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 Support 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 Decanamide, N-[3-(dimethylamino)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 requirement 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 products. The request covers several CAS numbers 

for a group of related materials that are all derived from the reaction of 

dimethylamidopropylamine (DMAPA, CAS Reg No. 109-55-7) with linear C8-C18 alkyl fatty 

acids. The Agency is not aware of any current residential 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/reproductive 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 submission for Fatty Nitrogen Derived Amides 

class. Coco APDMA has moderate acute oral toxicity with an LD50 of 300 mg/kg/day and is 

corrosive and irritating to the skin and eye, respectively. Coco APDMA and its broader class of 

HPV analogues are negative for genotoxicity across a series of in vitro assays. A combined 

repeated dose toxicity and reproduction and developmental toxicity screening test was conducted 

in rats with Coco APDMA via oral gavage under OECD 422 guidelines. No treatment-related 

effects were detected in the reproductive or developmental parameters examined. The no 

observed adverse effect level (NOAEL) for repeat dose toxicity was 15 mg/kg/day, and the 

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 established for Coco APDMA in an OECD 422 

study, but the lowest observed adverse effect level (LOAEL) of 45 mg/kg/day was limited to 

localized gastric irritation due to the route of entry (oral gavage) and the corrosive nature of the 

material, typical of surfactants. 

No chronic studies are available for NADMAPA but negative findings for genotoxicity and no 

preneoplastic lesions were observed in the OECD 422 study on Coco APDMA that would 

suggest no potential for carcinogenicity for NADMAPA. The Agency used a qualitative structure 

activity relationship (SAR) database, DEREK Version 11, to determine if there were structural 

alerts suggestive of carcinogenicity. No structural alerts were identified for NADMAPA. Neither 

IARC nor other authoritative bodies have classified 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 the 
3

considerable similarities 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, the ToxSAC 

concluded that an additional uncertainty factor (UF) for extrapolation from subchronic toxicity 

study to a chronic exposure scenario would not be needed. As a result, the ToxSAC concluded 

that the typical 100-fold uncertainty factor would be sufficiently protective since it is not 

expected that humans’ response to local irritation/corrosiveness effects would be markedly 

different from animals. 

No acute endpoint of concern was identified in the available database. An acute reference dose 

(aRfD) is not considered warranted based on the corrosivity of the test material that resulted in 

direct tract/stomach irritation (when 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 intraspecies 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 and children would be adequately 

protected if the Food Quality Protection Act Safety Factor (FQPA SF) were reduced to 1X. 

Therefore, the cRfD is equal to cPAD. 

No carcinogenicity studies are available on NADMAPA. The Agency used a qualitative structure 

activity relationship (SAR) database, DEREK Version 11, to determine if there were structural 

alerts suggestive of carcinogenicity. 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 potential to be carcinogenic. 

Endpoints for short and intermediate term incidental oral and inhalation assessments for all 

durations of exposure were taken from the same study. Although route-specific inhalation 

toxicity studies are available, the NOAEL for the oral and inhalation studies 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 literature, 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 absorption and the ionized forms are not likely to 

exist in any significant concentrations, dermal risks are expected to be insignificant. A 

quantitative dermal risk assessment is not required. 

The residential, occupational and aggregate risk level of concern (LOC) is for MOEs that are less 

than 100 and is based on 10X for interspecies extrapolation from animals to humans and 10X for 

variation in sensitivity among humans. These LOCs are applicable to all populations, including 

individuals exposed in a residential setting and occupationally exposed workers. 

Exposure: Exposure to NADAMPA will be primarily through the oral route of exposure when 

eating food treated with pesticides containing the chemical. Inhalation exposure is not expected 

based on the physical/chemical properties which indicate that volatilization is unlikely. 
4

NADAMPA is expected to bind to soil and degrade rapidly; therefore, it has a very low potential 

to move to ground or drinking water. 

Dietary Exposure: Model estimates for oral exposure from the use of NADAMPA at 20% in 

herbicidal formulations (including exposure through drinking water) resulted in acceptable 

dietary exposure to all subpopulations. The most highly exposed subpopulation was children 1-2 

years old at 53.4% of the cPAD. 

Non-Dietary Exposure: Residential exposure to outdoor pesticide products were evaluated using 

Agency approved models to estimate the risk to residential handlers and post-application 

exposures. All exposure scenarios resulted in acceptable levels of risk to all subpopulations 

evaluated. 

Occupational exposure models showed that the use of this inert ingredient 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 believes there is acceptable risk from the use of 

NADAMPA as inert ingredients in herbicides formulations.

FQPA Conclusions: There was no evidence of increased susceptibility 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, which 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 limited 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 based on the forestomach lesions in rats, a very 

conservative hazard endpoint, coupled with the highly conservative exposure assessment and an 

absence of evidence of increased sensitivity, or neurotoxicity, supports the finding that the use of 

the standard 100X inter- and intra-species uncertainty facts are adequate to protect infants and 

children. 

Using a 100X uncertainty factor is very conservative since we are regulating 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 highly irritating and the toxicity was enhanced by 

the gavage dosing. Furthermore, humans 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 materials through personal soaps and shampoos. For 

Coco APDMA exposure at low percentages is conservatively assumed to be 5% or less of the 

overall formulation based on the ingredient list rankings of 19th or lower. For the broader 

NADMAPA materials, some exposure to CAS 7651-02-7 is possible via high-end hair care dye 
5

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 significant 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 uses on lawns or ornamentals for NADMAPA, there 

are no aggregate short- or intermediate term risks. 

For NADMAPA, the long-term aggregate risk includes 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 carcinogenicity; 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 invertebrates, rainbow trout, and avian species. An avian 

dietary study indicated NADMAPA is practically nontoxic to Northern Bobwhite.

Environmental Justice Statement: Potential areas of environmental 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 Address Environmental Justice in Minority 

Populations and Low-Income Populations," 

http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf. 

Occupational Exposure: Results indicate acceptable MOE values (greater than 100) for all 

occupational scenarios when gloves are worn. HED has previously indicated that the assumption 

that mixer/loaders will wear gloves is reasonable. 

Final Conclusions: Based on the findings in this risk assessment the Agency is granting an 

exemption from the requirement of a tolerance under 40 CFR 180.920 by establishing an 

exemption from the requirement 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 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 and/or unsaturated, as inert ingredients 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 NADMAPA 
6

materials. The Agency is not aware of any current residential or pesticidal 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 chemical characteristics of Coco APDMA, a substance representative of 

the physical and chemical properties of the 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-(dimethylamine)propyl] 

Coconut fatty acid, dimethylamidopropylamide 1-(N,NDimethylamino)-3-(Coconut Oil Amido)Propane 

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 Development (OECD). Draft Guidance Notes for the Estimation of 

Dermal Absorption Values, Environmental Directorate, Health 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 cm3/molecule-sec (half-life = 1.2 hrs) 

Log BCF (2) 1.198 L/kg; EPI Suite algorithm 
8

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 hr 

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. 

In 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 administration and evaluated for 15 days post dosing. At the dose-level of 

2000 mg/kg three females were found dead on day 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 the dose-level of 300 mg/kg three females were 

found dead on day 2 or 3. Hypoactivity or sedation, piloerection, dyspnea, hypersalivation, loud 

breathing and/or tonic-clonic convulsions were noted prior to their deaths. Hypoactivity, 

piloerection, dyspnea and hypersalivation were observed in three out of six surviving females on 

day 1. Loud breathing was noted in two out of three 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%). Additionally, 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 mortality 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 LD50 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-corrosive in a previous in vitro skin corrosion study (Study No. 2983/0001). 

Therefore for this in vivo corrosion study, the test item was evaluated 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. Clipping 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 original 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 means of a non-irritating semi-occlusive 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 alteration 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 cotton pad. Since the test item showed corrosive properties on this 

animal, the study was considered complete and no other exposure times were performed. 

The study reported that a very slight 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 was noted during the observation. 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 produce false positive responses 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 change 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 treated topically with Coco APDMA at 0.5% in corn 

oil once a week for a 3-week induction phase. Two 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 challenged 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 challenge with both test item concentrations. 

No clinical signs were recorded in the test or control animals during the course of the study. The 

body weights were within the range commonly recorded for this strain and age. Based on the 

above mentioned findings and in accordance with Regulation (EC) No 1272/2008, Coco 

APDMA does not have to be classified as skin sensitizer 

B.3.b. Local Lymph Node Assay 

A LLNA was conducted to assess the potential of a blend with concentration of >75% Coco 
11

APDMA along with 5 to 15% propylene glycol to cause contact sensitization by measuring 

lymphocyte proliferative responses from auricular 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 Chemical Co. Study ID 100272, April 

25, 2011). This study is a non-GLP investigative study that was conducted to evaluate 

potential sensitization of formulation components for Dow AgroSciences. Note, a second test 

material was included in this study (Ammonyx LO which has 30% lauramine oxide), but this 

is unrelated to Coco APDMA and this petition. 

Five female mice/group received 0.98% or 3.84% of test material, vehicle (1% L92) or 30% αhexylcinnamaldehyde (HCA; positive control) on days 1-3. On day 6, uptake of 3H-thymidine 

into the auricular lymph nodes draining the site of chemical application was measured five 

hours post administration. Proper conduct of the LLNA was confirmed via a positive response 

using 30% HCA, a moderate contact 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 indices (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 greater 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 Regulations (Bacterial Reverse Mutation Test, 

CIT/Study No. 36057 MMO, Coco amidopropyldimethylamine/CECA S.A, AkzoNobel Study, 

August 20, 2010, MRID 48556301). 

In an initial toxicity-mutation assay, the test substance 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 specified in the international guidelines. 

The vehicle controls and positive controls in the initial toxicity-mutation and confirmatory 

mutagenicity assays were within the acceptable historical ranges and fulfilled the requirements 

for a valid assay. Under the experimental conditions, 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 μg/plate for all the strains in the first experiment, 

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

● 6.25, 12.5, 18.8, 25, 37.5 and 50 μg/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 μg/plate in the TA 100 and TA 102 

strains and ≥ 50 μg/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 μg/plate for all the strains in the first experiment, 

● 7.81, 15.6, 31.3, 62.5, 125 and 250 μg/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 μg/plate in the TA 102 strain, 

≥ 125 μg/plate in the TA 1537, TA 98 and TA 100 strains and ≥ 250 μg/plate in the TA 

1535 strain. The test item did not induce any noteworthy increase 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 aberration test in cultured 

human lymphocytes to determine its potential to induce chromosome aberrations according to 

OECD 473 guidelines. 

The dose-level of 5000 μg/mL showed no precipitate, and the pH and osmolality were 

approximately 7.6 (7.4 for the vehicle control) and 400 mOsm/kg H2O (465 for the vehicle 

control), respectively. Therefore, the initial treatment-levels were 39.06, 78.13, 156.3, 312.5, 

625, 1250, 2500 and 5000 μg/mL, both with and without S9 mix were selected. Severe 

cytotoxicity was induced at all dose-levels, therefore the metaphases analysis was not performed 

and a new treatment was undertaken using a lower range of dose-levels as follows: 0.39, 0.78, 

1.56, 3.13, 6.25, 12.5, 25 and 50 μg/mL both with and without S9 mix. 

The frequency of cells with structural chromosome aberrations of the 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 μg/mL (up to 100% decrease). After the 20-hour treatment, a 

slight to severe decrease in the mitotic index was noted at dose-levels ≥ 6.25 μg/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 μg/mL (26 to 100% decrease). 

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

12.5 μg/mL for the 3-hour and the 20-hour treatments, the latter inducing a 79% and 49% 
13

decrease in the mitotic index, respectively, and b) 12.5 μg/mL, for the 44-hour treatment, 

which induced a 26% decrease in the mitotic index; the higher dose-level was too cytotoxic. 

In the 3-hour treatment, the dose-level of 12.5 μg/mL, was incorrectly selected for the metaphase 

analysis. This dose-level showed a decrease in the mitotic index indicating 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 significant increase in the frequency of cells with 

structural chromosomal aberrations was noted. 

B.4.b.2. Experiments with S9 

Cytotoxicity: At the 20-hour harvest time in the first experiment, a 29-100% decrease in the 

mitotic index was noted at dose-levels ≥ 6.25 μg/mL. At the 20-hour harvest time in the second 

experiment, a 99% decrease in the mitotic index was noted at 25 μg/mL. At the 44-hour harvest 

time (second experiment), a 100% decrease in the mitotic index was noted at 25 μg/mL. 

Metaphase Analysis: The dose-levels selected for metaphase analysis were as follows: 1.56, 

3.13 and 6.25 μg/mL for the 20-hour harvest time in the first experiment, the latter inducing a 

29% decrease in the mitotic index; the higher dose-levels were too cytotoxic. Levels of 3.13, 

6.25 and 12.5 μg/mL were used for the 20-hour harvest time in the second experiment, the higher 

dose-level being too cytotoxic. A level of12.5 μg/mL was used for the 44-hour harvest time, the 

higher dose-level being too cytotoxic. No significant increase in the frequency of cells with 

structural chromosomal aberrations was noted in either experiment and at either harvest time. 

B.5. Reproductive and Developmental Toxicity for Coco APDMA 

A combined repeated dose toxicity and reproduction and developmental toxicity 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 systemic toxicity and 

potential adverse effects of the test item on reproduction (including offspring 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 toxicity 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 toxicity was observed. It would not be possible 

to show significant clinical reactions to treatment at higher dose levels without 

inducing intolerable gastric 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 eight 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 Fourteen Day Repeated Dose Oral (Gavage) 

Range-Finding Toxicity Study in the Rat, which demonstrated signs of irritation/corrosivity of 
14

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). Clinical signs, behavioral 

assessments, body weight change and food and water 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 lactation. During the lactation phase, daily 

clinical observations were performed on all surviving offspring, together with litter size and 

offspring weights and assessment of surface righting 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 parental females from each dose group on Day 4 post 

partum. Hematology and blood chemistry were evaluated 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 salivation 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 with 5 mg/kg/day. There were no treatment-related 

changes in behavioral parameters, functional performance, 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 remaining 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 detected for corpora lutea, implantation 

counts, litter size or litter viability for treated animals when compared to controls. There were 

no intergroup differences in sex ratio (percentage male offspring) for litters treated compared to 

controls. Offspring body weight gain and litter weights at birth and subsequently on Days 1 and 

4 post partum were comparable to controls. No obvious clinical signs of toxicity 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 significant 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 the 
15

stomach. No toxicologically significant 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 chromosome 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 Cancer (IARC) nor other authoritative bodies have 

classified Coco APDMA as a carcinogen. Several genotoxicity tests for multiple analogues of 

Coco APDMA have shown this class of chemicals to be non-mutagenic within the HPV program 

(http://www.epa.gov/HPV/pubs/summaries/fantdrad/c13319rt.pdf). The National Toxicology 

Program (NTP) has conducted carcinogenicity studies 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 diethanolamine condensate (CAS 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 Toxicology and Carcinogenesis Studies of Lauric 

Acid Diethanolamine Condensate (CAS NO. 120-40-1) in F344/N Rats and B6C3F1 Mice 

(Dermal Studies), 1999), and oleic acid diethanolamine condensate (NTP Tech Rep Ser., Jul; 

481:1-198. NTP Toxicology and Carcinogenesis Studies of Oleic Acid Diethanolamine 

Condensate (CAS No. 93-83-4) in F344/N Rats 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-related 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 NTP 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 Series 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 carcinogenic. EPA has made a clear distinction between 

the diethanolamine and dimethylaminopropyl amine moiety (which is more closely related to 

Coco APDMA). EPA recently concluded (US EPA, Diethanolamine Salts of Alkyl(C8-C24) 

Benzenesulfonic Acid (DEA-JITF CST8 Inert Ingredients), Human Health Risk Assessment to 

Support Proposed Exemption from the Requirement of a Tolerance When Used as inert 

Ingredients in pesticide Formulations, Document D367001, July 23, 2009) that diethanolamine 

has not been shown to be mutagenic or carcinogenic in rats; however, there is evidence of 

carcinogenicity in mice: IARC (2000) has reviewed the carcinogenicity of diethanolamine and 

found that diethanolamine is not classifiable as to its carcinogenicity to humans (Group 3). In 

contrast to diethanolamine, for dimethylaminopropyl amine (US EPA, 

Dimethylaminiopropylamine, Isopropylamine, Ethanolamine and Triethanolaime Salts of 
16

Alkyl(C8-C24) Benzenesulfonic Acid (JITF CST8 Inert Ingredients), Human Health Risk 

Assessment to Support Proposed Exemption from the Requirement of a Tolerance When Used as 

inert Ingredients in pesticide Formulations, Document D366022, July 23, 2009), EPA concluded 

there are no explicit concerns for carcinogenic potential. This conclusion was based on DEREK 

Version 11 with no structural alerts identified for dimethylaminopropylamine, 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 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 Coco APDMA and the NADMAPA materials in the proposed use pattern. 

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 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 and corrosive effects, the ToxSAC concluded that 

an additional uncertainty factor (UF) for extrapolation from subchronic toxicity study to a 

chronic exposure scenario would not be needed. As a result, the ToxSAC concluded that the 

typical 100-fold uncertainty factor would be sufficiently 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 Information 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 Information 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 - negative 

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 with the HPV FND toxicity database. Most 

importantly, repeat dose information indicate NOEL values of 100 mg/kg bw/day or greater have 

been observed for these analogues and there are no stated concerns for developmental or 

reproductive toxicity. No evidence of mutagenicity was determined in several types of tests 

(bacterial reverse gene mutation, mammalian forward 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 LD50 of 300 mg/kg/day and is corrosive 

and irritating to the skin and eye, respectively. 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 UFA = 

10x 

UFH = 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 . 

UFA = extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among members 

of the human population (intraspecies). UFL = use of a LOAEL to extrapolate a NOAEL. UFS = use of a short-term 

study for long-term risk assessment. UFDB = to account for the absence of data or other data deficiency. FQPA SF = 

Food Quality Protection Act Safety Factor. PAD = population 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 apply 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 completeness of the database on toxicity and exposure unless EPA 

determines that a different margin of exposure (safety) 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 value 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 departure (POD) at 15 mg/kg, and supports a lower FQPA SF. The 

alkyl amides analogue information 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 forestomach lesions in rats, a very conservative 

hazard endpoint, coupled with the highly conservative exposure assessment and an absence of 

evidence of increased sensitivity, or neurotoxicity, supports the finding that the use of the 

standard 100X inter- and intra-species uncertainty facts are adequate to protect infants and 

children. 

Using a 100X uncertainty factor is very conservative since we are regulating based on portal of 

entry effects for which inter-species differences as well as variability among humans are likely to 
19

be relatively small. This class of compounds is highly irritating and the toxicity was enhanced 

by the gavage dosing. Furthermore, humans lack a forestomach which serves as a storage 

reservoir in rodents. Based on the weight of evidence, EPA has 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 FQPA SF were reduced to 1X. That decision is based on the 

following findings: 

 i. The toxicity database for the N-alkyl(C8-C18) dimethylamidopropylamines is 

adequate for FQPA assessment. The available data included acute toxicity studies, mutagenicity 

and the Reproduction/Developmental Toxicity Screening Test in rats (OECD 422). The available 

OECD 422 study evaluated reproductive parameters and developmental toxicity parameters in 

rats. In addition, it also evaluated hematology, clinical chemistry, organ weights and 

histopathological parameters. No effects on these parameters were observed at the highest dose 

tested. 

 ii. No effects on Functional Observation Battery and motor activity parameters were 

observed in the Reproduction/Developmental Toxicity Screening Test in rats (OECD 422). Since 

there is no indication that the N-alkyl(C8-C18) dimethylamidopropylamines are neurotoxic 

chemical and there is no need for a developmental 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 and 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 short in the OECD 422 study, there is no need 

for an additional uncertainty factor because the effects observed were related 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 similarities 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 concluded that an additional uncertainty factor for 

extrapolation from subchronic toxicity 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 irritation/corrosiveness effects 

would be markedly differentbased on duration of exposure. 

 vi. There are no residual uncertainties identified in the exposure 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) dimethylamidopropylamines in drinking water and 

with regard to potential residential exposures. These assessments will not underestimate the 

exposure and risks posed by the N-alkyl(C8-C18) dimethylamidopropylamines

V. Exposure 

A. Dietary Exposure 

a. Residue of concern. 
20

The residues of concern for this risk assessment are all the parent NADMAPA compounds. 

 b. Drinking Water Residue Profile. 

For the purpose of the screening level dietary risk assessment to support 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 acute and chronic dietary risk assessments for the 

parent compounds and for the metabolite of concern. The Agency considers the value of 100 ppb 

to be a high end, conservative assumption that is not likely to underestimate 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 assessment for NADMAPA is not 

required.

 ii. Chronic exposure. In conducting the chronic dietary exposure assessment, EPA used food 

consumption information from the United States 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 submitted for NADMAPA. In the absence of specific 

residue data, EPA has developed an approach which 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 commodity from a list of high-use insecticides, 

herbicides, and fungicides. A complete description 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 and 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 tolerance 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 concentration of the active ingredient. 

 

The Agency believes the assumptions used to estimate 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 exposure. 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 ingredient; rather there is generally a combination of 

different inert ingredients used which additionally reduces the concentration of any single inert 

ingredient in the pesticide product in relation to that of the active ingredient. 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 quantities 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 will serve as a guide to the potential level of 

inert ingredient residues is the active ingredient with the highest tolerance level. This assumption 

overstates residue values because it would be highly unlikely, given the high number of inert 

ingredients, that a single inert ingredient or class of ingredients would be present at the level of 

the active ingredient in the highest tolerance for every commodity. 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 produce 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 choose the highest possible 

residue that could be found on food and assumed that all food contained this residue. No 

consideration was given to potential degradation between harvest and consumption even though 

monitoring data shows that tolerance 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 conservative 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 activity relationship (SAR) database, DEREK11, to 

determine if there were structural alerts suggestive of carcinogenicity. No structural alerts for 

carcinogenicity were identified. IIAB has determined, 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 proposed 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 required 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 risk 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 account 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 exposure through drinking water) 

resulted in acceptable dietary exposure to all subpopulations. The chronic dietary exposure from 

food and water to NADMAPA is 16.5% of the cPAD for the U.S. population and 53.4% of the 

cPAD for children 1-2 years old, the most highly 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. population 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 performed 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 Dietary 

(95th 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 used as an inert ingredient in herbicidal 

pesticide products that are registered for specific crop uses that will not result in either indoor or 
23

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 ingredient. In this assessment, representative 

scenarios based on end-use product application methods and labeled 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 potential for exposure to NADMAPA materials through 

personal soaps and shampoos. For NADMAPA materials exposure at low percentages is 

conservatively assumed to be 5% or less of the overall formulation based on the ingredient list 

rankings of 19th or lower. Also for NADMAPA materials, some exposure to CAS 7651-02-7 is 

possible via high-end hair care dye 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 

significant exposures. Although dermal absorption data for un-ionized amines are available in 

the literature, 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 absorption and the ionized 

forms are not likely to exist in any significant concentrations, 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 cPAD for exposure via consumer products. 

Further details of this residential 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 Exemption 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 NADMAPA; 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 formulations with NADMAPA, there are no aggregate 

short- or intermediate term risks. Short-and intermediate-term residential exposure to Nalkyl(C8-C18) could occur via cosmetic use. While the lack of reliable exposure data precluded 

the ability to perform a quantitative risk assessment for these uses, the highly conservative nature 

of the chronic dietary risk assessment would be protective of any uses potential short-and 

intermediate-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. 
24

Long-term Aggregate Risk. For NADMAPA, the long-term aggregate risk includes dietary 

exposures to food and drinking water only, which do not exceed IIAB’s level of concern. 

Chronic aggregate risks are not of concern. Long-term residential exposure to N-alkyl(C8-C18) 

could occur via cosmetic use. While the lack of reliable exposure data precluded the ability to 

perform a quantitative risk assessment for these uses, the highly conservative nature of the 

chronic dietary risk assessment would be protective 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 considering whether to establish, modify, or 

revoke a tolerance, the Agency consider “available information” concerning the cumulative 

effects of a particular pesticide'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 tolerance 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 determine which chemicals have a common mechanism 

of toxicity and to evaluate the cumulative effects 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 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). 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 air and a strong preference for soil over water in the environment 

with a persistence time in the environment on the order of 3 months. 

X. Ecological Effects 
25

No ecological toxicity studies are available for the NADMAPA group. There 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-(dimethylamino) propyl] ranging from 2.9 to 48 mg/L. 

The 48-hour effective concentration of 50% (EC50) value was 15 mg/L with a 95% confidence 

interval of 12 to 17 mg/L. The slope of the concentration-response 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-(dimethylamino) 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 LC50

value was empirically derived to be 50 mg/L with a 95% confidence interval of 34 mg/L and 

above. The no-mortality concentration and NOEC 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 LD50 value for northern bobwhite 

was calculated to be 561 mg/kg with a 95% confidence 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 are slightly toxic to Northern Bobwhite based 

on acute toxicity (MRID 48117107). 

A dietary LC50 study (OPPTS 850.2200) was conducted on the Northern Bobwhite at doses of 0, 

562, 1000, 1780, 3160 or 5620 ppm. The dietary LC50 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 concentration tested. The no mortality concentration was 5620 

ppm. The no observed effect concentration, based 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 concentrations of amides, C5-C9, N-[3-

(dimethylamino) propyl] and evaluated for effects on cell density, area under the growth curve 

(biomass) and growth rate (OPPTS 850.5400). The 96-hour EC50, based on cell density, was 

estimated to be 1.25 mg/L with a 95% confidence interval of 1.17 to 1.32 mg/L. The effective 

50% reduction of biomass concentration (EbC50), 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 (ErC50), based on growth rate, was 2.13 mg/L with the 95% confidence interval of 

2.08 to 2.18 mg/L. At 96-hours, Dunnett’s test indicated that cell density and growth rate were 

significantly reduced (p<0.05) in the 1.3 and 2.7 mg amides, C5-C9, N-[3-(dimethylamino) 

propyl]/L treatment groups relative to the negative 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 negative control. Effects Concentration at 20% 
26

(EC20) values, calculated as a 96-hour no adverse effect concentration (NOAEC) estimate, were 

0.92, 0.77, and 1.48 mg/L for cell density, biomass and growth rate, respectively (MRID 

48117109). 

The algal species used in this study is not one of the four that is listed in the study guideline; 

therefore, the optimal concentrations or environmental conditions are not listed for this species. 

However, all the environmental factors for the study 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 infants 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 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 Address Environmental Justice in Minority Populations and 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-established procedures. In line with OPP policy, HED estimates 

risks to population subgroups from pesticide exposures that are based on patterns of that 

subgroup’s food and water consumption, and activities in and around the home that involve 

pesticide use in a residential setting. Extensive data on food consumption patterns are compiled 

by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used 

in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed 

and categorized by subgroups based on age, season of the year, ethnic group, and region of the 

country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups 

and exposure assessments are performed when conditions or circumstances warrant. Whenever 

appropriate, non-dietary exposures based on home use of pesticide products and associated risks 

for adult applicators and for toddlers, youths, and adults entering or playing on treated areas 

postapplication are evaluated. Further considerations are currently in development as OPP has 

committed resources and expertise to the development of specialized software and models that 

consider exposure to bystanders and farm workers 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 Limits 

 
27

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

XV. Occupational Exposure 

Occupational exposure considerations are a potential part of new inert use petitions based on 

general principles established during 2009 JITF reviews (US EPA, JITF, D364751, 5/7/2009). 

Coco APDMA is used to represent the broader NADMAPA materials in this calculation. For 

Coco APDMA, the shortened example calculations 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 starting point here. This model is conservative and assumes 100% 

dermal absorption, a 60 kg bodyweight, high application 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 amount 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 formulated product/A, based on a density 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 has been modified to 6% and airblast is 

removed because it is not applicable to herbicides.

Table 7. Occupational Exposure and Risk for Coco APDMA 

Scenario Unit Exposure 

mg material/lb 

handled 

Applic. 

Rate lb 

/unit 

Units Treated Avg. Daily Exposure4 

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 501 
28

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 Exemption 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 SLGlove 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 + inhalation avg daily exposures) 

15 mg/kg / (0.032 + 0.0278 ) = 250 

Results indicate acceptable MOE values (greater than 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 gloves 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) Acute Oral Toxicity Up And Down Procedure In Rats. Project 

Number: 26611. Unpublished report prepared by Eurofins/Product Safety Laboratories. July 16, 

2009. 

MRID 48117111: Oley SD (2009) Acute Dermal Toxicity Study in Rats. Project Number 26612. 

Unpublished study prepared by Eurofins/Product Safety Laboratories. July 16, 2009. 

MRID 48117112: Oley SD (2009) Primary Eye Irritation Study in Rabbits. Project Number: 

26613. Unpublished study prepared by Eurofins/Product 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/Product Safety Laboratories. July 16, 2009. 

MRID 48117114: Oley SD (2009) Dermal Sensitization 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 Reverse Mutation Assay with a Confirmatory 

Assay. Unpublished study prepared by Covance Laboratories Inc. August 21, 2009. 

MRID 48117119: Xu Y (2009) In Vivo Mouse Bone Marrow Micronucleus Assay. Unpublished 

study prepared by Covance Laboratories Inc. August 13, 2009. 

MRID 48205701: Van Ginkel CG (2009) Biodegradability 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 Characterization for MON 51803, a Surfactant to 

be used in XXX Formulations. Unpublished study prepared by Monsanto Company. June 24, 

2010. 

MRID 48117102: Walsh K (2010). Adsorption/Desorption of [14C] for MON 51803 in Five 

Soils. Unpublished study prepared by Ricerca Biosciences, LLC. June 10, 2010. 

MRID 48117103: Grommes S and DiFrancesco D (2010). Hydrolysis of [14C]MON 51803 in pH 

4, pH 7 and pH 9 Buffered Water. Unpublished study prepared by Ricerca Biosciences, LLC. 

June 4, 2010. 

MRID 48117104: Herczog KJS (2010). Rate of Degradation of [14C]MON 51803 in Three Soils 

Under Aerobic Conditions. Unpublished study prepared 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/science/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 

------------------------------------------------------------------------------- 

 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% 

-------------------------------------------------------------------------------