UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

SUBJECT: 

PC Code(s): 000439 

Decision No.: 452864 

PetitionNo(s).: NA 

August 24, 2011 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

Summary of Human Health Effects Data for the Alkyl (CI0-CI6) 

Dimethyl Amine Oxide (ADAO) Registration Review Decision 

Document. 

DP Barcode(s)/No(s): D392701 

Registration Number (s): 

3573-62 

Regulatory Action: Human Health Registration 

Review 

Risk Assess Type: Single Chemical Case No(s).: 5003 

TXRNo.:NA 

MRlD No(s).: NA 

FROM: 

TO: 

THRU: 

CAS No(s): 70592-80-2 

40 CFR: None 

Nathan Mottl, Biologist flat41~ €-2. 'f- l( 

Risk Assessment and Science Support Branch (RASSB) 

Antimicrobials Division (75 1 OP) 

Seiichi Murasaki, Chemical Review Manager 

Regulatory Management Branch II 

Antimicrobials Division (751 OP) 

Lance Wormell, Team Leader 

Regulatory Management Branch II 

Antimicrobials Division (75 1 OP) .// ~ 

Nader Elkassabany, Branch Chief 

Risk Assessment and Science Support Branch (RASSB) 

Antimicrobials Division (75 1 OP) 

Page 1 of 17 
Page 2 of 17

EXECUTIVE SUMMARY

The Antimicrobials Division (AD) Registration Review Team has evaluated the status 

of the human health assessments for the Alkyl (C10-C16) Dimethyl Amine Oxide 

(ADAO) case (registration review case 5003). The ADAO Case consists of only one

active ingredient and one registered product in the ADAO case (PC Code 000439). 

ADAO is sold for use as a concentrated dishwashing detergent that contains 5.2% Amine 

Oxide as the antibacterial active ingredient. The registered label indicates that ADAO is 

intended for hand washing of dishes, dishware, cutlery, utensils, and cutting boards, and

the label provides directions for both general dishwashing and instructions on how to kill 

germs on dishes and utensils. To kill germs the product should be applied manually as a 

concentrate directly onto dishware, spread over the surface and allowed to stand 5 minutes 

before rinsing. Information from MRID 46008812 indicates that ADAO is a good 

surfactant with excellent surface active products and good foaming characteristics.

Based on the dishwashing detergent use pattern, ADAO is intended for household 

settings as an indirect food use preservative. Labeling use directions indicate that all 

treated surfaces (e.g., dishes/utensils, and cutting boards) must be rinsed with potable 

water prior to any contact with food. There are some public health claims for this pesticide 

when used as a disinfectant. ADAO is formulated a ready-to-use detergent solution. 

EPA examined the hazard and exposure databases for the ADAO case to determine 

whether changes in science policy or deficiencies in the databases materially affected the 

overall risk picture. ADAO was first registered as a pesticide in November 1999. A 

Reregistration Eligibility Decision (RED) document has not been issued for ADAO since 

this chemical was registered after November 1, 1984. The primary source of information 

for this assessment was registration records for the only registered product (EPA Reg. 

3573-62) and applicable Agency risk assessment memoranda pertaining to this registration 

(D253878 and D253849). 

For ADAO active ingredient, during registration there were no pesticide tolerances or 

exemptions from the requirement of tolerances for the active ingredient. EPA conducted 

an indirect dietary assessment in registration (D253849). EPA does not anticipate a new 

dietary assessment will not be needed for registration review.

On October 9, 2009, EPA established an exemption from the requirement of a 

tolerance for residues of ADAO when used as an inert ingredient in pesticide 

formulations applied to raw agricultural commodities pre- and post-harvest for use as a 

surfactant. EPA will need to consider the inert ingredients for the aggregate assessment of 

ADAO.
Page 3 of 17

Post-registration the registrant submitted several studies, including two rabbit

subchronic dermal studies (MRID 46008813 and MRID 46049702), a chronic mouse 

dermal study (MRID 45853101), acute dermal studies (MRID 46008805, 46008807) and 

several other acute toxicity studies. The Agency will review these studies as part of the 

registration review process. 

The potential occupational handler exposure scenarios identified by the Agency after 

review of the end-use labels include (1) dermal exposure while handling dishes, and (2) 

machine washing. There are also potential dietary concerns from indirect exposure to 

ADAO from plates and utensils treated with amine oxide as well as aggregate exposure 

based aggregating active and inert exposures. 

Section 1. Chemical Identity

ADAO is an antimicrobial surfactant. ADAO is a surfactant and active ingredient used 

in detergents (see structure on Table 2). According to the information for the technical 

active ingredient (32% aqueous solution), ADAO is lipophilic has an estimated log Kow 

of 5.3 and is completely soluble in water. The aqueous solution has a boiling point of 100

oC at one atmosphere and a vapor pressure of 17.5 mm Hg at 20oC. The only registered

active product contains 5.2% active ingredient (ai.). Table 1 presents the chemical 

identity of ADAO.

 Although there is only one active ingredient registered (PC Code 000439, CAS 70592-80-

2), there are several inerts registered under the Alkyl (C10 - C16) dimethyl amine oxide

(ADAO) group. The ADAO inerts include CAS Registry numbers 1643-20-5, 2571-88-2, 

2605-79-0, 332-27-2, 61788-90-7, 68955-55-5, 70592-80-2, 7128-91-8, 85408-48-6 and 

85408-49-7 (U.S. EPA, 2009). 

The justification for grouping the amine oxides (ADAO) into a category is based on 

their structural and functional similarity. All of the substances in this category are 

surfactants, consisting of a polar “head” (the amine oxide) and a relatively inert, 

hydrophobic “tail” (the long alkyl substituent). The structural variations in the category 

are threefold: 1) the nature of the second and third substituents on the amine are either 

methyl groups or hydroxyethyl groups; 2) the long alkyl chain ranges in length from 8 to 

20 carbons; and 3) the long alkyl chain may contain one or two double bonds (i.e. 

unsaturation) as in C18:1 (oleyl) or C18:2 (linoleyl). Alkyl chain lengths range from 8 to

20 with 12 and 14 being predominant (OECD HPV SIDS, 2008).

Table 1. Chemical Identity

Common 

Name

Alkyl (C10 - C16) dimethyl amine oxide

Synonyms Amine Oxide

PC Code 000439

CAS registry 

number

70592-80-2
Page 4 of 17

Registration 

Review Case 

No.

5003

Structure

Vapor 

Pressure

17.5 mm Hg at 20oC

Section 2. Toxicology

The Agency has reviewed toxicity studies submitted for the one ADAO active 

ingredient (PC Code 000439) in the case. The toxicological database for ADAO is 

currently comprised of registrant submitted studies submitted to the Agency or obtained 

from the registrants from published open literature. 

In September 2009, the Agency reviewed the toxicology of Alkyl (C10 - C16) 

dimethyl amine oxide or ADAO for an exemption from the requirement of a tolerance

when used as inert ingredients in pesticide formulations. The ADAO inert case included

CAS registry numbers 1643-20-5, 2571-88-2, 2605-79-0, 332-27-2, 61788-90-7, 68955-

55-5, 70592-80-2, 7128-91-8, 85408-48-6 and 85408-49-7. For the inert assessment, the 

Agency concluded the toxicology database was considered adequate for FQPA assessment 

and no additional toxicology studies were required (U.S. EPA, 2009). 

For registration review, the Agency made the determination that toxicology data from 

structural and functionally similar ADAO inets such as Lauramine oxide (CAS # 1643-20-

5), and N,N-dimethyl-1-methyldodecylamine oxide (CAS # 60729-78-4), etc. could all be 

used to support the remaining toxicology data requirements for the one ADAO active 

ingredient (CAS 70592-80-2; P.C. Code 000439).

Therefore, at this time the Agency does not anticipate the need for additional 

toxicology data. However, this guidance does not preclude the Agency from requiring, 

pursuant to FIFRA section 3(c)(2)(B), additional data it deems necessary to assess the 

risks or benefits of an active ingredient, at a later time.

Acute Toxicity

Table 2 summarizes the acute toxicity of ADAO (PC Code 00439, CAS # 70592-80-

2). 

Table 2: Acute Toxicity Studies

STUDY GLN RESULTS TOXICITY 

CATEGORY

Acute Oral GLN 81-1/

MRID 44475201

LD50 = combined: 4.8 gm/kg III

Acute Dermal GLN 81-2/

MRID 44475202

LD50 = 1.88 gm/kg II
Page 5 of 17

Acute Inhalation GLN 81-3/ Waiver granted NA

Primary Eye

Irritation 

GLN 81-4/

MRID 44434904

Corrosive I

Primary Dermal 

Irritation

GLN 81-5/

MRID 44434905

Corrosive I

Dermal 

Sensitization

MRID 44434906 Dermal Sensitizer NA

Mutagenicity

Ames Test

ADAO (CAS 70592-80-2) was tested for potential to induce cell transformation in

vitro in Syrian hamster embryo cells and Salmonella typhimurium strains TA98 and 

TA100 with and without metabolic activation (MRID 44434908). According to the study 

results, amine oxide failed to induce cell transformation in vitro and mutation in the Ames 

test either with or without activation.

Lauramine oxide, (CAS # 1643-20-5) was tested in the Ames Salmonella assay both 

with and without activation. Tester strains TA 1535. TA 1538, TA 100, and TA 98 were 

used in the lauramine oxide assay, tester stratins TA 98, TA 100, TA 1535, TA 1537, and 

TA 1538 were used in the N, N-dimethyl-1-alkyl cocoamine-N-oxide assay and tester 

strains TA 98 and TA 100 were used in the N, N-dimethyltetracecylamine N-oxide assay. 

All of the above assays were negative both with and without metabolic activation (EPA, 

2009).

Salmonella typhimurium strains TA1535, TA1537, TA98, TA100 were treated with 0, 

5, 15, 50, 150, 500, and 1500 ug/plate of NINOX® HCDO and Escherichia coli strain 

WP2uvrK was treated with 0, 15, 50, 150, 500, 1500 and 5000 ug/plate NINOX® HCDO 

using the Ames plate incorporation method. Each plate was prepared in triplicate, both 

with and without the addition of a rat liver homogenate metabolizing system (10% S9). 

NINOX® HCDO caused a visible reduction in the growth of the bacterial lawn to all 

of the bacterial tester strains both with and without metabolic activation. No test material 

precipitate was observed on the plates at any of the doses tested in either the presence or 

absence of S9-mix.

Mouse Micronucleus and Chromosome Aberrations Assays:

The effect of N,N-dimethyl-1-methyldodecylamine oxide (CAS RN 60729-78-4) was 

evaluated in the mouse micronucleus test (EPA,2009). The test material was administered 

to eight week-old male and female mice as 0.1 mL/10 g in a single dose. There was no 

statistical increase in micronuclei. This chemical was also tested for its potential to induce 

micronuclei and chromosomal aberrations in the bone marrow of Chinese hamsters. 

Hamsters were administered the test material in water i.p. at dosage levels of 160, 300, 

and 700 mg/kg bw. There was no increase in either micronuclei or chromosomal 

aberrations in the treated hamsters (U.S. EPA, 2009).
Page 6 of 17

In a chromosome aberrations assay, duplicate cultures of human lymphocytes, treated 

with NINOX® HCDO, were evaluated for chromosome aberrations at 0, 39.06, 78.13, and 

156.25 ug/ml. A positive control was also included. Four treatment conditions were used 

for the study, 4 hours exposure with the addition of an induced rat liver homogenate 

metabolizing system (S9) with cell harvest after a 20-hour expression period and a 4-hour 

exposure in the absence of S9 with a 20-hour expression period, this was Experiment 1. In 

Experiment 2 the 4-hour exposure with addition of S9 was repeated (using a 2% final 

concentration of S9), while in the absence of S9 the exposure time was increased to 24 

hours (U.S. EPA, 2009).

The solvent and positive controls were appropriate and within historical control range. 

NINOX® HCDO, did not induce any statistically significant increases in the frequency of 

cells with aberrations (excluding gaps) in two separate experiments. NINOX® HCDO 

was shown to be non-clastogenic to human lymphocytes in vitro (U.S. EPA 2009).

Cell Transformation Assay

In a published study (MRID 44434908), N,N-dimethyldodecylamine oxide (29.1% 

a.i.) in dimethylsulfoxide or distilled water, was tested as one of a series of surfactants in 

three runs of an in vitro mammalian cell transformation assay using Syrian hamster 

embryo cells at concentrations of 0.1-20 ug/mL, and in a single microbial gene mutation 

assay using Salmonella typhimurium strains TA98 and TA100, with and without 

metabolic activation at concentrations of 10-200 ug/plate. In the cell transformation assay, 

cultures were exposed to the test compound for eight days prior to evaluation for 

transformed colonies. In the microbial gene mutation assay, the standard plate 

incorporation test with a preincubation step was performed; S9 homogenates for metabolic 

activation were made from polychlorinated biphenyl induced rat livers. No exogenous 

metabolic activation system was used in the cell transformation assay.

N,N-dimethyldodecylamine oxide was moderately toxic to Syrian hamster embryo 

cells at 20 ug/mL and was extremely toxic to S. typhimurium strains TA98 and TA100 at 

200 ug/plate in the absence of metabolic activation. N,N-dimethyldodecylamine oxide did 

not induce transformation in Syrian hamster embryo cells and was not mutagenic in S.

typhimurium strains TA9S and TA100 with or without metabolic activation at any 

concentration. Findings with the positive controls confirmed the sensitivity of the 

microbial gene mutation assay to detect mutagenesis. However, a weak response with the 

positive control in the transformation assay reduced the sensitivity of the test system to 

detect transformation.

Dominant Lethal Assay

ADAO (CAS 70592-80-2) was also tested in a dominant lethal assay (MRID 

44475204), groups of 20 male C3D2F1/J mice were exposed orally to ADAO in water for 5 

consecutive days at dose levels of 0, 10, 100, or 1000 mg/kg, then mated sequentially to 

groups of untreated female mice (1 male: 2 females) for seven 7-day periods. Females 

were sacrificed 13 or 14 days from the midpoint of the mating periods and assessed for 

total implantations, resorptions and dead embryos. The incidence of pregnancy, average 
Page 7 of 17

total implantations per pregnant female, average number of fetal deaths per pregnant 

female, and the mutagenic index were calculated for each mating period and the collective 

(except mutagenic index) mating periods. Between control and treated animals, there 

were no indications of reduced fertility nor variations in the dominant lethal parameters 

measured. 

Subchronic Toxicity

A subchronic oral study in rats (MRID 4475203) was conducted to assess repeat oral

exposure. ADAO (CAS 70592-80-2) was administered in the diet for 13 weeks to 4 

groups of rats (40 per group, 20 male and 20 female) at levels of 0.1, 0.2, and 0.4% in the 

diet (equivalent to 0, 63, 112, and 236 mg/kg for females and 0, 80, 150, and 301 mg/kg 

for males). ADAO produced decreased body weight gain at a dose of 236 mg/kg/day in 

males and 301 mg/kg/day in females as well as increased incidence of cataracts. 

Statistically significant differences in mean body weight were observed in females dosed 

at the 0.2% level. As a result the lowest observed effect level (LOEL) of 112 mg/kg/day 

and a no observed effect level (NOEL) of 63 mg/kg/day was established based on 

decreased body weight gain for females. This oral subchronic toxicity study in rats is 

classified as acceptable as per guideline 82-1a and satisfies subdivision F guideline

requirements.

The registrant submitted a 28/91 day rabbit dermal toxicity study (MRID 46049702)

and a 91-day rabbit dermal toxicity study (MRID 46008813) which examined the active 

ADAO ingredient (CAS 70592-80-2). This study examined dermal toxicity of a group 

containing 5 male and 5 female New Zealand White rabbits to liquid detergent containing 

at a dose volume of 2 mL/kg/bw/day. The dose levels were 0, 0.5, 1.0, and 2.5% final 

formula in distilled water. The detergents were applied dermally to the shaved backs of 

the rabbits for 6 hr/day, 5 days/week, for a total of 65 treatments over 91 days. The 

NOAEL of 2.5% (equivalent to 2.5 mg AO/kg bw/day) was based on a lack of systemic

endpoint. However, it should be noted that at the high dose there was slight to moderate 

erythema, edema, atonia, and desquamation which was also noted at the mid dose as well. 

No other treatment related effect was noticed.

The Agency does not anticipate the need for an inhalation subchronic toxicity study 

since the currently registered product uses are not sprayed and does not generate potential 

respirable aerosols during dish washing. 

Neurotoxicity

No data are available. However, evidence of neurotoxicity was noted in the combined 

repeated dose toxicity study in rats. Total locomotor activity was reduced at the high dose 

(250 mg/kg/day) and in females only. There were no signs of neurotoxicity in other 

studies. However, EPA concluded that the reduction in locomotor activity was due to 

toxicity at the high dose rather than due to neurological toxicity. The conclusion is based 

on the following: effects were seen only in one sex at the high dose, the effect was 

transient, neurotoxicity was not observed at the lower doses in this study, neurotoxicity 

was not observed in any other study in the database, and fetal susceptibility was not 

observed in the developmental and reproduction studies. Therefore, EPA concluded that 
Page 8 of 17

further assessment of neurotoxicity is not necessary and that a developmental 

neurotoxicity study is not required. 

Developmental

Rat

A developmental toxicity study for ADAO (32% w/v) (CAS # 70592-80) in rats was 

conducted a part of registration (MRID 44762401). In this study, ADAO was 

administered to 25 female rats at dose levels of 0, 25, 100, and 200 mg/kg/day from days 

6-19 gestation. The maternal NOAEL was determined to be 25 mg/kg/day based the effect 

of decreased body weight gain of female rate at the next dose level of 100 mg/kg/day 

(LOAEL). The development NOAEL was also 25 mg/kg/day based on an increased 

incidence of skeletal variations secondary to decreased body weight gain at a LOAEL of 

100 mg/kg/day. This study was reviewed by the Agency and classified by the Agency as 

acceptable (guideline) and satisfies the data requirement for a developmental toxicity 

study (OPPTS 870.3700) in rats.

Female Charles River CD rats were administered lauramine oxide (CAS RN 1643-20-

5) by gavage daily during days 7 to 17 (inclusive) of gestation at doses of 50, 100, and 200 

mg/kg bw/day (Lion Corporation, 1979). Approximately two-third of the animals in each 

group were killed on day 20 of gestation for examination of their uterine content, while 

the remaining one-third was permitted to deliver their young naturally and rear their 

offspring until weaning on day 25 post partum. Fl animals were then paired at 10 weeks 

of age and females were sacrificed at day 20 of pregnancy for examination of their uterine 

content.

Treatment at 200 mg/kg bw/day was associated with a reduction of maternal body 

weight and food intake (less than 10%) and with elevated water consumption. In females 

killed on day 20 of gestation mean fetal weight was depressed, which was associated with 

a slight retardation of fetal ossification. However, in females allowed to litter, parturition, 

survival, growth and development of the F1 offspring were unaffected. Subsequent 

growth, mating performance and fertility were similar in all F1 groups. Fetal and 

placental weights were slightly elevated, compared to concurrent controls, in Fl females 

derived from F0 females that received 200 mg/kg bw/day. No teratogenic effects were 

observed.

The NOEL was set at 100 mg/kg bw/day for both the maternal and 

developmental toxicity. The LOEL was 200 mg/kg bw based on reduced maternal 

body weight and food intake and increased water consumption in the dams and on a 

slight reduction in fetal ossification.

Rabbit

Female New Zealand white rabbits were administered lauramine oxide (CAS RN 

1643- 20-5) by gavage at dosage levels of 0, 40, 80, and 160 mg/kg bw from gestation 

days 6 though 18 (Lion Corporation, 1980). Dams were generally unaffected by treatment 

with the test substance although body weight gain was depressed in all dose groups at a 
Page 9 of 17

level not exceeding 10%. At 40 mg/kg bw terminal body weight was similar to the 

controls. Three females treated at 80 and another three treated at 160 mg/kg bw died or 

were killed in extremis, but no direct involvement the test substance was apparent. No 

fetal malformations were observed, and litter response and development were unaffected 

by treatment. 

The NOAEL for both the maternal and developmental was considered to be > 160 

mg/kg bw.

2-Generation Reproduction Toxicity Study

In a 2-generation rat reproduction study, animals received 0, 750, 1500, and 3,000 

ppm lauramine oxide (CAS Reg. 1643-20-5) in the diet for 6.5 weeks (Lion Corporation 

1979). Dosage levels were then reduced to 0, 188, 375, and 750 ppm for the remainder of 

the study based on excessive effects of body weight gain. Based on the body weights and 

food consumption data, the dosage levels were equivalent to 0, 11, 20, and 40 mg/kg 

bw/day. Slight reductions in weight gain were observed for both parental animals and 

their offspring. In F1 pups, body weight was decreased 4-12% from days 1-25 at all 

doses. Statistical significance was attained at ≥ 375 ppm at post partum day 25 when the 

pups were getting the majority of their food from the diet. The reason for the reduction in 

body weight is unclear; however, body weight gain in these animals was constant and 

comparable in magnitude to the control animals. Additionally, all treated animals reached 

an adult body weight comparable to control animals. Therefore, the decrease in body 

weight gain and body weight in pups was not considered adverse effects. Mating 

performance, fertility and conception rate were not affected by treatment in either 

generation. There was slight reduction in the number of F2 offspring born at the high 

dose; however, there were no adverse effects of treatment on litter size at birth, liver birth 

index and birth weight in either generation. No macroscopic or histopathologic changes 

were attributable to treatment. The NOAEL for parental, offspring and reproductive

toxicity was considered to be greater than 750 ppm, equivalent to > 40 mg/kg bw/day. 

In a combined repeated dose toxicity study with the reproduction/developmental 

toxicity screening test (MRID 47444301), lauramine oxide (30.27%) was administered by 

gavage to 10 HanRcc: WIST (SPF) rats/sex/dose at dose levels of 0, 40, 100, or 250 

mg/kg/day (corrected for purity). The P generation parents were dosed for 14 days 

(females) and 28 days (males) before they were mated to produce the F1 litters (U.S. EPA, 

2009). 

The LOAEL for parental toxicity is 100 mg/kg/day based on hyperkeratosis, 

parakeratosis, squamous cell hyperplasia, submucosal inflammation and submucosal 

edema in the forestomach. The NOAEL is 40 mg/kg/day. The LOAEL for reproductive 

toxicity was 250 mg/kg/day base on a decrease in the gestation index. The NOAEL is 100 

mg/kg/day. The developmental LOAEL is 250 mg/kg/day based on mortality and 

decreased body weights. The NOAEL is 100 mg/kg/day.

This study is classified as acceptable/guideline and satisfies the guideline requirements 

(OPPTS 870.3650) for a combined repeated dose toxicity study with the 

reproduction/developmental toxicity screening in the rat.
Page 10 of 17

Chronic Toxicity and Carcinogenicity

Male and female ICR mice were dermally administered ADAO at concentrations of 0, 

0.05%, 0.13%, and 0.26% (on a 100% active basis, equivalent to 0, 1.1, 2.8, and 5.6 

mg/kg bw/day) to the clipped skin once daily three times per week for 104 weeks (MRID 

4583101). Compound-related skin irritation limited the dose selection for chronic 

exposure. There were no statistically significant differences in hematology, clinical 

chemistry, urinalysis, group average body weight, organ weights and organ to body weight 

ratios in treated groups when compared to the controls. No skin tumors were observed in 

any group. There was no evidence of a systemic carcinogenic response. ADAO was not 

carcinogenic to mice by the dermal route of exposure up to dosage levels of 5.6 mg/kg 

bw/day based on active ingredient content of the test material (U.S. EPA 2009). 

In a chronic toxicity/oncogenicity study (MRID 44586201), ADAO (27% a.i.) was 

administered to CD rats (50/sex/dose) in the food for 104 weeks at dose levels of 0, 0.01, 

or 0.2% which is equivalent to 0, 4.24, 42.3, 87.4 mg/kg/day in female rats and 0, 5.23, 

52.6, and 107 mg/kg/day. 

No significant differences were not in survival rates, hematological parameters, 

clinical chemistry, urinalysis, and organ weights or histopathology were noted. Body 

weights and food consumption were significantly lower for high-dose males and females

and the researchers in the study observed an increased incidence of cataracts. No 

differences of toxicological concern were noted at the 0.1 and 0.01% dosages. The 

chronic LOEL for this study is 0.2% [87.4/107 (M/F) mg/kg/day) based on decreased 

body weight and opthalmological opacities/cataracts. The chronic NOEL is 0.1% 

[42.3/52.6 (M/F) mg/kg/day]. Under the conditions of this study, ADAO did not show any 

signs of oncogenicity to CD rats. EPA reviewed this study (D247460) and found that the 

chronic toxicity/oncogenicity study is classified as acceptable as per guideline §84-5a and 

satisfies the Subdivision F guideline requirements for a chronic toxicity study §83-1 and a 

carcinogenicity study §83-2 in rats.

Metabolism and Pharmacokinetics

No metabolism and pharmacokinetics data were submitted for the active ingredient. 

However, metabolism and pharmacokinetics data were in a recent inert risk assessment. 

The alkyl dimethyl amine (ADM) is initially demethylated to generate a long chain alkyl 

(fatty acid) amine. Monoamine oxidase converts the long chain alkyl amine to the 

corresponding fatty acid and ammonia (U.S. EPA 2009). 

Fatty acids are metabolized primarily by beta oxidation resulting in successive releases 

of acetic acid, which enters into intermediary metabolism or is metabolized ultimately to

carbon dioxide and water. The C12-C18 alkyl amines may be relatively poor substrates 

for monoamine oxidases, and the lower alkyl amines, C5-C10 are more readily oxidized 

by these enzymes (U.S. EPA 2009).

In a series of studies, radiolabeled test material was administered orally to rats or 

dermally to rats, rabbits, and mice. In the rat metabolism and tissue distribution portions of 
Page 11 of 17

the oral study, 4 male rats each were administered a single oral dose of 100 mg/kg bw 

[methyl-14C] dodecylamine, N,N dimethyl-N-oxide and 4 female rats each were 

administered 100 mg/kg bw [1-dodecyl 14C] dodecylamine, N, N-dimethyl-, N-oxide. In 

the excretion study, radioactivity in urine, feces, and expired CO2 were determined at 24, 

48, and 72 hours post-dose. In the tissue distribution study, tissues/organs were collected 

at 48 and 72 hours post-dose and radioactivity was determined. In addition, three bileduct cannulated male rats were administered a single oral dose of 40 or 100 mg/kg bw 

[methyl-14C] dodecylamine, N,N dimethyl-, N-oxide and radioactivity was examined in 

the urine, feces, bile and carcass 24, 48, and 72 hours post-dose (U.S. EPA 2009).

In the rat metabolism and tissue distribution portions of the oral study, 4 male rats 

each were administered a single oral dose of 100 mg/kg bw [methyl-14C] dodecylamine, 

N,N dimethyl-N-oxide and 4 female rats each were administered 100 mg/kg bw [methyl14C] dodecylamine, N, N-dimethyl, N-oxide and radioactivity was examined in the urine, 

feces, bile and carcass 24, 48, and 72 hours post-dose (U.S. EPA 2009).

C12 ADAO was absorbed in rats and extensively and rapidly excreted. The 

distribution of C12 ADMO was similar between males and females. Among all the tissues 

analyzed, the largest amount and the highest concentration of radioactivity were found in 

the liver. The fractions of dosed radioactivity appearing in the liver, kidney, and blood 

reached maxima within 1 hour after the oral dose. The excretion of radioactivity was 

rapid with approximately 70% and greater excreted within 24 hours. The major excretory 

pathway was urine followed by expired CO2 with much less found in feces and bile (U.S. 

EPA 2009).

Section 3. Dietary Assessment

Dietary

In July, 1999 AD reviewed a dietary exposure study entitled “Human Exposure 

Calculations for Dodecyl dimethyl Amine Oxide (DDAO)” (MRID 44434910) (D253878, 

D244309, and D253849) which was submitted by the registrant. The study estimated 

concentration of residues found on dishes and utensils. However, the study was found to 

have deficiencies so the Food and Drug Administration (FDA) worst case calculations 

described in the “Sanitizing Solutions: Chemistry Guidelines for Food Additive Petitions” 

was used to estimate dietary exposure (D253849) and the Agency later used the dietary 

exposure estimates to do a human health risk assessment (D253848). The acute and 

chronic dietary risk was assessed and was found to be acceptable for all subpopulations 

listed (i.e. < 100% of the acute and chronic RfD). A new indirect dietary assessment is not 

anticipated as needed.

Drinking Water

Although likely to be infrequent, dietary exposures via drinking water may occur via 

dish washing and drinking from a cup that has ADAO residues. The registrant provided 

calculations for the levels of ADAO in drinking water and the Agency used this data in the 
Page 12 of 17

past to develop a drinking water risk assessment in registration (D253848). A new 

drinking water assessment is not anticipated as needed.

Section 4. Occupational/Residential Exposure

There is potential short- and intermediate-term exposure to for residential uses only. 

According to the label there are only “directions for household uses.” The potential 

residential handler exposure scenarios identified by the Agency after review of the labels 

include (1) dermal exposure while hand washing dishes with detergent, and (2) washing

hands in sink. Although washing hands with detergent is not a registered use, it is likely 

that this product could be used for this purpose. Product use data will be essential to 

categorize the uses to refine these risk assessments. The Agency expects that only the 

dermal route will need to be assessed for handler exposure. Based on the use of this 

product it is not expected to aerosolize. Post-application exposures would be expected to 

be minimal.

Section 5. Aggregate and Cumulative Exposure

In examining aggregate exposure, EPA takes into account the available and reliable 

information concerning exposures to residues in food and drinking water, nonoccupational pesticide exposures, and inert uses. EPA expects that the dietary and 

residential risks will need to be aggregated. Section 408(b)(2)(D)(v) 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.” 

Unlike other pesticides for which EPA has followed a cumulative risk approach based 

on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity 

finding as to ADAO and any other substances and ADAO does not appear to produce a 

toxic metabolite produced by other substances. For the purposes of this tolerance action, 

therefore, EPA has not assumed that ADAO has a common mechanism of toxicity with 

other substances. For the purposes of this action, therefore, EPA has not assumed that 

ADAO has 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 the policy statements 

released by EPA’s Office of Pesticide Programs concerning common mechanism 

determinations and procedures for cumulating effects from substances found to have a 

common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

Section 6. Incidents

There have been no human incidents reported in any of the OPP databases (e.g. OPP 

Incident Data System (IDS)) associated with exposure to ADAO as a detergent.

Section 7. Anticipated Data Needs

The Antimicrobial Division (AD) anticipates requiring further exposure studies for 

ADAO for registration review (see Table 3). The studies and a brief rationale are listed 

below. Further clarification of the rationale for these studies are provided in Appendix A. 
Page 13 of 17

Table 3: Human Health Data Needs Based on End Use Labels

Study Needed Guideline Rationale (also see Appendix B)

Product Use 875.1700 (Handler)

875.2800 (Postapplication)

Product use data will be needed to characterize any 

uncertainties with regard to the use or application of this 

chemical.

Dermal Exposure 875.1200 Dermal Exposure data will be needed to estimate 

exposure to washing dishes using 2-hand immersion.

Data Reporting 875.1600 The data are needed to interpret the dermal exposure 

data collected.

Section 8. Tolerances

ADAO currently has an inert tolerance exemption under 40 CFR 180.910 for use as a 

surfactant in pesticide formulations (U.S. EPA, 2009). Based on review of Title 21 CFR, 

FDA does not maintain a clearance for this chemical. EPA does not maintain a tolerance 

or exemption from the requirement of a tolerance for residues for the ADAO active

ingredient.

Section 9. Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential 

adverse outcomes from exposure to chemicals. Collectively, these studies include acute, 

subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, 

developmental, reproductive, and general or systemic toxicity. These studies include 

endpoints which may be susceptible to endocrine influence, including effects on endocrine 

target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, 

pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard 

assessments, EPA evaluates acute tests and chronic studies that assess growth, 

developmental and reproductive effects in different taxonomic groups. As part of its

reregistration decision, EPA reviewed these data and selected the most sensitive endpoints 

for relevant risk assessment scenarios from the existing hazard database. However, as 

required by FFDCA section 408(p), ADAO is subject to the endocrine screening part of 

the Endocrine Disruptor Screening Program (EDSP). 

EPA has developed the EDSP to determine whether certain substances (including 

pesticide active and other ingredients) may have an effect in humans or wildlife similar to 

an effect produced by a “naturally occurring estrogen, or other such endocrine effects as 

the Administrator may designate.” The EDSP employs a two-tiered approach to making 

the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays 

to identify the potential of a chemical substance to interact with the estrogen, androgen, or 

thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and 

are found to have the potential to interact with E, A, or T hormonal systems will proceed 

to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests 

are necessary based on the available data. Tier 2 testing is designed to identify any adverse 

endocrine-related effects caused by the substance, and establish a dose-response 

relationship between the dose and the E, A, or T effect. 
Page 14 of 17

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. 

Between October 2009 and February 2010, EPA issued test orders/data call-ins for the 

first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert 

ingredients. ADAO is not among the group of 58 pesticide active ingredients on the 

initial list to be screened under the EDSP. Accordingly, as part of registration review, 

EPA will issue future EDSP orders/data call-ins, requiring the submission of EDSP 

screening assays for ADAO. For further information on the status of the EDSP, the 

policies and procedures, the list of 67 chemicals, future lists, the test guidelines and the 

Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/.

Section 10. References

D244309. Memorandum from D. Aviado, Biologist, RASSB to D. Edwards, Branch 

Chief, RMB1. Subject Human Exposure Data Considerations: Review of Indoor Surface 

Residue Data Submitted in Support of Product Registration for Cleaning Magic I 

Containing a New Active Ingredient Chemical: Alkyl (C10-16) Dimethyl Amine Oxide 

(Amine Oxide). October 5, 1998

D253848. Memorandum from T. McMahon, Senior Toxicologist, RASSB to V. Noble, 

Product Manager, RMB1. Subject Amine Oxide: AD Risk Assessment of the Active 

Ingredient. Chemical No. 000439. Submission S538885. July 23, 1999.

D253849. Memorandum from R. Quick, Chemist, RASSB to V. Noble, Product Manager, 

RMB1. Subject: Review of the Proctor and Gamble Company New Chemical Registration 

for Alkyl (C10-16) Dimethyl Amine Oxide in Support of the Product Registration for the 

Product, Cleaning Magic I. July 23, 1999.

D269139. Memorandum from T. McMahon, Senior Toxicologist, RASSB to V. Noble, 

Product Manager, RMB1. Subject: Memorandum: AD’s Response to Data Waiver 

Requests and Other Data Issues for the Active Ingredient. Chemical No. 000439 Sept 25, 

2000.

MRID 46008812. Safety Testing of Dodecyl Dimethyl Amine Oxide. E.V. Buehler, J.G. 

Voss, D.L. Updyke, and C.M. Burnett. Procter and Gamble Company. January 30, 1967.

OECD HPV SIDS, 2008. Amine oxides Organisation for Economic Co-operation and 

Development (OECD) High Production Volume (HPV), Screening Information Data Set

(SIDS) initial assessment report, 2006.

U.S. EPA 2009. Memorandum from L. Austin, PhD., Toxicologist Inert Ingredient 

Assessment Branch (IIAB) to P.V. Shah, Branch Chief, IIAB. C10-18-

Alkyldimethylamine oxides: Human Health Risk Assessment and Ecological Effects 

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

Used as Inert Ingredients in Pesticide Formulations. Petition No. 5E7003 and 8E7316. 

September 22, 2009.
Page 15 of 17

APPENDIX A: HUMAN EXPOSURE
Page 16 of 17

Guideline Numbers: 875.1200 

Study Titles: Dermal Exposure (Indoor)

Rationale for Requiring the Data

Note: Dermal exposure data are needed for both residential and occupational uses. The selection 

of an outdoor versus an indoor site is based on the high end exposure scenario. In almost all 

cases, repeating an exposure study for the same scenario outdoors and indoors is not necessary.

The potential for dermal exposure is very likely for exposure scenarios involving washing dishes 

with detergents. The existing CMA data base and PHED for these scenarios are limited in scope 

for QA/QC and number of monitoring units. EPA presented the need for additional handler 

exposure data to the January 2007 Science Advisory Panel (SAP) as well as to the April 2007 

Human Studies Review Board (HSRB) and both groups agreed that additional data are warranted. 

The criteria for the dermal exposure data are based on the potential for dermal exposure from the 

labeled uses (e.g., residential exposures from washing dishes) and evidence of toxicity. If the 

toxicological endpoints from ADAO are used to assess the risks, there is an endpoint selected for 

the dermal route.

Practical Utility of the Data

1. How will the data be used?

The dermal exposure data will be used to assess dermal exposures from washing dishes. For 

occupational uses, the dermal exposure data will be used to assess the short-, and intermediateterm exposures. The dermal exposure data will be used to determine the accuracy of the dermal 

risks to both residence and occupational workers.

2. How could the data impact the Agency’s future decision-making?

If risks warrant mitigation, the dermal exposure data will provide the types of mitigation necessary 

such as lowering application rates or potential removal of uses from the label.

Guideline Numbers: 875.1600

Study Title: Data Reporting and Calculations

Rationale for Requiring the Data

For all exposure studies this data requirement is required to facilitate the review of the data.

Practical Utility of the Data

1. How will the data be used?

The study report and all raw data/calculations will be reviewed for the adequacy of the data.

2. How could the data impact the Agency’s future decision-making?

This data requirement is triggered if an exposure study is conducted. The data are needed to 

interpret the dermal exposure data collected.
Page 17 of 17

Guideline Numbers: 875.1700

Study Title: Product Use Information

Rationale for Requiring the Data

Product use information is a description of how the product is actually applied; it is not 

afield study. A description of how this product is used would provide for a 

comprehensive realistic assessment of its potential applications. The description of the 

application techniques would be used to define the exposure scenarios to be assessed in 

the risk assessment.

Practical Utility of the Data

1. How will the data be used?

A complete description of product use would ensure that the risk assessment is inclusive 

of the types of exposures occurring during residential and occupational use.

2. How could the data impact the Agency’s future decision-making?

The need for a risk assessment as needed under Registration Review would require that 

the risk assessor understands how the product is applied.