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

ME M ORANDUM

SUBJECT:

PC Code(s): 000439

Decision No.: 452864
PetitionNo(s).: NA August 24, 2 0 11 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION

Summary of Human Health E ffects Data for the Alkyl (CI0-CI6) Dimethyl Amine Oxide (AD A O) Registration Review Decision Document.

DP Barcod e (s)/No(s): D392701 Registratio n 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

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- l(

Risk Assessment and Scienc e Support Branch (RASSB) Antimicrobials Division (75 1 OP)

Seiichi Murasaki, Chemical R eview Manager Regulatory Management Branch II Antimicrobials Division (75 1 OP)

Lance Wormell, Team Lead e r Re g ulatory Management Branch II
Antimicrobials Division (75 1 OP) .//

### ~
Nader Elkassabany, Branch C hie f Risk Assessment and Scienc e Support Branch (RASSB) Antimicrobials Division (75 1 OP)

Page 1 of 1 7Page 2 of 17 EXECUTIVE SUMMARY

The Antimicrobial s Division (AD) Registratio n Review Team has evaluated the status of the huma n health assessments for the Alkyl (C10

- C16) Dimethyl Amine Oxide ( ADAO ) case ( registration review case 5 0 03 ). 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 con centrated 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 t he product should be applied manually as a concentrate directly onto dishware, spread over the surface and allowed to stand 5 minutes befo re 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 i ndirect food use preservative

. L abeling 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

o verall risk picture. ADAO was first registered as a pesticide in November 1999. A R eregistration E ligibility D ecision (RED) document h as not been issued for ADAO since this chemical was registered after November 1, 1984. The primary source of information f

or 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 registr ation 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 hand ling dishes , and (2) machine washing

. There are also potential dietary concerns from indirect exposure to ADAO from plates and utensils tre ated with amine oxide as well as aggregate exposure based aggregating active and inert exposure s

. Section 1. Chemical Identity

A DAO is a n 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 a n estimated log Kow of 5. 3 and is completel y soluble in water

. The aqueous solution has a boiling point of 100 oC at one atmosphere and a va por pressure of 17.5 mm Hg at 20oC. The only registered active product contain s 5.2 % active ingredient (ai.). Table 1 presents the chemical identity of ADAO

. Although there is only one active ingredient registered (PC Code 000 439, CAS 70592

- 80

- 2), t here are several inerts registered under the A lkyl (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 (A DA O) 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 H PV SIDS, 2008)

.

Table 1

. Chemical Identity Common Name A lkyl (C10

- C16) dimethyl amine oxide

Synonyms Amine Oxide PC Code 000439 CAS registry number 70592

- 80

- 2Page 4 of 17 Registration Review Case No. 5003

Structure

Vapor Pressure 17.5 mm Hg at 20oC

Sec tion 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 fr om the requirement of a tolerance when used as inert ingredients in pesticide formulations

. The ADAO inert case include d CAS r egistry 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 th e 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 inet s 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 requirement s 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, t his guidance does not preclude the Agency from requiring, pursuant to FIFRA section 3(c)(2)(B), additional data it deems necessary to assess the

r isks 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 LD 50 = combined: 4 .8 g m /kg III

Acute Dermal GLN 81

- 2/ MRID 44475202 LD 50 = 1.88 g m /kg IIPage 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 444 3490 5 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, a mine 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, T A 1535, TA 1537, and TA 1538 were used in the N, N

- d imethyl

- 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 m ethod. 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 b oth 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 micro nuclei. 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 aberration s 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

- ho ur 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 abe rrations (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 muta tion 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
met abolic 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 abse nce 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 wit h 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 C 3 D 2 F 1 /J mice were exposed orally to A DAO 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, averagePage 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 a nd 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 fe males and 0, 80, 150, and 301 mg/kg for males). AD AO 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 accept able as per guideline 82

- 1a and satisfies subdivision F guideline requirement s.

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 ing redient ( 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 i n 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 endpoin t . However, it should be noted that at th e 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 n eed for an inhalation sub c hronic 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 thatPage 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

a dministered 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/d ay (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
accep table (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 gestatio n 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 s lightly elevated, compared to concurrent controls, in Fl females derived from F0 females that received 200 mg/kg bw/day. No teratogenic effects were observed.

T he NOEL was set at 100 mg /kg bw/day for both the maternal and developmental toxicity. The LOE L 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 aPage 9 of 17 l evel 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 ex cessive 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 we ight 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 wei ght 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; how ever, 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
ga vage 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, 20 09)

. 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 a nd 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 administ ered 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 t he 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 cont rols. 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 t he 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 consum ption 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. EP A 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 i nitially 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

- C 10 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 ofPage 11 of 17 the oral s tudy, 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 bile

duc t 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 th e 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 [methyl

14C] do decylamine, 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 wit hin 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).

S ection 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 acceptabl e 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 washi ng 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 thePage 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 re gistered 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 expo sure

. Based on the use of this product it is not expected to aerosolize. P ost

- application exposure s would be expected to be minimal.

S ection 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, non

occupational 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, wh en 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 metabol ite 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.g ov/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 Antim icrobial 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 collec ted.

Section 8 . Tolerances

ADAO currently has a n inert tolerance exemption under 40 CFR 180.9 10 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 outcom es 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 endpoi nts 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

re registration decision

, EPA reviewed these data and selected the most sensitive en dpoints 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).

E PA has developed the ED SP 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 ma y 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 thyro id (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 secti on 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 A DAO

. 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 1 0

. Reference s
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 Registratio n 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 Reg istration 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 Toxicologis t, RASSB to V. Noble

, Product Manager , RMB1. Subject: Memor andum: 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. Mem orandum 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 W hen Used as Inert Ingredients in Pesticide Formulations. Petition No. 5E7003 and 8E7316. September 22, 2009.Page 15 of 17 A PPENDIX A : HUMAN EXPOSUREPage 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 wa rranted.

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 ass ess 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 w ashing dishe s . For occupational uses, the dermal exp osure data will be used to assess the short

- , and intermediate

term 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 futu re 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 Repor ting 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/calcu lations 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 colle cted.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.