gastri c pathological changes

. No treatment-related effects were detected in the reproductive or developmental parameters examined.

Study Design: Coco APDMA was administered to ten male and ten female Wistar HanTM:RccHanTM:WIST strain rats for up to ei ght weeks (including a two week maturation phase, pairing, gestation and early lactation for females) at dose levels of 5, 15 and 45 mg/kg bw/day. Dose level selection was based on a F ourteen Day Repeated Dose Oral (Gavage) Range-Finding Toxicity Study in the Rat, which de monstrated signs of ir ritation/corrosivity of14 the stomach at all dose levels tested; 25, 50 and 100 mg/kg bw/day. Control groups of ten
males and ten females were dosed with vehicle alone (corn oil). Clini cal signs, behavioral assessments, body weight change and food and wa ter consumption were monitored during the study. Pairing of animals within each dose group was undertaken on a one male: one female basis within each treatment group on Day 15 of the study, with females subsequently being
allowed to litter and rear their offspring to Day 5 of lactat ion. During the lactation phase, daily clinical observations were pe rformed on all surviving offspri ng, together with litter size and offspring weights and assessment of surface righ ting reflex. Extensive functional observations were performed on five selected males from each dose group after the completion of the mating phase, and for five selected parent al females from each dose group on Day 4 post
partum . Hematology and blood chemistry were evaluate d prior to termination on five selected males and females from each dose group. Males were terminated on Day 43, followed by the termination of all surviving females and offspring on Day 5 post partum . All animals were subjected to a gross necropsy examination, and a histopathology evaluation of selected tissues was performed.

Parental In-Life Observations: There were no unscheduled deaths related to treatment. During clinical observations, episodes of increased saliv ation were evident in animals of either sex treated with 15 and 45 mg/kg/day throughout the treatment period. An isolated incident of noisy respiration was also evident in one male treated with 45 mg/kg/day on Day 4. These effects were
not detected in animals of either sex treated w ith 5 mg/kg/day. There we re no treatment-related changes in behavioral parameters, functional perf ormance, or sensory reactivity. Females treated with 45 mg/kg/day showed a reduction in body weight gain, with four females showing body weight losses from 1 to 4g during the first week of treatment. No effects on body weight were detected in males treated with 45 mg/kg/day or animals of either sex treated with 5 or 15 mg/kg/day. No adverse effects on food consumption, water consumption or food efficiency were
detected.

Reproductive Performance: There were no treatment-related effects on mating or conception rates for treated animals at any dose level. With the exception of one 45 mg/kg/day pair, which mated thirteen days following pairing, the remain ing paired animals mated within the first four days of pairing. There were no differences in gestation lengths; all animals showed gestation lengths between 22 to 24 days.

Litter Responses : No significant differences were dete cted for corpora lutea, implantation counts, litter size or litter viab ility for treated animals when compared to controls. There were no intergroup differences in sex ra tio (percentage male o ffspring) for litters treated compared to controls. Offspring body weight ga in and litter weights at birth and subsequently on Days 1 and

4 post partum were comparable to controls. No obvious cl inical signs of toxi city were detected for offspring from treated females when compared to controls, and no treatment-related macroscopic abnormalities were detected for interim death or terminal sacrifice.

Laboratory Analysis: There were no toxicologically sign ificant effects detected in the hematological parameters or blood chemistry parameters measured.

Parental Postmortem Analysis : No treatment-related effects were detected in the organ weights measured. At necropsy, one male treated with 45 mg/kg/day had a raised limiting ridge in the15 stomach. No toxicologically signi ficant effects were detected in females treated with 45 mg/kg/day or in animals of either sex treated with 5 or 15 mg/kg/day. The histopathology exam revealed treatment-related microscopic findings in the stomach consisting of erosion, ulceration and hyperplasia/hyperkeratosis of the forestomach and erosion of the glandular region that was evident in two males and all females treated with 45 mg/kg/day.

B.7 Chronic Toxicity/Carcinogenicity

No chronic studies are available for Coco APDMA, but it did not show any mutagenic activity in
the bacterial reverse mutation test and was negative in the chro mosome aberration test. IIAB has determined that the NOAEL for repeat dose toxicity was 15 mg/kg/day, and the NOAEL for reproductive and developmental toxicity was 45 mg/kg/day.

Neither International Agency for Research on Can cer (IARC) nor other aut horitative bodies have classified Coco APDMA as a carcinogen. Several genotoxicity tests for multiple analogues of
Coco APDMA have shown this class of chemical s to be non-mutagenic within the HPV program (http://www.epa.gov/HPV/pubs/summaries/fantd rad/c13319rt.pdf). The National Toxicology Program (NTP) has conducted carcinogenicity st udies with the related compounds coconut oil acid diethanolamine condensate (NTP Tech Rep Ser., Jan; 479:5-226. Toxicology and carcinogenesis studies of coconut oil acid dietha nolamine condensate (C AS No. 68603-42-9) in F344/N rats and B6C3F1 mice (dermal studies) 2001), lauric acid diethanolamine condensate (NTP Tech Rep Ser., Jul; 480:1-200. NTP Toxico logy and Carcinogenesis Studies of Lauric Acid Diethanolamine Condensate (CAS NO. 1 20-40-1) in F344/N Rats and B6C3F1 Mice (Dermal Studies), 1999), and ol eic acid diethanolamine condens ate (NTP Tech Rep Ser., Jul; 481:1-198. NTP Toxicology and Ca rcinogenesis Studies of Ol eic Acid Diethanolamine Condensate (CAS No. 93-83-4) in F344/N Ra ts and B6C3F1 Mice (Dermal Studies), 1999). Together these studies are supportive of a low concern for carcinogenicity for this class of compounds. As concluded in the NTP report for coconut oil acid diethanolamine condensate, tumor types that were increased in a dose-rela ted manner were strongly correlated with the concentration of free diethanolamine present as a contaminant. In addition, the pattern of response was highly consistent with the NT P study for diethanolamine (Toxicology and Carcinogenesis Studies of Diethanolamine (CAS No. 111-42-2) in F344/N Rats and B6C3F1 Mice (Dermal Studies). Technical Report Seri es No. 478. NIH Publication No. 99-3968. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, Research Triangle Park, NC. NTP, 2001). Therefore, in the absence of free diethanolamine, this class of chemicals does not appear to be carcino genic. EPA has made a cl ear distinc tion between the diethanolamine and dimethylaminopropyl amine moiety (which is more closely related to Coco APDMA). EPA recently concluded (US EP A, Diethanolamine Salts of Alkyl(C8-C24) Benzenesulfonic Acid (DEA-JITF CST8 Inert I ngredients), Human Health Risk Assessment to Support Proposed Exemption from the Requirement of a Tolerance When Used as inert Ingredients in pesticide Formulations, Docu ment D367001, July 23, 2009) that diethanolamine has not been shown to be mutagenic or carcinoge nic in rats; however, there is evidence of carcinogenicity in mice: IARC (2000) has reviewed the carcinogenicity of diethanolamine and
found that diethanolamine is not cl assifiable as to its carcinogeni city to humans (Group 3). In contrast to diethanolamine, for dimethylaminopropyl amine (US EPA, Dimethylaminiopropylamine, Isopropylamine, Et hanolamine and Triethanolaime Salts of16 Alkyl(C8-C24) Benzenesulfonic Acid (JITF CS T8 Inert Ingredients), Human Health Risk Assessment to Support Proposed Exemption from th e Requirement of a Tolerance When Used as inert Ingredients in pesticide Formulations , Document D366022, July 23, 2009), EPA concluded there are no explicit concerns fo r carcinogenic potential. This conclusion was based on DEREK
Version 11 with no structural al erts identified for dimethyl aminopropylamine, isopropylamine,
ethanolamine and triethanolamine.

Since the only evidence of carcinogenic activity for this class of chemicals is attributed to the contaminant diethanolamine, and it is not expected to be present in the finished products, the Agency does not expect carcinogenic activity from the NADMAPA class of compounds. Therefore, IIAB has determined, based on the revi ew of the analogue class information as well
as the in vitro studies directly on Coco APDMA, that there is little evidence for carcinogenic
concern for Coco APDMA and the NADMAPA ma terials in the proposed use pattern.

Although the duration of exposure was 90 days, ther e is no need for an additional uncertainty
factor because the effects do not seem to increase in severity over time (4 weeks to 13 weeks). Based on the lack of progression of severity of effects with time along with the considerable
similarities of effects across the species tested and the observation that the vast majority of the
effects observed were related to local irritation an d corrosive effects, the ToxSAC concluded that an additional uncertainty factor (UF) for extrapolation fr om subchronic toxicity study to a chronic exposure scenario would not be neede d. As a result, the ToxSAC concluded that the typical 100-fold uncertainty factor would be suffici ently protective since it is not expected that humans’ response to local irritation/corrosiveness effects would be markedly different from
animals.

B.7. Metabolism and Pharmacokinetics

No direct information on animal metabolism is available for Coco APDMA. It is generally known that the amide linkage is often preserved in the metabolism of amide herbicides, such as isoxaben and propyzamide (Metabolic Pathways of AgroChemicals, Part One: Herbicides and Plant Growth Regulators, The Royal Society of Chemistry, Cambridge, 1988) and that amines undergo oxidative amine metabolism followed by excretion.

Table 4. Summary of HPVIS Database Inform ation on Toxicity Endpoints for CAS 68140- 01-2 (Coco APDMA) Based on Read across Principles

Study CAS Name Read Across Result Acute Toxicity 124-26-5 Octadecanamide LD50 >10 g/kg 112-84-5 13-Docosenamide, (13Z) LD50 >5000 mg/kg 61790-31-6 Amides, tallow, hydrogenated LD50 >5 g/kg 120-40-1 Dodecanamide, N,N-bis(2hydroxyethyl) 3 studies: LD50 > 3.5 g/kg; LD50 > 5 ml/kg; LD50 > 2 g/kg 68603-42-9 Amides, coco, N,Nbis(hydroxyethyl 4 studies: LD50 value > 5 g/kg; LD50 > 5.0 g/kg; LD50 > 5.0 ml/kg; LD50 value > 2 g/kg.68155-20-4 Amides, tall-oil fatty, N,Nbis(hydroxyethyl) No deaths, no value stated.17 Table 4. Summary of HPVIS Database Inform ation on Toxicity Endpoints for CAS 68140- 01-2 (Coco APDMA) Based on Read across Principles

Study CAS Name Read Across Result 68140-00-1 Amides, coco, N-(hydroxyethyl) 5 studies: LD50 >5 g/kg; >5 g/kg; >2 g/kg; = 7.4 g/kg; >5 mL/kg 68155-06-6 Amides, C12-18, N,Nbis(hydroxyethyl) LD50 value > 10.0 g/kg 110-30-5 Octadecanamide, N,N'-1,2ethanediylbis- No deaths, no LC50 value
stated. 71820-35-4 Fatty acids, tall-oil, low-boiling, reaction products with 1- piperazineethanamine 2 studies: LD50 (male) = 3610 mg/kg and LD50 for (female) = 4260 mg/kg; LD50 value > 5000 mg/kg Repeated Dose Toxicity 112-84-5 13-Docosenamide, (13Z) NOEL = 7500 mg/kg 120-40-1 Dodecanamide, N,N-bis(2hydroxyethyl) NOEL = 50 mg/kg/day

68140-00-1 Amides, coco, N-(hydroxyethyl) NOAEL >750 mg/kg bw/day Genetic Toxicity 142-78-9 Dodecanamide, N-(2hydroxyethyl) In vitro Bacterial reverse mutation assay - negati ve Reproductive Toxicity 120-40-1 Dodecanamide, N,N-bis(2- hydroxyethyl) See Repeated Dose toxicity records for CAS RN 120-
40-1 and 68140-00-1 and Developmental toxicity
records 68140-00-1 Amides, coco, N-(hydroxyethyl) See Repeated Dose toxicity records for CAS RN 120-
40-1 and 68140-00-1 and Developmental toxicity
records Developmental Toxicity/Terat ogenicity 68603-42-9 Amides, coco, N,Nbis(hydroxyethyl) NOAEL (maternal) = 1000 mg/kg/day; NOAEL (fetal) = 1000 mg/kg/day

In addition to the above HPVIS data, a set of toxicity studies exists for two related amide analogues: octanamide, N,N-dimethyl (CAS 1118–92–9) and decanamide, N,N-dimethyl (CAS 14433–76–2). Information from the EPA 2005 Final Rule (30) has been resummarized here in support for Coco APDMA and is congruent w ith the HPV FND toxic ity database. Most importantly, repeat dose information indicate NO EL values of 100 mg/kg bw/day or greater have been observed for these analogues and there ar e no stated concerns for developmental or reproductive toxicity. No evidence of mutagenicity was determined in several types of tests (bacterial reverse gene mutation, mammalian forw ard gene mutation, chromosomal aberrations, and unscheduled DNA synthesis).

C. Toxicity Endpoint Selection

C.1. Acute Toxicity

Coco APDMA has moderate acute oral toxicity with an LD 50 of 300 mg/kg/day and is corrosive and irritating to the skin and eye, respectivel y. IIAB has determined that based on the acute toxicology data, an acute endpoint is not required.18 Table 5. Summary of Toxicological Doses and Endpoints for Coco APDMA for Use in
Human Health Risk Assessment
Exposure/Scenario Point of Departure
and Uncertainty/Safety

Factors RfD, PAD,
LOC for Risk

Assessment Study and Toxicological Effects

Acute dietary (Females 13–50 years of age) No POD identified None None selected

Acute dietary (General population including infants and children) No POD identified None None selected

Chronic dietary (All populations) NOAEL= 15 mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1x Chronic RfD

= 0.15 mg/kg/day

cPAD = 0.15 mg/kg/day ARMAK 2096: Oral (Gavage) Combined Repeat Dose Toxicity Study with Reproduction/Developmental Toxicity Screening Test in the Rat (OECD 422), Project Number 3076-0007, 2011, MRID 48621602. LOAEL =
not identified Cancer (Oral, dermal, inhalation) There is little evidence for carcinogenic concern for Coco APDMA and the NADMAPA
materials .

UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. UF S = use of a short-term study for long-term risk assessment. UF DB = to account for the absence of data or other data deficiency. FQPA SF = Food Quality Protection Act Safety Factor. PAD = popu lation adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern.

IV. FQPA Safety Factor Considerations

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.

The reproductive and development NOAEL in the OECD 422 study is 45 mg/kg, which is higher than the proposed point of de parture (POD) at 15 mg/kg, and supports a lower FQPA SF. The alkyl amides analogue informati on coupled with limited exposure from the crop-only herbicide use pattern also supports a lower FQPA SF. The FQPA safety factor can be reduced to 1x for this group of chemicals since regulation based on the fore stomach lesions in rats, a very conservative hazard endpoint, coupled with the highly conser vative exposure assessmen t and an absence of evidence of increased sensitivity, or neurotoxic ity, supports the finding that the use of the
standard 100X inter- an d intra-species uncertainty facts are adequate to protect infants and
children.

Using a 100X uncertainty factor is very conserva tive since we are regulat ing based on portal of entry effects for which inter-species differences as well as variability among humans are likely to19 be relatively small. This class of compounds is highly irritating and the toxicity was enhanced by the gavage dosing. Furthermore, humans l ack a forestomach which serves as a storage
reservoir in rodents. Based on the weight of evidence, EPA ha s reduced the 10X FQPA safety
factor to 1X.

EPA has determined that reliable data show the safety of infants and children would be adequately protected if the FQ PA SF were reduced to 1X. That decision is based on the following findings: i. The toxicity database for the N-al kyl(C8-C18) dimethylamidopropylamines is adequate for FQPA assessment. The available data included acute toxicity studies, mutagenicity and the Reproduction/Developmental Toxicity Scr eening Test in rats (OECD 422). The available OECD 422 study evaluated reproductive parameters and developmental toxicity parameters in rats. In addition, it also evaluated hemato logy, clinical chemistry, organ weights and histopathological parameters. No effects on these parameters we re observed at the highest dose
tested. ii. No effects on Functional Observation Battery and motor activity parameters were observed in the Reproduction/Developmental Toxici ty Screening Test in rats (OECD 422). Since
there is no indication that th e N-alkyl(C8-C18) dimethylami dopropylamines are neurotoxic chemical and there is no need for a developmen tal neurotoxicity study or additional uncertainty factor to account for neurotoxicity. iii. There is no evidence that the N-alkyl(C8- C18) dimethylamidopropylamines result in increased susceptibility of infants a nd children based on the results of the Reproduction/Developmental Toxicity Screening Test in rats. in in utero rats or rabbits in the prenatal developmental studies. iv. There is no evidence of immunotoxicity in the available database. Therefore, there is no need for the immunotoxicity study or additional uncertainty factor. v. Although the duration of exposure was s hort in the OECD 422 study, there is no need for an additional uncertainty factor because the effects observed were rela ted to local irritation
due to corrosive nature of these chemicals. Based on the lack of progression of severity of effects with time along with the considerable similaritie s of effects across the species tested and the observation that the vast majority of the effects observed were related to local irritation and corrosive effects, EPA has previously conclude d that an additional unc ertainty factor for extrapolation from subchronic toxi city study to a chronic exposure scenario would not be needed for highly irritating substances. As a result, the typical 100-fold uncertainty factor is sufficiently protective since it is not expected that humans’ response to local irrita tion/corrosiveness effects would be markedly differentba sed on duration of exposure.
vi. There are no residual uncerta inties identified in the expos ure databases. The dietary food exposure assessments were performed using the highly conservative I-DEEM model. EPA also made conservative (protective) assumptions in the ground and surface water modeling used to assess exposure to the N- alkyl(C8-C18) dimethylamidopropyl amines in drinking water and with regard to potential residential exposur es. These assessments will not underestimate the exposure and risks posed by the N-al kyl(C8-C18) dimethylamidopropylamines V. Exposure

A. Dietary Exposure

a. Residue of concern.20 The residues of concern for this risk a ssessment are all the parent NADMAPA compounds.

b. Drinking Water Residue Profile.

For the purpose of the screening level dietary risk assessment to suppor t this request for an exemption from the requirement of a tolerance for NADMAPA, a value of 100 ppb based on screening level modeling was used for both the acut e and chronic dietary risk assessments for the parent compounds and for the metabolite of con cern. The Agency considers the value of 100 ppb to be a high end, conservative assu mption that is not likely to unde restimate drinking water risks.

c. Food Residue Profile

i. Acute exposure . No adverse effects attributable to a single exposure of NADMAPA was seen in the toxicity databases. Therefore, an acute dietary risk assessme nt for NADMAPA is not required.

ii. Chronic exposure

. In conducting the chronic dietary exposure assessment, EPA used food consumption information from the United Stat es Department of Agriculture (USDA) [1994– 1996 and 1998] Nationwide Continuing Surveys of Food Intake by Individuals (CSFII). As to residue levels in food, no residue data were subm itted for NADMAPA. In the absence of specific residue data, EPA has developed an approach wh ich uses surrogate information to derive upper bound exposure estimates for the subject inert ingredient. Upper bound exposure estimates are based on the highest tolerance for a given comm odity from a list of high-use insecticides, herbicides, and fungicides. A complete descriptio n of the general approach taken to assess inert ingredient risks in the absence of residue data is contained in the memorandum entitled “Alkyl Amines Polyalkoxylates (Cluster 4): Acute a nd Chronic Aggregate (Food and Drinking Water) Dietary Exposure 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.

In the dietary exposure assessment, the Agency assumed that the residue level of the inert ingredient would be no higher than the highest to lerance for a given commodity. Implicit in this assumption is that there would be similar rates of degradation (if any) between the active and inert ingredient and that the concentration of inert ingredient in the scenarios leading to these highest of tolerances would be no higher than the concentrati on of the active ingredient.

The Agency believes the assumptions used to esti mate dietary exposures lead to an extremely conservative assessment of dietary risk due to a series of compounded conservatisms. First, assuming that the level of residue for an inert ingredient is equal to the level of residue for the active ingredient will overstate e xposure. The concentration of active ingredient in agricultural products is generally at least 50 percent of the product and often can be much higher. Further, pesticide products rarely have a single inert ingred ient; rather there is ge nerally a combination of different inert ingredients used which additionally reduces the concentration of any single inert ingredient in the pestic ide product in relation to that of the active ingr edient. In the case of NADMAPA, EPA made a specific adjustment to the dietary exposure assessment to account for the use limitations of the amount of NADMAPA that may be in formulations (no more than 20%21 by weight) in pesticide and assumed that the NADMAPA is present at the maximum limitations rather than at equal quantitie s with the active ingredient.

Second, the conservatism of this methodology is compounded by EPA’s decision to assume that, for each commodity, the active ingredient which w ill serve as a guide to the potential level of inert ingredient residues is the act ive ingredient with th e highest tolerance level. This assumption
overstates residue values becau se it would be highly unlikely, given the high number of inert ingredients, that a single inert i ngredient or class of ingredients would be present at the level of the active ingredient in the hi ghest tolerance for every comm odity. Finally, a third compounding conservatism is EPA’s assumption that all foods contain the inert ingredient at the highest tolerance level. In other words, EPA assumed 100 percent of all foods are treated with the inert ingredient at the rate and manner necessary to pr oduce the highest residue legally possible for an active ingredient. In summary, EPA chose a very conservative method for estimating what level of inert residue could be on food, then used this methodology to choos e the highest possible
residue that could be found on food and assumed that all food contained this residue. No consideration was given to pot ential degradation between harv est and consumption even though monitoring data shows that tolera nce level residues are typically one to two orders of magnitude higher than actual residues in food when distributed in commerce.

Accordingly, although sufficient information to quantify actual residue levels in food is not available, the compounding of these conserva tive assumptions will lead to a significant exaggeration of actual exposures. EPA does not believe that this approach underestimates exposure in the absence of residue data.

iii. Cancer exposure.

The Agency used a qualitative structure activ ity relationship (SAR) database, DEREK11, to determine if there were structural alerts sugges tive of carcinogenicity. No structural alerts for carcinogenicity were identified. IIAB has determin ed, based on the review of the analogue class
information as well as the in vitro studies directly on Coco APDMA, that there is little evidence for carcinogenic concern for NADMAPA in the propos ed use pattern. Therefore, a cancer dietary exposure assessment is not necessary to assess cancer risk.

d. Analytical Methodology

Since this request is for an exemption from the requirement of a tolerance, an analytical method for enforcement purposes is not re quired to support this action.

B. Dietary (Food and Water) Exposure and Risk Characterization

i. Acute Dietary Exposure and Risk

No adverse effects attributable to a single exposure to NADMAPA were seen in the toxicity databases; therefore, an acute dietary ri sk assessment is not appropriate and an acute aggregate risk assessment is not a concern.22 ii. Chronic Dietary Exposure and Risk

A chronic aggregate risk assessment takes into a ccount exposure estimates from chronic dietary consumption of food and drinking water. Model estimates for oral exposure from the use of
NADAMPA at 20% in herbicidal formulations (including ex posure through drinking water) resulted in acceptable dietary e xposure to all subpopulations. The chronic dietary exposure from
food and water to NADMAPA is 16.5% of the cP AD for the U.S. population and 53.4% of the cPAD for children 1-2 years old, the most hi ghly exposed population subgroup. The chronic dietary exposure estimates for food and drinking water are below the Agency’s level of concern (<100% cPAD) for the U.S. populati on and all population subgroups.

iii. Cancer Dietary Exposure and Risk

The Agency has not identified any concerns for carcinogenicity relating to; therefore, a cancer dietary exposure assessment was not performe d and an aggregate risk assessment is not a

concern.

Table 6. Summary of Dietary (Food and Drinking Water) Exposure and Risk for
NADMAPA

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 0.024694 16.5

All Infants (< 1 year old) 0.046876 31.3

Children 1-2 years old 0.080097 53.4

Children 3-5 years old 0.063950 42.6

Children 6-12 years old 0.037750 25.2

Youth 13-19 years old 0.022000 14.7

Adults 20-49 years old 0.018287 12.2

Adults 50+ years old 0.016390 10.9

Females 13-49 years old 0.017546 11.7

The most highly exposed subgroup is bolded.

B. Residential (Non-Occupational) Exposure

The term “residential exposure” is used in this document to refer to non-occupational, nondietary exposure (e.g., for lawn and garden pest control, indoor pest control, termiticides, and flea and tick control on pets). NADMAPA may be us ed as an inert ingredient in herbicidal pesticide products that are register ed for specific crop uses that will not result in either indoor or23 outdoor residential exposures. No exposure to NADMAPA will occur via residential herbicidal products, as the proposed uses are for crops only.

A screening level residential exposure and risk assessment was completed for products containing NADMAPA materials as an inert ingr edient. In this assessment, representative scenarios based on end-use produc t application methods and labe led application rates were selected. For the general population some exposure to NADMAPA materials could occur via cosmetic use (at very low concentrations), but not for younger children

. A review of general information indicates there is also poten tial for exposure to N ADMAPA materials through personal soaps and shampoos. For NADMAPA mate rials exposure at low percentages is conservatively assumed to be 5% or less of the overall formulation base d on the ingredient list rankings of 19th or lower. Al so for NADMAPA materials, some exposure to CAS 7651-02-7 is possible via high-end hair care dye kits and c onditioners, primarily for adults. There is no reliable data for this exposure to adults; howev er, such uses are not expected to result in significant exposures. Although derm al absorption data for un-ioni zed amines are available in the literature, data for the salt forms are not. Sinc e dermal exposure to these amines will be to the ionized forms which are likely to have minimal potential for dermal absorption and the ionized forms are not likely to exist in any significant co ncentrations, dermal risks are expected to be insignificant. A quantitative dermal/inhalation risk assessment is not required. The current dietary risk assessment is highly conservative and protective of any uses potential exposure via consumer products because the exposed population, children 1-2 years old, utilize only 53% of the cPAD leaving about 47% of the cP AD for exposure via consumer products.

Further details of this re sidential exposure and risk analysis can be found at http://www.regulations.gov in the memorandum entitled JITF Inert Ingredients. Residential and Occupational Exposure Assessment Algorithms and Assumptions Appendix for the Human Health Risk Assessments to Support Proposed Exem ption from the Requirement of a Tolerance When Used as Inert Ingredients in Pesticide Formulations ” (D364751, 5/7/09, Lloyd/LaMay in docket ID number EPA-HQ-OPP-2008-0710.

VII. Aggregate Risk

Acute Aggregate Risk

. There was no hazard attributable to a single exposure seen the in the toxicity database for the NADM APA; therefore an acute aggregate risk assessment is not required.

Short- and Intermediate-term Aggregate Risk . Since no residential or commercial uses on lawns or ornamentals are proposed for herbicide form ulations with NADMAPA, there are no aggregate
short- or intermediate term risks. Short-a nd intermediate-term residential exposure to Nalkyl(C8-C18) could occur via cosmetic use. Wh ile the lack of reliable exposure data precluded the ability to perform a quantitative risk assessm ent for these uses, the highly conservative nature of the chronic dietary risk assessment would be protective of any us es potential short-and
intermediate-term residen tial exposure via consumer uses. and EPA has determined that there are no concerns for short-term aggregate risk for the N-alkyl(C8-C18) dimethylamidopropylamines.24 Long-term Aggregate Risk. For NADMAPA, the long-term aggregate risk includes dietary exposures to food and drinki ng water only, which do not exceed IIAB’s level of concern. Chronic aggregate risks are not of concern. Long-term residen tial exposure to N-alkyl(C8-C18)
could occur via cosmetic use. Wh ile the lack of reliable exposure data precluded the ability to perform a quantitative risk assessment for thes e uses, the highly conservative nature of the chronic dietary risk assessment would be protecti ve of any uses potential long-term residential exposure via consumer uses. and EPA has determined that there are no concerns for short-term aggregate risk for the N-alkyl(C8- C18) dimethylamidopropylamines.

Cancer Aggregate Risk. The Agency has not identified any concerns for carcinogenicity for NADMAPA; therefore, an aggregate cancer exposure assessment was not performed.

VIII. Cumulative Exposure

Cumulative effects from substances with a common mechanism of toxicity . Section 408(b)(2)(D)(v) of FFDCA requires that, when c onsidering whether to establish, modify, or revoke a tolerance, the Agency consider “ava ilable information” concerning the cumulative effects of a particular pesticid e's residues and “other substances that have a common mechanism of toxicity.”

EPA has not found NADMAPA to share a common mechanism of toxicity with any other substances, and NADMAPA do not appear to produce a toxic metabolite produced by other substances. For the purposes of this toleran ce action, therefore, EPA has assumed that the
NADMAPA does not have a common mechanism of toxicity with other substances. For information regarding EPA's efforts to determ ine which chemicals have a common mechanism of toxicity and to evaluate the cumulative eff ects of such chemicals, see EPA's website at http://www.epa.gov/pesticides/cumulative

.

IX. Enviromental Fate

Information on physical properties for Coco APDMA provided in Table 2 based on an AkzoNobel MSDS (MSDS for ARMEEN* APA C-1, AkzoNobel, MSDS # 15-14630, http://www.surfactants.akzonobel.com/ msds_eu_2.cfm?Region=1&Product=2067 , accessed May 17, 2010), IUCLID (Amides, coco, N-[3 -(dimethylamine)propyl], IUCLID, 19-Feb-2000, http://ecb.jrc.ec.europa .eu/IUCLID-DataSheets/68140012.pdf , accessed on May 3, 2010) and EPISUITES (US EPA, Estimation Programs In terface SuiteTM for Microsoft® Windows v 4.10 http://www.epa.gov/oppt/expos ure/pubs/episuite.htm ; United States Environmental Protection Agency, Washington, DC, USA, downloaded on August 1, 2011). The EPI SUITES models were
used to estimate values for environmental behavior for CAS 68140-01-2 (via the CAS look-up function and the preexisting associated SMILES code). The results of the fugacity modeling show negligible partitioning to ai r and a strong preference for soil over water in the environment with a persistence time in the envi ronment on the orde r of 3 months.

X. Ecological Effects25 No ecological toxicity studies are available for the NADMAPA group. Ther e are data available for a related compound: C5-C9, N-[3-(dimethylamino) propyl]. The results of the studies would be expected to be comparable to that seen for the NADMAPA group.

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 effective con centration of 50% (EC 50 ) value was 15 mg/L w ith a 95% confidence interval of 12 to 17 mg/L. The slope of the concentration-res ponse curve was 8.202. The noimmobility concentration and the NOEC were both 6.0 mg/L. This study indicates that 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 test 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% confiden ce interval of 1.17 to 1.32 mg/L. The effective 50% reduction of biomass concentration (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 effective 50% inhibition of growth rate (ErC 50 ), based on growth rate, was 2.13 mg/L w ith the 95% confidence interval of 2.08 to 2.18 mg/L. At 96-hours, Dunnett’s test indicat ed that cell density a nd growth rate were significantly reduced (p<0.05) in the 1.3 and 2.7 mg amides, C5-C9, N-[3-(dimethylamino) propyl]/L treatment groups relative to the negati ve 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 when compared to the ne gative control. Effects Concentration at 20%26 (EC 20) values, calculated as a 96-hour no adverse e ffect concentration (NOAEC) estimate, were 0.92, 0.77, and 1.48 mg/L for cell density, bioma ss 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.

XI. Determination of Safety

Based on these risk assessments, EPA concludes that there is a reasonable certainty that no harm will result to the general population, or to in fants and children from aggregate exposure to
residues of NADMAPA when used as an inert ingredient in herbicidal pesticide formulations
under 40 CFR 180.920.

XII. 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 ).

As a part of every pesticide risk assessment , OPP considers a large variety of consumer subgroups according to well-esta blished procedures. In line w ith OPP policy, HED estimates risks to population subgroups fr om pesticide exposures that ar e based on patterns of that subgroup’s food and water consumption, and activ ities 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 Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered fo od uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess diet ary exposure to smaller, specialized subgroups and exposure assessments are performed when c onditions or circumstances warrant. Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for t oddlers, youths, and adults enteri ng or playing on treated areas postapplication are evaluated. Furt her considerations are currently in development as OPP has committed resources and expertise to the developm ent of specialized software and models that consider exposure to bystanders and farm worker s as well as lifestyle and traditional dietary patterns among specific subgroups.

XIII. Human Studies

This assessment does not rely on any studies in which human subjects were intentionally exposed to a pesticide.

XIV. International Limits27 There are no international established MRLs for NADMAPA compounds at this time.

XV. Occupational Exposure

Occupational exposure consideratio ns are a potential part of ne w inert use petitions based on general principles established during 2009 JI TF reviews (US EPA, JITF, D364751, 5/7/2009). Coco APDMA is used to represent the broade r NADMAPA materials in this calculation. For Coco APDMA, the shortened example calculat ions from the 2011 screening assessment for hexelene glycol tolerance exemption utilized by the Health Effects Division’s Science Policy Counsel for Exposure (ExpoSAC; US EPA 4/20/2011, docket EPA-HQ-OPP-20100330-0004)
were reviewed and used as a st arting point here. This model is conservative and assumes 100% dermal absorption, a 60 kg bodyweight, high applica tion volume (120 acres treated a day) and ultimately assumes gloves are used by mixer loaders. For the planned uses, specific inputs on product density and application rate are available to refine the am ount of inert ingredient/acre.
Planned uses for Coco APDMA in herbicide products will have a recommended maximum of 4.75 pts/A which is ~6 lb formul ated product/A, based on a dens ity of 1171 g/L and conversion
factors:

1171 g/L x 3.785 L/gal x 1 lb/454 g = 9.76 lbs/gal. or 1.22 lbs/pt Max single application is 4.75 pts/ac. 4.75 pts/ac x 1.22 lbs/pt = 5.795 lbs product/A

The maximums and typical percentage of 20 and 10% in the formulation translate to:

5.795 lb product x 0.2 = 1.16 lbs Coco APDMA /A 5.795 lb product x 0.1 = 0.58 lbs Coco APDMA /A

Exposures have been assessed against the systemic NOAEL of the OECD 422 study of 15 mg/kg/day. The default 100% dermal absorption ha s been modified to 6% and airblast is removed because it is not applicable to herbicides.

Table 7. Occupational Exposu re and Risk for Coco APDMA

Scenario Unit Exposure mg material/lb
handled Applic.
Rate lb
/unit Units Treated Avg. Daily Exposure 4 mg ai/kg bw/day MOE

Hexelene glycol example* Mixer/Loader – Liquid – Open Pour
50% max in
formulation

100% dermal Dermal: SLNoGlove
2.9 SLWithGlove
0.023 Inhal. 0.0012 0.13 lb
ai/A 1200 A/day Dermal: SLNoGlove
7.54 SLWithGlove
0.0598 Inhal. 0.00312 No Glove 66
With Glove

7946

Coco APDMA Refined Mixer/Loader – Liquid – Open Pour

20% formulation
at 6% dermal Dermal: SLNoGlove
2.9 SLWithGlove
0.023 Inhal. 0.0012 1.16 lb
ai/A 1200 A/day Dermal: SLNoGlove
4.037 SLWithGlove
0.0320 Inhal. 0.02784 No Glove
3.7 With
Glove 250
10% formulation
at 6% dermal Dermal: SLNoGlove
2.9 SLWithGlove
0.023 Inhal. 0.0012 0.58 lb
ai/A 1200 A/day Dermal: SLNoGlove
2.0184 SLWithGlove
0.0139 Inhal. 0.01392 No Glove
7.4 With
Glove 50128 Applicator – Ground-boom – Open Cab

20% formulation
at 6% dermal Dermal: SLNoGlove
0.014 SLWithGlove
0.014 Inhal. 0.00074 1.16 lb
ai/A 200 A/day Dermal: SLNoGlove
0.00325 SLWithGlove
0.00325 Inhal.

0.002861 No Glove
2460 With
Glove 2460

10% formulation
at 6% dermal Dermal: SLNoGlove
0.014 SLWithGlove
0.014 Inhal. 0.00074 0.58 lb
ai/A 200 A/day Dermal: SLNoGlove
0.00162 SLWithGlove
0.00162 Inhal.

0.001431 No Glove
4900 With
Glove 4900

Aerial Applicator

20% formulation
at 6% dermal Dermal: SLNoGlove
0.005 Inhal.

0.000068 1.16 lb
ai/A 1200 A/day Dermal: SLNoGlove
0.00696 Inhal.

0.001578 No Glove

1760

10% formulation
at 6% dermal Dermal: SLNoGlove
0.005 Inhal.

0.000068 0.58 lb
ai/A 1200 A/day Dermal: SLNoGlove
0.000348 Inhal.

0.001578 No Glove

3500

*US EPA PC Code 868601, 2-methyl-2, 4-pentanediol(HEXYLENE GLYCOL); Human Health Risk Assessment and Ecological Effect Assessment to Support Proposed Ex emption from the Requirement of a Tolerance When Used as Inert Ingredients in Pesticide Formulations (Pre- and Post-harvest use under CFR 180.920 and direct application to animals (under CFR 180.930), April 20, 2011; docket EPA-HQ-OPP-20100330-0004.

Per example mixer-loader calculation for SLGlov e at 20% max and 6% dermal absorption:

Avg Daily Exposure = 0.023 mg/lb* 1.16 lb/A*1200 A/day *6% = 0.032 mg/kg bw/day 60 kg And an example calculation for No Glove MOE at 20% max and 6% dermal absorption:

MOE = NOEL /(dermal + inha lation avg daily exposures) 15 mg/kg / (0.032 + 0.0278 ) = 250

Results indicate acceptable MOE values (greater th an 100) for these driver applicator scenarios as well as for Mixer/Loaders when gloves are worn. HED has previously indicated that the assumption that mixer/loaders will wear glov es is reasonable (US EPA 4/20/2011, docket EPAHQ-OPP-20100330-0004; US EPA, AAA-JITF CST 1 Inert Ingredients, D366020, 7/14/2009).

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, 2009.29 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.

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, 2010.30 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.pdf

.31 Dietary Exposure Analysis

U.S. Environmental Protection Agency Ver. 2.00 DEEM-FCID Chronic analysis for HERBICIDE TOLERANCES (1994-98 data) Residue file name: F:\CoconutAmido-Amine\Inerts_Herbicide_100ppbH20.r98 Adjustment factor #2 used. Analysis Date 03-13-2012/14:45:35 Residue file dated: 03-13-2012/14:43:11/8 Reference dose (RfD, Chronic) = .15 mg/kg bw/day NOEL (Chronic) = 15 mg/kg bw/day COMMENT 1: Inert Herbicides Only + 100ppb H2O

=============================================================================== 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) 0.024694 607 16.5%

U.S. Population (spring season) 0.025044 599 16.7% U.S. Population (summer season) 0.023843 629 15.9% U.S. Population (autumn season) 0.024808 605 16.5% U.S. Population (winter season) 0.025114 597 16.7%

Northeast region 0.027011 555 18.0% Midwest region 0.024850 604 16.6% Southern region 0.022696 661 15.1% Western region 0.025624 585 17.1%

Hispanics 0.026637 563 17.8% Non-hispanic whites 0.023914 627 15.9% Non-hispanic blacks 0.025774 582 17.2% Non-hisp/non-white/non-black 0.029771 504 19.8%

All infants (< 1 year) 0.046876 320 31.3% Nursing infants 0.021864 686 14.6% Non-nursing infants 0.056371 266 37.6% Children 1-6 yrs 0.066978 224 44.7% Children 7-12 yrs 0.035577 422 23.7%

Females 13-19 (not preg or nursing) 0.020172 744 13.4% Females 20+ (not preg or nursing) 0.016444 912 11.0% Females 13-50 yrs 0.018984 790 12.7% Females 13+ (preg/not nursing) 0.021056 712 14.0% Females 13+ (nursing) 0.022086 679 14.7%

Males 13-19 yrs 0.023631 635 15.8% Males 20+ yrs 0.018718 801 12.5%
Seniors 55+ 0.016269 922 10.8%

Children 1-2 yrs 0.080097 187 53.4% Children 3-5 yrs 0.063950 235 42.6% Children 6-12 yrs 0.037750 397 25.2% Youth 13-19 yrs 0.022000 682 14.7% Adults 20-49 yrs 0.018287 820 12.2% Adults 50+ yrs 0.016390 915 10.9% Females 13-49 yrs 0.017546 855 11.7%

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