UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

MEMORANDUM 

DATE: May 13,2013 

SUBJECT: Methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate: Human Health Risk 

and Ecological Effects Assessment to Support Proposed Exemption from the 

Requirement of a Tolerance When Used as an Inert Ingredient in Pesticide 

Formulations. 

PC Code: 800664; CAS Reg. No: 1174627-68-9; Petition No. 2E8010 

Regulatory Action: Inert Tolerance Exemption 40 CFR 180.910 

FROM: Mark I. Dow, Ph.D., Senior Biologist AJ/~ Inert Ingredients Assessment Branch B) 

Registration Division (RD) 7505P ~ 

TO: P.V. Shah, Ph.D., Branch Chief 

Inert Ingredients Assessment Branch , · 

RD 7505P 

I. EXECUTIVE SUMMARY 

This is the Decision Document for Methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate (CAS 

Reg. No. 1174627-68-9). The firm SciReg, Inc. (12733 Director's Loop, Woodbridge, VA 

22192), on behalfofRhodia Inc. (CN 7500,8 Cedar Brook Drive, Cranbury, NJ 08512-7500) has 

submitted a request to the Environmental Protection Agency (EPA or "the Agency") to exempt 

from the requirements of a tolerance Methyl 5-( dimethylamino )-2-methyl-5-oxopentanoate. 

Methyl5-(dimethylamino)-2-Methyl-5-oxopentanoate is not acutely toxic via the oral or dermal 

routs of exposure. LD5o values for rats are> 2000 mg/kg bw. It is not a primary eye irritant. It is 

not a primary skin irritant and it is not a dermal sensitizer. A repeat dose 

reproduction/developmental toxicity study showed no treatment related effects on mating, or 

fertility. There were no treatment related effects on gestation, litter size, litter growth and 

development as compared to controls. There was no systemic toxicity. The NOAEL for systemic 

toxicity was considered to be 1000 mglkg bw/day. A Bacterial Reverse Mutation Assay with 

Page 1 of I8 
Page 2 of 18

Salmonella typhimurium concluded Methyl-5 did not induce mutagenic activity. A Gene Mutation 

Assay with Chinese hamster cells showed no reproducible dose dependent increase in gene 

mutation frequency. A Chromosome Aberration Test with Human Lymphocytes In Vitro showed 

no signs of cells carrying structural chromosomal aberrations. There was no evidence of an 

increase in polyploidy metaphases after treatment with Methyl-5. A Mammalian Erythrocyte 

Micronucleus Test with mice revealed no statistically significant decreases in the PCE/NCE ratio 

therefore Methyl-5 is considered to be negative for genotoxicity. Methyl-5 is considered nonmutagenic. There are no known data that directly suggest that Methyl 5-(dimethylamino)-2-

methyl-5-oxopentanoate is carcinogenic. Based on the absence any toxicity at the limit dose, lack 

of mutagenicity concerns, and lack of carcinogenicity triggers in the Derek analysis, EPA 

concluded that Methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate is unlikely to pose a cancer 

risk at anticipated human exposures. Neurotoxicity was not observed in a 

reproduction/developmental toxicity screening study in rats where neurotoxic parameters were 

evaluated. Immunotoxicity studies were not available for review. However, signs of 

immunotoxicity were not observed in any of the submitted studies. 

The available toxicity study indicates that Methyl-5 has a very low overall toxicity. The NOAEL 

is 1,000 mg/kg bw/day (limit dose). Since signs of toxicity were not observed at the limit dose an 

endpoint of concern for risk assessment purposes was not identified. Therefore, since no endpoint 

of concern was identified for the acute and chronic dietary exposure assessments and short and 

intermediate terms dermal and inhalation exposure assessments, a quantitative risk assessment for 

Methyl-5 is not necessary.

EPA has not found Methyl-5 to share a common mechanism of toxicity with any other substances, 

and Methyl-5 does 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 Methyl-5 does not have 

a common mechanism of toxicity with other substances.

Based on the lack of toxicological effects of concern and upon the conditions discussed 

above, the 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 the Methyl 5-

(dimethylamino)-2-methyl-5-oxopentanoate when used as an inert ingredient in pesticide 

formulations under 40 CFR 180.910.

II. BACKGROUND

The firm SciReg, Inc. (12733 Director’s Loop, Woodbridge, VA 22192), on behalf of Rhodia Inc. 

(CN 7500, 8 Cedar Brook Drive, Cranbury, NJ 08512-7500) has submitted a request to the 

Environmental Protection Agency (EPA or “the Agency”) to exempt from the requirements of a 

tolerance Methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate (CASRN 1174627-68-9; PC Code 

800664) when used as an inert ingredient in registered pesticide products. As an inert ingredient, 

the purpose is use as a solvent in emulsifiable concentrate formulations. The requested use rate is 

20-30 % (by weight) of final product formulations. Hereafter, the compound may be referred to as 

“methyl 5”. 
Page 3 of 18

III. INERT INGREDIENT PROFILE

A. The proposed use of Methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate (CASRN 

1174627-68-9) is a solvent in pesticide products having emulsifiable concentrate formulations. 

Such products may be used on agricultural crops. 

B. Physical Chemical Properties

Some of the physical and chemical characteristics of Methyl 5-(dimethylamino)-2-methyl-5-

oxopentanoate , along with its structure and nomenclature, are found in Table 1.

Table 1. Physical and Chemical Properties of 

Methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate

Parameter Value Source

Structure

MRID 48784201

CAS # 1174627-68-9

Molecular Formula C9H17NO3

Molecular Weight 187.12 g/mol

Common Names

Physical State Clear yellowish liquid at room 

temperature

Melting Point (°C) 280±2o C at 760 mm Hg at 0o C

Boiling Point (°C) 280o C

Density 1.043 g/cm3 at 20o C

Vapor Pressure <0.01 Pa at 20o C

Partition Coefficient 

(usually the Log P or Kow) Log KOW 0.39 (extrapolated)

Water Solubility Totally miscible 3- 40o C

>490 g/L at 24o C

Adsorption Coefficient KOC <17.8

Log KOC <1.25

Hydrolysis

pH 4 and 7; stable

pH 9; 1⁄2 life at 20o C = 626 hr

At 30o C = 188 hr

At 40o C = 66 hr

Henry's Law Constant

O N

O O
Page 4 of 18

IV. HAZARD ASSESSMENT

A. Summary of Toxicity Data

Methyl 5-(dimethylamino)-2-Methyl-5-oxopentanoate is not acutely toxic via the oral or dermal 

routs of exposure. LD50 values for rats are > 2000 mg/kg bw. It is not a primary eye irritant. It is 

not a primary skin irritant and it is not a dermal sensitizer. A repeat dose 

reproduction/developmental toxicity study showed no treatment related effects on mating, or 

fertility. There were no treatment related effects on gestation, litter size, litter growth and 

development as compared to controls. There was no systemic toxicity. The NOAEL for systemic 

toxicity was considered to be 1000 mg/kg bw/day. A Bacterial Reverse Mutation Assay with 

Salmonella typhimurium concluded Methyl-5 did not induce mutagenic activity. A Gene Mutation 

Assay with Chinese hamster cells showed no reproducible dose dependent increase in gene 

mutation frequency. A Chromosome Aberration Test with Human Lymphocytes In Vitro showed 

no signs of cells carrying structural chromosomal aberrations. There was no evidence of an 

increase in polyploidy metaphases after treatment with Methyl-5. A Mammalian Erythrocyte 

Micronucleus Test with mice revealed no statistically significant decreases in the PCE/NCE ratio 

therefore Methyl-5 is considered to be negative for genotoxicity. Methyl-5 is considered nonmutagenic. There are no known data that directly suggest that Methyl 5-(dimethylamino)-2-

methyl-5-oxopentanoate is carcinogenic. Based on the absence any toxicity at the limit dose, lack 

of mutagenicity concerns, and lack of carcinogenicity triggers in the Derek analysis, EPA 

concluded that Methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate is unlikely to pose a cancer

risk at anticipated human exposures. Neurotoxicity was not observed in a 

reproduction/developmental toxicity screening study in rats where neurotoxic parameters were 

evaluated. Immunotoxicity studies were not available for review. However, signs of 

immunotoxicity were not observed in any of the submitted studies. 
Page 5 of 18

B. Toxicity Profile

Acute Toxicity

Table 2. Summary of Acute Toxicity of Methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate 

Guideline No. Study Type MRIDs # Results

Toxicity 

Category

81-1 Acute Oral - rat 48784215 LD50 > 2000 mg/kg IV

81-2 Acute Dermal -

rat

48784216 LD50 > 2000 mg/kg IV

81-3 Acute Inhalation -

rat

N/A Not available

81-4 Primary Eye 

Irritation rabbit

48784217 Minimally irritating 

81-5 Primary Skin 

Irritation

48784218 Not a dermal irritant

81-6 Dermal 

Sensitization

48784219 Not a sensitizer

Acute Oral Toxicity

A single-dose oral toxicity study was conducted according to OECD Guideline 423; OPPTS 

870.110. The study was conducted at a dose level of 2000 mg/kg bw. Two groups of 3 female 

CRL: (WI) BR Wistar rats (approx 9-10 wks of age) were treated with Methyl-5 by oral gavage. 

No mortality occurred within 24 hrs in the first test group of 3 females. A second, confirmatory 

test was conducted on another group of 3 females. Since no mortality was observed no further 

testing was conducted. Clinical observations were performed on all animals at 30 minutes, 1,2,3,4 

and 6 hr after treatment and for 14 days thereafter. Gross necropsy was performed at Day After 

Treatment (DAT) 14. No clinical signs were observed after treatment. There were no changes in 

body weight gain. It was concluded that the LD50 of Methyl-5 is greater than 2000 mg/kg bw for 

female CRL: (WI) BR rats

(MRID 48784215).

Acute Dermal Toxicity

Acute dermal toxicity was evaluated using OECD Guidelines No. 402, method B3 Acute Toxicity 

(Dermal) No. 440/2008. Five male and 5 female Wistar rats (1 group of 10) were given a single, 

24 hour, semi-occluded dermal application of undiluted Methyl-5 to intact skin at a dose of 2000 

mg/kg bw. Clinical signs and body weight were monitored during the study. There were no 

mortalities. Red/brown staining was noted around the snout of 2 males during the day of dosing. 
Page 6 of 18

No other signs of systemic toxicity were noted. There were no signs of dermal irritation. One 

female showed a loss of body weight during the first week. No abnormalities were noted at 

necropsy. It was concluded that the dermal LD50 for Wistar rats was > 2000 mg/kg bw (MRID 

48784216).

Acute Eye Irritation

An acute eye irritation study was conducted according to OECD No. 405, 2002). A volume of 0.1 

ml of test substance was administered to the conjunctival sac of the left eye of New Zealand White 

rabbits, right eyes were untreated. Eyes were examined at 1, 24, 48, 72 hours and 1 and 2 weeks 

after application. Initial Pain Reaction (IPR) score of 2 was noted in all animals. At 1 hour after 

treatment, conjunctival redness (score 2) was observed in all animals, conjunctival chemosis (score 

3) was noted in all animals, conjunctival discharge (score 3) was noted in all animals and corneal 

opacity (score 1, extension 4) was observed in 2 females. At 2 weeks after treatment there were no 

clinical signs observed therefore the study was terminated. During the entire study, the control eye 

of each animal remained symptom free (MRID 48784217). Under the study conditions utilized, 

the test article is considered to be minimally irritating to the rabbit eye.

Acute Skin Irritation

An acute skin irritation study was conducted according to OECD No. 404, 2002 using New 

Zealand White rabbits. Methyl-5 was administered undiluted in a single 0.5 ml dose. Gauze was 

placed on a previously clipped area and Methyl-5 administered to the gauze. A second gauze 

patch was placed over the test area and secured with an adhesive clear plastic patch. After 4 hours 

remaining Methyl-5 was removed with water. There was no effect on body weight, no mortality 

and no clinical signs of toxicity. Animals were observed at 1, 24, 48 and 72 hours after patch 

removal and were scored according to the Draize (1959) system. No clinical signs (i.e., erythema 

or oedema) were observed on the skin of treated animals (MRID 48784218). Under the 

conditions used in the study, the test article is considered to be non-irritating to the skin of a rabbit.

Skin Sensitization/Local Lymph Node Assay

A skin sensitization test was performed using female CBA/J@Rj mice. Two doses were tested, a 

50, 25 and 10 % concentration w/v. Methyl-5 was dissolved in Acetone: Olive oil (AOO) 4:1 

mixture. The maximum attainable concentration was 50%. Three groups of 4 animals each 

received doses of 50, 25 and 10%. The negative control group of 4 animals received AOO. The 

positive control group of 4 animals received 25 % (w/v) hexylcinnamaldehyde (HCA) in AOO. 

The applicability and biocompatibility of the Methyl-5 on the animals’ ears at the maximum 

concentration was acceptable. Doses of 25μl/ear was applied for three consecutive days i.e., days 

1,2 and 3. There was no treatment on days 4, 5 and 6. On day 6 cell proliferation in the local 

lymph nodes was measured by incorporation of tritiated methyl thymidine. Stimulation index 

values of 1.2, 1.6 and 1.7 at concentrations of 50%, 25% and 10% respectively were observed. 

The positive control, hexylcinnamaldehyde (25% dissolved in AOO) elicited a significant 

lymphoproliferative response with a stimulation index of 9.4. Therefore, Methyl-5 does not show 

sensitization potential using the Local Lymph Node Assay (MRID 48784219). 
Page 7 of 18

Mutagenicity

Bacterial Reverse Mutation Assay

The mutagenic potential of Methyl-5 was evaluated with Bacterial Reverse Mutation Assay using 

Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537 and the tryptophanrequiring auxotroph strain of Escherichia coli strain WP2 uvrA in the presence and absence of a 

post mitochondrial supernatant (S9) fraction prepared from rat livers of phenobarbital/βnaphthoflavone-induced rats. Test concentrations were 5000, 1581, 500, 158.1, 50, 15.81 and 5 

μg/plate. In the initial mutation test and confirmatory mutation test all of the observed revertant 

colony number increases were of minor intensity, not dose related, without any biological 

significance as compared to the historical control range.

The revertant colony numbers of the solvent control plates were within the historical control data 

range. The reference mutagens showed the expected increase in the number of revertant colonies, 

the viability of the bacterial cells was checked by a plating experiment in each test. The tests did 

not induce gene mutations by base pair changes or frame shifts in the genome of the strains tested. 

It was concluded the Methyl-5 did not induce mutagenic activity (MRID 48784221).

Gene Mutation Assay

The potential of Methyl-5 to cause gene mutation was evaluated using a Gene Mutation Assay at 

the HPRT locus in V79 Chinese hamster ovary cells. Two tests were conducted. In the first, cells 

were exposed to Methyl-5 for 4 hours, with and without metabolic activation. In the second test 

the treatment time was 4 hours with metabolic activation and 24 hours without metabolic 

activation. The highest test concentration was 2220μg/mL and was equal to a molar concentration 

of about 10mM. No substantial or reproducible dose dependent increase in mutation frequency 

was observed. Reference mutagens used as positive controls induced distinct increases in mutant 

colonies. It was concluded that methy-5 did not induce gene mutations at the HPRT locus in V79 

Chinese hamster ovary cells. Methyl-5 is considered non mutagenic (MRID 48784222).

Chromosome Aberration Test in Human Lymphocytes In Vitro

Methyl-5 was evaluated with a Chromosome Aberration Test in Human Lymphocytes In Vitro. 

Range finding test concentrations in μg/mL were 14.4, 25.2, 77.3, 135.3 236.7, 414.2, 724.9, 

1268.7 and 2220.0. The following study design was performed.

Without S9 mix With S9 mix

Exp. I Exp. II Exp. I & II

Exposure Period 4 hrs. 22 hrs. 4 hrs.

Recovery 18 hrs. 18 hrs.

Preparation Interval 22 hrs. 22 hrs. 22hrs.

The test was conducted according to OECD Guideline 473. The results were that in the absence 

and presence of S9 mix, no cytotoxicity was observed up to highest concentration exposed. In 

both independent tests, neither statistically nor biologically relevant increases in the number of 

cells carrying structural chromosomal aberrations were observed after treatment with Methyl-5. 
Page 8 of 18

There was no evidence of an increase in polyploidy metaphases after treatment. Positive controls 

induced statistically significant increases in cells with structural chromosomal aberrations. 

Methyl-5 is considered to be nonclastogenic in the in vitro chromosome aberration test at the 

highest dose tested (MRID 48784223).

Mammalian Erythrocyte Micronucleus Test

A Mammalian Erythrocyte Micronucleus Test (OECD No. 474; OPPTS 870.5395) was conducted 

using albino Hsd: ICR (CD-1) mice. A range-finding study was conducted to determine a suitable 

dose level and route of administration. The dose selected was the maximum tolerated dose of 

2000 mg/kg and 1000 mg/kg bw and 500 mg/kg bw were chosen as the two lower dose levels. 

There was no difference in responses of males and females so only males were used in the test. 

Since there was no evidence of toxicity when 2000 mg/kg bw was administered orally, it was 

considered necessary to administer the dose intraperitoneally (i.p.). Animals were sacrificed at 24 

and 48 hours, the bone marrow extracted and smear preparations were made and stained. 

Polychromatic (PCE) and normochromatic (NCE) erythrocytes were scored for the presence of 

micronuclei. 

Seven male mice were given distilled water i.p. or orally dosed with cyclophosphamide to serve as 

vehicle and positive controls. Control animals were sacrificed at 24hr.

There were no premature deaths seen in any of the dose groups. Clinical signs were observed in 

animals dosed with Methyl-5 at and above 1000 mg/kg bw in both the 24 and 48-hr dose groups. 

Signs were hunched posture, ptosis and atiaxia. Animals dosed at 2000 mg/kg bw in the 24hr and 

48hr dose groups showed clinical signs at 10 minutes after dosing, exhibited decreased respiratory 

rate, labored respiration and loss of righting reflex. Statistically significant decreases in the 

PCE/NCE ratio were not observed in any of the dose groups as compared to the vehicle control 

group. However, the observation of the clinical signs was taken to indicate that systemic 

absorption had occurred and exposure to the target tissue had been achieved. 

There were no statistically significant increases in the frequency of micronucleated PCE in any of 

the dose groups. The positive control group exhibited marked increase in the incidence of 

micronucleated polychromatic erythrocytes thus confirming the sensitivity of the test system. It 

was concluded the Methyl-5 is not genotoxic under the conditions of the test (MRID 48784224).

Carcinogenicity

Carcinogenicity data were not available to assess the cancer potential of Methyl-5. Therefore, 

cancer potential was evaluated based on DEREK modeling. In this model, the likelihood of cancer 

preditions is based on the presence of specific chemical structures. With regard to Methyl-5, 

DEREK triggered the alert “irritation of the gastrointestinal tract”, with a level of likelihood 

“Plausible”. However, based on the chemical structure of Methyl-5 (i.e., shorter carbon chain), the 

lack of adverse effects at the limit dose (1000 mg/kg/day) particularly the lack of gastrointestinal 

effects or irritation (can lead to neoplastic lesions if persistent) even following acute exposure and 

the lack of mutagenicity the alert in the DEREK model for Methyl-5 is not considered predictive 
Page 9 of 18

of a particular toxicological concern or carcinogenicity potential. Therefore, based on the lack of 

mutagenicity and on the weight of evidence, Methyl-5 is considered not likely to be carcinogenic.

Repeat Dose Reproduction/Developmental Toxicity

A repeat dose oral gavage study was conducted on 10 male and 10 female Wistar 

HanTM:RccHanTM:Wist rats for eight weeks (including a 2-week maturation phase, pairing, 

gestation and early lactation for females). The study followed OECD Guideline No. 422. Doses 

were 30, 300 and 1000 mg/kg bw/day. A control group of ten males and 10 females was dosed 

with vehicle only (distilled water). Extensive functional observations were performed on five 

males from each dose group after mating and 5 females from each dose group on Day 4 post 

partum. Adult males were terminated on Day 43, females and offspring were terminated on Day 5 

post partum. All animals were given gross necropsy examination and histopathological evaluation 

was performed on selected tissues. 

There was no mortality during the study. Clinical findings were limited to transient episodes of 

increased salivation. This was observed in one male at 300 mg/kg bw/day on Day After Treatment 

(DAT) 17 and among animals of either sex at 1000 mg/kg bw/day between DAT 30 and 45.

There were no treatment-related changes in behavioral parameters or functional performance. 

There were no treat-related changes in sensory activity. Body weight gain in test animals was 

comparable to control animals. There were no differences in water consumption between test 

animals and control animals.

There were no treat-related effects on mating in animals of either sex in any of the doses testes. 

There were no treat-related differences in fertility in animals at any dose. There were no 

differences in gestation lengths as compared to controls. There were no differences in litter size or 

litter growth and development as compared to the controls. 

There was no evidence of treatment-related changes in hematology or blood chemistry. At 

necropsy there were no macroscopic abnormalities detected. 

There was an increase (p<0.01) in absolute and relative liver weight in males at the 1000mg/kg 

bw/day dose. Females at this dose showed an increase (p<0.05) in absolute and relative kidney 

weight as compared to the controls. Individual values fell within the historical ranges for rats of 

the age and strain used in the study. Therefore, increased liver and kidney weights were not 

considered adverse.

Treatment related microscopic findings were confined to minimal to slight centrilobular 

hepatocyte hypertrophy in four out of five males at the 1000 mg/kg bw/day dose.

Treatment-related effects in males and females occurred at the highest dose, 1000 mg/kg bw/day 

and consisted of episodes of increased salivation in either sex and a statistically significant 

increase in absolute and relative liver weights with centrilobular hepatocyte enlargement in males 

at the highest dose. These changes however, were not considered to be of toxicological 
Page 10 of 18

significance. The NOAEL for systemic toxicity was considered to be 1000 mg/kg bw/day (MRID 

48784220) . 

Neurotoxicity

Neurotoxicity was not observed in a reproduction/developmental toxicity screening study in rats 

where neurotoxic parameters were evaluated. Therefore, a developmental neurotoxicity study is 

not required.

Immunotoxicity

Immunotoxicity studies were not available for review. However, signs of Immunotoxicity were 

not observed in any of the studies that were submitted. EPA concluded that Immunotoxicity 

studies are not required at this time. 

C. Toxicity Endpoint Selection

The available toxicity study indicates that Methyl-5 has a very low overall toxicity. The NOAEL 

is 1,000 mg/kg bw/day (limit dose). Since signs of toxicity were not observed at the limit dose an 

endpoint of concern for risk assessment purposes was not identified. Therefore, since no endpoint 

of concern was identified for the acute and chronic dietary exposure assessments and short and 

intermediate terms dermal and inhalation exposure assessments, a quantitative risk assessment for 

Methyl-5 is not necessary.

V. FQPA Safety Factor considerations

1. In general. Section 408(b)(2)(c) of FFDCA provides that EPA shall apply an additional tenfold 

(10X) margin of 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 based on reliable data that a different margin of 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 available to 

EPA support the choice of a different factor.

2. Prenatal and postnatal sensitivity. 

There is no evidence of qualitative or quantitative susceptibility of infants and children in 

the available database.

3. Conclusion. 

As part of its qualitative assessment, the Agency did not use safety factors for assessing 

risk, and no additional safety factor is needed for assessing risk to infants and children. 

The available toxicity studies suggest low toxicity of Methyl 5-(dimethylamino)-2-methyl5-oxopentanoate. The toxicity database for Methyl 5-(dimethylamino)-2-methyl-5-

oxopentanoate contains acute oral, dermal, and inhalation toxicity studies; skin, eye, and 
Page 11 of 18

sensitization studies; mutagenicity studies (gene mutation, chromosomal aberrations assay), 

including in vivo micronucleus assay; and reproduction/Developmental Toxicity Screening 

Study in the rat. There is no indication, based upon the available data, that Methyl 5-

(dimethylamino)-2-methyl-5-oxopentanoate is a neurotoxic or immunotoxic chemical or 

results in increased qualitative or quantitative susceptibility in infants or children. Based 

on this information, there is no concern, at this time, for increased sensitivity to infants and 

children to this chemical when used as inert ingredient in pesticides formulations.

VI. EXPOSURE

A. Dietary Exposure

Dietary exposure to methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate can occur from 

eating food treated with pesticide formulations containing this inert ingredient. In addition, food 

can pick up residues of methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate that has been used in 

pesticide formulations applied to treat food contact surfaces, thus resulting in indirect exposure. 

However, since an endpoint of concern for risk assessment was not identified, a quantitative 

dietary exposure assessment for methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate was not 

conducted 

 i. Acute exposure. No adverse effects attributable to a single exposure of Methyl 5-

(dimethylamino)-2-methyl-5-oxopentanoate was seen in the toxicity databases. Therefore, acute 

dietary risk assessments for Methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate is not required.

 ii. Chronic exposure. A chronic dietary exposure assessment was not conducted for Methyl 5-

(dimethylamino)-2-methyl-5-oxopentanoate because no toxicological endpoint of concern was 

identified for chronic dietary exposure. The available studies/literature contained no evidence of a 

chronic dietary endpoint of concern.

iii. Dietary exposure from drinking water: Dietary exposure from drinking water to methyl 5-

(dimethylamino)-2-methyl-5-oxopentanoate can occur by drinking water that has been 

contaminated by run-off from a pesticide treated area and from antimicrobial formulations used in 

food-contact surface sanitizing solutions. Since an endpoint for risk assessment was not identified, 

a quantitative dietary exposure assessment from drinking water for methyl 5-(dimethylamino)-2-

methyl-5-oxopentanoate was not conducted.

B. Residential (Non-Occupational) Exposure

From non-dietary exposure. The term “residential exposure” is used in this document to 

refer to non-occupational, non-dietary exposure (e.g., for lawn and garden pest control, indoor pest 

control, termiticides, and flea and tick control on pets). Methyl-5 may be used in inert ingredients 

in pesticide products that are registered for specific uses that may result in both indoor and 

outdoor residential exposures. 

However, since there are no toxicological effects of concern occurring below the limit dose 

of 1,000 mg/kg bw/day, it is not necessary to conduct assessments of residential (nonoccupational) exposures and risks. There are no dermal or inhalation toxicological endpoints of 

concern to the Agency therefore quantitative assessments have not been conducted.
Page 12 of 18

VII. AGGREGATE RISK

Acute Aggregate Risk. There was no hazard attributable to a single exposure seen the in the 

toxicity database for the Methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate; therefore an acute 

aggregate risk assessment is not required. 

Short-term Aggregate risk. Short-term aggregate exposure takes into account short-term 

residential exposure plus chronic exposure to food and water (considered to be a background 

exposure level). Methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate could be used as an inert 

ingredient in pesticide products that could result in short-term residential exposure. 

Since there are no oral, dermal or inhalation toxicological endpoints of concern which occur below 

the limit dose of 1,000 mg/kg bw/day, it is not necessary to aggregate dermal and inhalation 

exposures with estimated dietary exposures. 

Using the conservative exposure assumptions described above, EPA has concluded that the 

combined short-term aggregated food, water exposures result in aggregate MOEs of > 100. 

Residential Postapplication Exposure

Assessments of Residential Post-application exposure are not necessary since there are no 

toxicological endpoints of concern at doses less than 1,000 mg/kg bw/day, the limit testing dose.

VIII. AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION

Acute Aggregate Risk

There was no hazard attributable to a single exposure seen the in the toxicity database for Methyl-5

therefore, an acute aggregate risk assessment is not required.

Short-Term/Intermediate-Term Aggregate Risk 

Short-term and intermediate-term aggregate risk assessments for Methyl-5 were not conducted. 

The assessments are not necessary since there are no dermal or inhalation toxicological effects of 

concern below the limit dose of 1,000 mg/kg bw/day. There are no risks that exceed the Agency’s 

level of concern. 

IX. 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.”
Page 13 of 18

EPA has not found Methyl-5 to share a common mechanism of toxicity with any other 

substances, and Methyl-5 does 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 Methyl5 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.

X. ENVIRONMENTAL FATE

A study was conducted to evaluate the Ready Biodegradability of Methyl-5. The purpose was to 

determine the oxygen consumption in a closed flask with inoculated mineral medium by 

measuring the change in pressure in a respirometer. Methyl-5 was added to a chemically defined 

liquid medium which was inoculated with a small population of microorganisms. The inoculum 

was prepared from different sources: activated sludge and extracts of a sandy loam soil and 

sediment. The consumption of oxygen was determined from the change in pressure in the 

respirometric flask for 28 days. In addition, a blank control containing only inoculum; a procedure 

control containing inoculum and the reference item sodium benzoate; an abiotic sterile control 

containing sterilizing agent CuSO4, Methyl-5 but no inoculum; and a toxicity control containing 

inoculum, Methyl-5 and sodium benzoate were tested concurrently to monitor the suitability of the 

microbial population. 

Based on the Biological Oxygen Demand (BOD) analysis, the mean degradation of Methyl-5 was 

33.7% after 28 days. Based on these results the classification of “ready biodegradability” was not 

given to Methyl-5 (MRID 48784209). 

A Zahn-Wellens Test was used to determine the Inherent Biodegradability of Methyl-5. Sludge 

used for the definitive test was pre-adapted to Methyl-5. The pre-adaptation of the sludge was 

conducted for a period of approximately 5 weeks. Activated sludge was used to determine 

inherent biodegradability in an aerobic aqueous medium following its mineralization by 

disappearance of dissolved organic carbon (DOC). The amount of DOC of the reference item, 

ethylene glycol, was measured to assess the potential for degradation. Two test vessels containing 

the Methyl-5 and inoculum were set up. Two blank controls (containing inoculum) and a 

procedure control (containing inoculum and reference dose) were established to evaluate the 

activity of the microbial population in the activated sludge and the adequacy of the test procedure. 

Test flasks were incubated for the definitive test in the dark under aerobic conditions for a period 

of 28 days. According to OECD Guideline 302B, the test is considered valid if the procedure 

control shows the removal of the reference compound by at least 75% within 14 days.

Based on DOC analysis, 97;1 and 95.1% of degradation were found at day 7 in test suspension A 

and B respectively. Also based on the DOC analysis, an average biodegradation of 95.8 % of 

Methyl-5 after 28 days was determined. The study indicates Methyl-5 is inherently biodegradable 

(MRID 48784210). 
Page 14 of 18

XI. ECOLOGICAL EFFECTS

An acute toxicity test was conducted on the Zebrafish (Brachydanio rerio). The test was 

conducted according to OECD Guideline No. 203 for the testing of chemicals. The test was 

conducted over 96 hours under static conditions. A test aquarium and a control aquarium each 

containing 7 fish. According to the authors Methyl-5 has no toxic effect on fish up to at least the 

limit dose concentration of 100mg/L. Therefore a limit test was performed using only this 

concentration. The 24hr, 48hr, 72hr, and 96hr LC50 value > 100 mg/L. 

96 hr LC0 (NOEC) 100 mg/L

96 hr LOEC >100 mg/L

96 hrLC100 >100 mg/L. Since the study was conducted at the limit dose, no statistical 

analyses were necessary or were conducted. The results were taken from the raw data (MRID 

48784211). 

The acute toxicity of Methyl-5 on Daphnia magna was assessed using the Acute Immobilization 

Test. Since significant toxicological response was not observed during preliminary range finding 

testing, only one test concentration was used i.e., 100 mg/L. Four test vessels and one control 

vessel each contained twenty Daphnia. Each vessel contained approximately 40 ml test solution. 

In this test the results were:

24hr EC50 value >100.0 mg/L

48hr EC50 value >100.0 mg/L

48hr EC0 (NOEC) 100.0 mg/L

48hr LOEC >100.0 mg/L

48hr EC100 >100.0 mg/L

Results were determined directly from the raw data (MRID 48784212). 

The acute toxicity of Methyl-5 on algae was assessed using the unicellular algal species 

Pseudokirchneriella subcapitata (Selenastrum capricornutum). The test was a 72 hour exposure 

period. Significant toxicity was not observed in a range finding study therefore only one test 

concentration, 100 mg/L was used in the test. There were six test replicates. At the study outset 

the algal cell count was 104 cells/mL. The results were:

72hr EbC50 (biomass) >100.0 mg/L

72hr ErC50 (growth rate) >100.0 mg/L

72hr EyC50 (yield) >100.0 mg/L

72hr NOEC 100.0 mg/L

72hr LOEC >100.0 mg/L

The results were not subjected to statistical analysis and are reported from the raw data (MRID 

48784213).

Methyl-5 was tested to determine any effect it might have on the respiration of activated sewage 

sludge. The test method was OECD No. 209 (1984) “Activated Sludge, Respiration Inhibition 

Test”, Method C.11. Activated sewage sludge was exposed to an aqueous solution of Methyl-5 at 

concentrations of 10, 32, 100, 320 and 1000 mg/L for 3 hours at 21± 1o C with the addition of a 

synthetic sewage as a respiratory substrate. Rate of respiration was determined after 3 hours 

contact time and compared to a control and a reference material, 3,5dichlorophenol. The results 

were that exposure to Methyl-5 indicate a 3 hour EC50 of > 1000 mg/L. The No Observed Effect 
Page 15 of 18

Concentration (NOEC) after 3 hours was 1000 mg/L. The 3 hour EC50 of the reference material as 

6.9 mg/L. Statistical analyses were considered unnecessary (MRID 48784214).

XII. DETERMINATION OF SAFETY

Based on the lack of toxicological effects of concern and upon the conditions discussed 

above, the 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 the Methyl 5-

(dimethylamino)-2-methyl-5-oxopentanoate when used as an inert ingredient in pesticide 

formulations under 40 CFR 180.910.

XIII. 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.

XIV. HUMAN STUDIES

This assessment does not rely on any studies in which human subjects were intentionally exposed 

to a pesticide. 

XV. INTERNATIONAL LIMITS: None

XVI. RISK CHARACTERIZATION

This is the Decision Document for Methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate (CAS 

Reg. No. 1174627-68-9). The firm SciReg, Inc. (12733 Director’s Loop, Woodbridge, VA 

22192), on behalf of Rhodia Inc. (CN 7500, 8 Cedar Brook Drive, Cranbury, NJ 08512-7500) has 
Page 16 of 18

submitted a request to the Environmental Protection Agency (EPA or “the Agency”) to exempt 

from the requirements of a tolerance Methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate.

Methyl 5-(dimethylamino)-2-Methyl-5-oxopentanoate is not acutely toxic via the oral or dermal 

routs of exposure. LD50 values for rats are > 2000 mg/kg bw. It is not a primary eye irritant. It is 

not a primary skin irritant and it is not a dermal sensitizer. A repeat dose 

reproduction/developmental toxicity study showed no treatment related effects on mating, or 

fertility. There were no treatment related effects on gestation, litter size, litter growth and 

development as compared to controls. There was no systemic toxicity. The NOAEL for systemic 

toxicity was considered to be 1000 mg/kg bw/day (the Limit Dose). A Bacterial Reverse Mutation 

Assay with Salmonella typhimurium concluded Methyl-5 did not induce mutagenic activity. A 

Gene Mutation Assay with Chinese hamster cells showed no reproducible dose dependent increase 

in gene mutation frequency. A Chromosome Aberration Test with Human Lymphocytes In Vitro

showed no signs of cells carrying structural chromosomal aberrations. There was no evidence of 

an increase in polyploidy metaphases after treatment with Methyl-5. A Mammalian Erythrocyte 

Micronucleus Test with mice revealed no statistically significant decreases in the PCE/NCE ratio 

therefore Methyl-5 is considered to be negative for genotoxicity. Methyl-5 is considered nonmutagenic. There are no known data that directly suggest that Methyl 5-(dimethylamino)-2-

methyl-5-oxopentanoate is carcinogenic. Based on the absence any toxicity at the limit dose, lack 

of mutagenicity concerns, and lack of carcinogenicity triggers in the Derek analysis, EPA 

concluded that Methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate is unlikely to pose a cancer 

risk at anticipated human exposures. Neurotoxicity was not observed in a 

reproduction/developmental toxicity screening study in rats where neurotoxic parameters were 

evaluated. Immunotoxicity studies were not available for review. However, signs of 

immunotoxicity were not observed in any of the submitted studies. 

The available toxicity study indicates that Methyl-5 has a very low overall toxicity. The NOAEL 

is 1,000 mg/kg bw/day (limit dose). Since signs of toxicity were not observed at the limit dose an 

endpoint of concern for risk assessment purposes was not identified. Therefore, since no endpoint 

of concern was identified for the acute and chronic dietary exposure assessments and short and 

intermediate terms dermal and inhalation exposure assessments, a quantitative risk assessment for 

Methyl-5 is not necessary.

EPA has not found Methyl-5 to share a common mechanism of toxicity with any other substances, 

and Methyl-5 does 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 Methyl-5 does not have 

a common mechanism of toxicity with other substances.

Based on the lack of toxicological effects of concern and upon the conditions discussed above, the

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 the Methyl 5-

(dimethylamino)-2-methyl-5-oxopentanoate when used as an inert ingredient in pesticide 

formulations under 40 CFR 180.910.
Page 17 of 18

REFERENCES

Agh, I. 2010. Acute Toxicity Test with DV-SOLV 1059 on Zebrafish (Brachydanio rerio)

OPPTS Guideline 850.1075, Rhodia Inc. CN 7500 8 Cedar Brook Dr. Cranbury, NJ

08512; MRID 48784211

Agh, I. 2010. Acute Immobilization Test with DV-SOLV 1059 on Daphnia (Daphnia magna)

OPPTS Guideline 850.1010. Rhodia Inc. CN 7500 8 Cedar Brook Dr. Cranbury, NJ 

08512; MRID 48784212.

Agh, I. 2010. Growth Inhibition Test with DV-SOLV 1059 on Algae (Pseudokirchneriella

Subcapitata) OPPTS Guideline 850.5400. Rhodia Inc. CN 7500 8 Cedar Brook Dr. 

Cranbury, NJ 08512; MRID 48784213.

Agh, I. 2009. The Testing of DV-SOLV 1059 with Bacterial Reverse Mutation Assay. OPPTS

Guideline 870.5100. Rhodia Inc. CN 7500 8 Cedar Brook Dr. Cranbury, NJ 08512; 

MRID 48784221.

Baumgartner, D. 2010. DV-SOLV 1059: Determination of the Ready Biodegradability. OPPTS

Guideline 835.3110. Rhodia Inc. CN 7500 8 Cedar Brook Dr. Cranbury, NJ 08512; 

MRID 48784209.

Bohnenberger, S. 2011. Chromosome Aberration Test in Human Lymphocytes In Vitro with

Rhodiasolv Polarclean. OPPPTS Guideline 870.5375. Rhodia Inc., CN 7500 8 Cedar 

Brook Dr. Cranbury, NJ 08512; MRID 48784223.

Brown, R. 2012. Rhodiasolv Polarclean: Micronucleus Test in the Mouse. OPPTS Guideline

870.5395. Rhodia Inc., CN 7500 8 Cedar Brook Dr. Cranbury, NJ 08512; MRID 

48784224.

Clarke, N. Rhodiasolv Polarclean: Assessment of the Inhibitory Effect on the Respiration

Of Activated Sewage Sludge. OPPTS Guideline 850.6800. Rhodia Inc. CN 7500 8 Cedar 

Brook Dr. Cranbury, NJ 08512; MRID 48784214.

de Lanty, P. 2009. DV-SOLV 1059: Main Physico-Chemical Properties. OPPTS Guideline

830.6302 – 830.7950. Rhodia Inc. CN 7500 8 Cedar Brook Dr. Cranbury, NJ 08512; 

MRID 48784201.

Ilic, V. 2010. DV-SOLV 1059: Determination of the Inherent Biodegradability (Zahn-Wellens

Test. OPPTS Guideline 835.3200. Rhodia Inc. CN 7500 8 Cedar

Brook Dr. Cranbury, NJ 08512; MRID 48784210.

McRae, L. and P. Watson. 2012. Rhodiasolv Polarclean: Oral Gavage Combined Repeat Dose

Toxicity Study with Reproduction/Developmental Toxicity Screening Test in the Rat.

OPPTS Guideline 870.3650. Rhodia Inc. CN 7500 8 Cedar Brook Dr. Cranbury, NJ 

08512; MRID 48784220.
Page 18 of 18

Nagy, K. 2009. Acute Oral Toxicity Study (Acute Toxic Class Method) of Test Item DV-SOLV

1059 in Rats. OPPTS Guideline 870.1100. Rhodia Inc. CN 7500 8 Cedar

Brook Dr. Cranbury, NJ 08512; MRID 48784215.

Pooles, A. 2011. Rhodiasolv Polarclean: Acute Dermal Toxicity (Limit Test) in the Rat. 

OPPTS Guideline 870.1200. Rhodia Inc. CN 7500 8 Cedar Brook Dr. Cranbury, NJ 

08512; MRID 48784216.

Travaszi, J. 2010. DV-SOLV 1059: Acute Eye Irritation Study in Rabbits. OPPTS Guideline

870.2400. Rhodia Inc. CN 7500 8 Cedar Brook Dr. Cranbury, NJ 08512; MRID

48784217.

Torok-Batho, M. 2009. Skin Sensitization: Local Lymph Node Assay with DV-SOLV

1059. OPPTS Guideline 870. 2600. Rhodia Inc., CN 7500 8 Cedar Brook Dr. Cranbury, 

NJ 08512; MRID 48784219.

Wollny, H. 2011. Gene Mutation Assay in Chinese Hamster V79 Cells In Vitro (V79/HPRT)

Rhodiasolv Polarclean. OPPTS Guideline 870.5300. Rhodia Inc., CN 7500 8 Cedar Brook 

Dr. Cranbury, NJ 08512; MRID 48784222.

Zelenak, V. 2010. DV_SOLV 1059: Acute Skin Irritation Study in Rabbits. OPPTS

Guideline 870.2500. Rhodia Inc. CN 7500 8 Cedar Brook Dr. Cranbury, NJ 08512; MRID

48784218.

cc:M.Dow(IIAB)

RDI: PV Shah; K. Leifer, L. Austin

M.I.Dow:S7958:PY1:(703)305-5533:IIAB:7505P