i

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division contact: [PV Shah, (703) 308-1846]

INSTRUCTIONS: Please utilize this outline in preparing the pesticide petition. In 

cases where the outline element does not apply, please insert “NA-Remove” and 

maintain the outline. Please do not change the margins, font, or format in your 

pesticide petition. Simply replace the instructions that appear in green, i.e., “[insert 

company name],” with the information specific to your action.

TEMPLATE:

[Rhodia Inc.]

[2E8010]

EPA has received a pesticide petition ([2E8010]) from [Rhodia Inc., c/o SciReg, 

Inc.], [12733 Director’s Loop, Woodbridge, VA 22192] proposing, pursuant to section 

408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to 

amend 40 CFR part 180.910 to establish an exemption from the requirement of a 

tolerance for [methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate (CAS No. 

1174627-68-9) and related reaction products, herein referred to as methyl 5-

(dimethylamino)-2-methyl-5-oxopentanoate, under 40 CFR 180.910 when used as an 

inert ingredient in pesticide formulations.] EPA has determined that the petition 

contains data or information regarding the elements set forth in section 408 (d)(2) of 

FDDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at 

this time or whether the data supports granting of the petition. Additional data may be 

needed before EPA rules on the petition.

A. Residue Chemistry

1. Plant metabolism.

2. Analytical method. [Rhodia is requesting that methyl 5-(dimethylamino)-2-

methyl-5-oxopentanoate be exempt from the requirement of a tolerance under 40

CFR 180.910. Therefore, Rhodia believes that an analytical method to determine 

residues in treated crops is not relevant.]

3. Magnitude of residues. [Rhodia is requesting that methyl 5-

(dimethylamino)-2-methyl-5-oxopentanoate be exempt from the requirement of a 

tolerance under 40 CFR 180.910. Therefore, Rhodia believes that data on the 

magnitude of residues in treated crops is not relevant.]
2

B. Toxicological Profile

1. Acute toxicity. [Acute Oral Toxicity

The acute oral toxicity of methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate was 

assessed in the rat in accordance with OECD Guideline No. 423 (2001) and U.S. EPA 

Guideline OPPTS 870.1100. The study was performed in compliance with the 

Principles of Good Laboratory Practice Regulations [Hungarian GLP Regulations: 

9/2001.(III.30.) EüM-FVM joint decree of the Minister of Health and the Minister of 

Agriculture and Regional Development] which corresponds to the OECD Principles 

of Good Laboratory Practice [ENV/MC/CHEM(98)17].

Two groups each of three female (W1) BR Wistar rats were treated with methyl 5-

(dimethylamino)-2-methyl-5-oxopentanoate by oral gavage administration at a dose 

of 2,000 mg/kg body weight. The test item was administered undiluted at a dose 

volume of 1.92 mL/kg. The animals were examined daily during the acclimatization 

period and mortality, viability and clinical signs were recorded. All animals were 

examined for clinical signs and mortality within the first 30 minutes and at 

approximately 1, 2, 3, 4 and 6 hours after treatment on Day 1 and once daily during 

test Days 2-15. Body weights were recorded on Day -1, Day 0 (prior to 

administration) and on Days 7 and 14. All animals were necropsied and examined 

macroscopically. 

All animals survived until the end of the study period. No clinical signs were 

observed during the course of the study. The body weight of the animals was within 

the range commonly recorded for rats of this strain and age. No macroscopic 

findings were recorded at necropsy. The median lethal dose LD50 (female rat) of 

methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate after single oral 

administration was found to be greater than 2,000 mg/kg body weight. 

Acute Dermal Toxicity

The acute dermal toxicity of methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate was 

assessed in the rat in accordance with OECD Guideline No. 402 (1987). The study was 

performed in compliance with UK GLP standards [Schedule 1, Good Laboratory 

Practice Regulations 1999 (SI 1999/3106 as amended by SI 2004/0994] which are in 

accordance with the OECD Principles of Good Laboratory Practice 

[ENV/MC/CHEM(98)17].

A group of ten Wistar (RccHan:WIST) rats (five males and five females) were given 

a single, 24 hour, semi-occluded dermal application of the undiluted test item to 

intact skin at a dose of 2,000 mg/kg body weight. Clinical signs and body weight 

development were monitored during the study. All animals were subjected to a 

gross necropsy. 
3

There were no deaths. Red/brown staining around the snout was noted in two males 

during the day of dosing. There were no other signs of systemic toxicity noted. There 

were no signs of dermal irritation. Animals showed expected gains in body weight 

over the study period except for one female which showed bodyweight loss during 

the first week but expected gain in body weight during the second week. No 

abnormalities were noted at necropsy. The acute dermal median lethal dose (LD50) 

of the test item in the Wistar strain rat was found to be greater than 2,000 mg/kg 

body weight. 

Primary Eye Irritation

The acute ocular irritation potential of methyl 5-(dimethylamino)-2-methyl-5-

oxopentanoate was assessed in the rabbit in accordance with OECD Guideline No. 

405 (2002) and U.S. EPA Guideline OPPTS 870.2400. The study was performed in 

compliance with the Principles of Good Laboratory Practice Regulations [Hungarian 

GLP Regulations 9/2001.(III.30.) EüM-FVM joint decree of the Minister of Health 

and the Minister of Agriculture and Regional Development] which corresponds to 

the OECD Principles of Good Laboratory Practice [ENV/MC/CHEM(98)17].

The test item was placed into the conjunctival sac of the left eye of each of three New 

Zealand White rabbits. The untreated right eye served as control. A volume of 0.1 

mL of the test item was administered as a single dose. The eyes were examined at 1, 

24, 48, amd 72 hours and 1 and 2 weeks after application of the test item.

Instillation of the test solution produced evidence of irritant effects in the eyes of all 

three rabbits. An Initial Pain Reaction (IPR) (score 2) was observed in all animals. 

One hour after the application, conjunctival redness (score 2) was observed in all 

animals, conjunctival chemosis (score 3) was noted in all animals, conjunctival 

discharge (score 3) was seen in all animals and corneal opacity (score 1, area 4) was 

observed in two animals. Effects were still observed at 24, 48, and 72 hours in all the 

animals with individual mean scores at 24, 48, and 72 hours after treatment as 

follows: 0.67, 0.33, 0.00 for iritis; 3.00, 2.67, 1.67 for conjunctival redness; 0.33, 1.33, 

0.67 for conjunctival chemosis; and 1.00, 1.00, 1.00 for corneal opacity.

At one week after treatment, conjunctival redness (score 1) was still present in two 

animals and corneal opacity (score 1, area 2) was observed in one rabbit. At two 

weeks after treatment, no clinical signs were observed, irritation was considered to 

be fully reversible within this period and the study was terminated. During the 

study, the control eye of each animal was symptom-free. The general state and 

behavior of animals were normal throughout the study period. There were no 

notable body weight changes during the study period. Based on the reported scores, 

the maximum mean total score (MMTS) can be calculated as 34/110 at 24-hours. 

The test substance is considered a moderate ocular irritant (modified Kay and 

Calandra interpretation of eye irritation). 

Primary Dermal Irritation
4

The acute skin irritation potential of methyl 5-(dimethylamino)-2-methyl-5-

oxopentanoate was assessed in the rabbit in accordance with OECD Guideline No. 

404 (2002) and U.S. EPA Guideline OPPTS 870.2500. The study was performed in 

compliance with the Principles of Good Laboratory Practice Regulations [Hungarian 

GLP Regulations 9/2001.(III.30.) EüM-FVM joint decree of the Minister of Health 

and the Minister of Agriculture and Regional Development] which corresponds to 

the OECD Principles of Good Laboratory Practice [ENV/MC/CHEM(98)17].

The test item was administered undiluted at a single dose of 0.5 mL to three New 

Zealand White rabbits. Gauze was placed onto the clipped skin of each rabbit, test 

item was applied to the gauze, additional gauze was placed over the test item and an 

adhesive clear plastic patch applied. The trunk was wrapped in clear plastic with 

medical tubing used to hold the patch in place. The untreated skin of each animal 

served as control. After four hours, the remaining test item was removed with water 

at body temperature. To assess skin irritation, animals were examined at 1, 24, 48 

and 72 hours after patch removal. Additional general examinations were performed 

daily.

There was no mortality and no systemic clinical changes were observed throughout 

the study. There was no effect of treatment on body weight. No clinical signs were 

noted on the skin of the treated animals at the 1, 24, 48 and 72 hours observations 

after patch removal (readings were 0 for both erythema and edema formation). As 

no clinical signs were observed up to 72 hours after patch removal, the study was 

terminated after the 72 hour observation. Based on these results, the test substance 

methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate is not considered a skin 

irritant.

Dermal Sensitization

The contact allergenic potential of methyl 5-(dimethylamino)-2-methyl-5-

oxopentanoate was assessed in the mouse in a local lymph node assay in accordance 

with OECD Guideline No. 429 (2002). The study was performed in compliance with 

the Principles of Good Laboratory Practice Regulations [Hungarian GLP 

Regulations 9/2001.(III.30.) EüM-FVM joint decree of the Minister of Health and the 

Minister of Agriculture and Regional Development] which corresponds to the OECD 

Principles of Good Laboratory Practice [ENV/MC/CHEM(98)17].

Based on the results of the preliminary compatibility test, the test item was dissolved 

in an acetone:olive oil 4:1 mixture (AOO). The maximum attainable concentration 

was 50%. The Preliminary Irritation/Toxicity Test was performed in CBA/J@Rj 

mice using two doses [test item concentrations of 50 and 25 (w/v) %] in the selected 

vehicle. The applicability and biocompatibility of the test item on the ears of animals 
5

at the maximum concentration of test item of 50% was acceptable. In the main 

assay, 20 female CBA/J@Rj mice were allocated to five groups of four animals each. 

Three groups received the appropriate formulation of methyl 5-(dimethylamino)-2-

methyl-5-oxopentanoate at concentrations of 50%, 25% and 10%, the negative 

control group received AOO and the positive control group received 25 (w/v) % αHexylcinnamaldehyde (HCA) in AOO. The test item solutions were applied on the 

dorsal surface of ears of experimental animals (25 μl/ear) for three consecutive days 

(Days 1, 2 and 3). There was no treatment on Days 4, 5 and 6. On Day 6, the cell 

proliferation in the local lymph nodes was measured by incorporation of tritiated 

methyl thymidine (3HTdR) and the values obtained were used to calculate 

stimulation indices (SI).

The animals did not show any clinical signs during the course of the study and no 

cases of mortality were observed. No local signs of irritation of the ear skin were 

detected. Stimulation Indices (S.I.) of 1.7, 1.6 and 1.2 were determined with the test 

item at concentrations of 10, 25 and 50% in AOO, respectively. The validity of the 

assay was demonstrated from the positive control substance HCA25% in AOO, with 

S.I. of 9.4. 

Based on the results of this study, the test substance methyl 5-(dimethylamino)-

2-methyl-5-oxopentanoate is not considered a skin sensitizer.]

2. Genotoxicty. [Bacterial Reverse Mutation Test

The potential of methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate to induce gene 

mutations in bacteria was assessed in accordance with OECD Guideline No. 471 

(1997) and U.S. EPA Guideline OPPTS 870.5100. The study was performed in 

compliance with the Principles of Good Laboratory Practice Regulations [Hungarian 

GLP Regulations 9/2001.(III.30.) EüM-FVM joint decree of the Minister of Health 

and the Minister of Agriculture and Regional Development] which corresponds to 

the OECD Principles of Good Laboratory Practice [ENV/MC/CHEM(98)17].

The assay was performed using Salmonella typhimurium strains TA98, TA100, 

TA1535, and TA1537, and Escherichia coli strain WP2 uvrA in two independent 

experiments in the plate incorporation test (experiment I) and the pre-incubation test 

(experiment II), both with and without liver microsomal activation at concentrations 

from 5 to 5,000 μg/plate. Each concentration, including the controls, was tested in 

triplicate.
6

The plates incubated with the test item showed normal background growth up to 

5,000 μg/plate with and without metabolic activation in both independent 

experiments. No toxic effects, evident as a reduction in the number of revertants 

(below the induction factor of 0.5), occurred in the test groups with or without 

metabolic activation. No substantial increase in revertant colony numbers of any of 

the five tester strains was observed following treatment with methyl 5-

(dimethylamino)-2-methyl-5-oxopentanoate at any dose level, either in the presence

or absence of metabolic activation (S9 mix). There was also no tendency of higher 

mutation rates with increasing concentrations in the range below the generally 

acknowledged border of biological relevance. Appropriate reference mutagens were 

used as positive controls and showed a distinct increase of induced revertant 

colonies. 

Under the experimental conditions of this study, the test item did not induce gene 

mutations by base pair changes or frameshifts in the genome of the strains used. 

Methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate is therefore considered to be 

non-mutagenic in this Salmonella typhimurium and Escherichia coli reverse mutation 

assay.

In Vitro Mammalian Cell Gene Mutation Test

The potential of methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate to induce 

gene mutations at the HPRT locus in V79 cells of the Chinese hamster in vitro was 

assessed in accordance with OECD Guideline No. 476 (1998). The study was 

performed in compliance with the OECD Principles of Good Laboratory Practice as 

revised in 1997 [C(97)186/Final].

The assay was performed in two independent experiments. The cells were exposed 

to the test item for four hours in the first experiment with and without metabolic 

activation. The second experiment was performed with a treatment time of four 

hours with and 24 hours without metabolic activation. The highest concentration of 

the test item was equal to a molar concentration of about 10 mM. The tested 

concentrations were from 17.3 to 2,220 μg/mL.

No substantial and reproducible dose dependent increase of the mutation frequency 

was observed in either main experiment. Appropriate reference mutagens, used as 

positive controls, induced a distinct increase in mutant colonies and, thus showed 

the sensitivity of the test system and the activity of the metabolic activation system. 

Under the experimental conditions reported, methyl 5-(dimethylamino)-2-methyl-5-

oxopentanoate did not induce gene mutations at the HPRT locus in V79 cells.

In Vitro Mammalian Chromosome Aberration Test
7

The potential of methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate to induce 

structural chromosomal aberrations in human lymphocytes in vitro was assessed in 

accordance with OECD Guideline No. 473 (1997). The study was performed in 

compliance with the OECD Principles of Good Laboratory Practice as revised in 

1997 [C(97)186/Final].

The test item, methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate, dissolved in 

deionized water, was examined in two independent experiments. In each 

experimental group, two parallel cultures were analyzed. Per culture, 100 

metaphases were scored for structural chromosomal aberrations. The highest 

applied concentration in this study (2,220 μg/mL of the test item, approximately 10 

mM) was chosen with regard to the molecular weight and the purity of the test item 

and with respect to the current OECD Guideline. Dose selection of the cytogenetic 

experiment was performed considering the toxicity data. The treatment 

concentrations were from 14.4 to 2,220 μg/mL.

In the absence and presence of S9 mix, no cytotoxicity was observed up to the 

highest applied concentration. In both independent experiments, neither a 

statistically significant nor a biologically relevant increase in the number of cells 

carrying structural chromosomal aberrations was observed after treatment with the 

test item. No evidence of an increase in polyploid metaphases was noticed after 

treatment with the test item as compared to the control cultures. Appropriate 

mutagens were used as positive controls. These induced statistically significant 

increases (p < 0.05) in cells with structural chromosome aberrations.

Under the experimental conditions reported, the test item did not induce structural 

chromosomal aberrations in human lymphocytes in vitro. Therefore, methyl 5-

(dimethylamino)-2-methyl-5-oxopentanoate is considered to be non-clastogenic in 

this chromosome aberration test, when tested up to the highest required 

concentration.

In vivo Mammalian Erythrocyte Micronucleus Test

The potential of methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate to produce 

damage to chromosomes or aneuploidy was investigated according to OECD 

Guideline 474 (1997). The study was performed in compliance with UK GLP 

standards [Schedule 1, Good Laboratory Practice Regulations 1999 (SI 1999/3106 as 

amended by SI 2004/0994] which are in accordance with the OECD Principles of 

Good Laboratory Practice [ENV/MC/CHEM(98)17].

The micronucleus test was conducted using the intraperitoneal route in groups of 

seven mice (males) at the maximum tolerated dose (MTD) of 2,000 mg/kg and with 

1,000 and 500 mg/kg as the two lower dose levels. Animals were killed 24 or 48 

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

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

presence of micronuclei. Additional groups of mice were given a single 
8

intraperitoneal dose of distilled water (seven male mice) or dosed orally with 

cyclophosphamide (five male mice), to serve as vehicle and positive controls, 

respectively. Vehicle and positive control animals were killed after 24 hours.

There were no premature deaths seen in any of the dose groups in the main test. 

Clinical signs consisting of hunched posture, ptosis and ataxia were observed in 

animals dosed with the test item at and above 1,000 mg/kg in both the 24 and 48-

hour dose groups Animals dosed at 2,000 mg/kg in both the 24 and 48-hour dose 

groups exhibited decreased respiratory rate, labored respiration and loss of righting 

reflex up to 10 minutes after dosing. The observation of the clinical signs was taken 

to indicate that systemic absorption had occurred and exposure to the target tissue 

had been achieved. No statistically significant decreases in the PCE/NCE ratio were 

observed in any of the test item dose groups when compared to the vehicle control 

group. There were no statistically significant increases in the frequency of 

micronucleated PCE in any test item dose groups. The positive control group 

showed a marked increase in the incidence of micronucleated polychromatic 

erythrocytes hence confirming the sensitivity of the system to the known mutagenic 

activity of cyclophosphamide under the conditions of the test. 

Methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate was considered to be nongenotoxic under the conditions of the test.]

3. Reproductive and developmental toxicity. [Combined Repeat Dose Toxicity 

with Reproduction/Developmental Toxicity Screening Test 

The systemic toxicity and potential adverse effects of methyl 5-(dimethylamino)-2-

methyl-5-oxopentanoate on reproduction including offspring development was 

investigated in accordance with OECD Guideline 422 (1996). The study was 

performed in compliance with UK GLP standards [Schedule 1, Good Laboratory 

Practice Regulations 1999 (SI 1999/3106 as amended by SI 2004/0994] which are in 

accordance with the OECD Principles of Good Laboratory Practice 

[ENV/MC/CHEM(98)17].

The test item was administered by oral gavage to three groups, each of ten male and 

ten female Wistar HanTM:RccHanTM:WIST strain rats, for up to eight weeks 

(including a two week maturation phase, pairing, gestation and early lactation for 

females), at dose levels of 30, 300 and 1,000 mg/kg bw/day. A control group of ten 

males and ten females was dosed with vehicle alone (distilled water). Clinical signs, 

behavioral assessments, body weight change, food and water consumption were 

monitored during the study. Pairing of animals within each dose group was 

undertaken on a one male:one female basis within each treatment group on Day 15 

of the study, with females subsequently being allowed to litter and rear their 

offspring to Day 5 of lactation. During the lactation phase, daily clinical 

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

offspring weights and assessment of surface righting reflex. Extensive functional 

observations were performed on five selected males from each dose group after the 
9

completion of the mating phase, and for five selected parental females from each 

dose group on Day 4 post partum. Hematology and blood chemistry were evaluated 

prior to termination on five selected males and females from each dose group. Adult 

males were terminated on Day 43, followed by the termination of all females and 

offspring on Day 5 post partum. All animals were subjected to a gross necropsy 

examination and histopathological evaluation of selected tissues was performed.

There were no deaths during the study. Clinical findings were confined to transient 

episodes of increased salivation in one 300 mg/kg bw/day male on Day 17 and 

among animals of either sex at 1,000 mg/kg bw/day between Days 30 and 46. There 

were no treatment-related changes in the behavioral parameters measured, 

functional performance or sensory reactivity. Weight development in all test 

animals was comparable to that of the controls throughout the treatment period. No 

adverse effects on food consumption, food efficiency or water consumption were 

detected in test animals in comparison with controls.

There was no evidence of treatment-related changes in the hematological 

parameters measured and no convincing treatment-related adverse effects identified 

for the biochemistry profile. There were no macroscopic abnormalities detected. An 

increase (p < 0.01) in absolute and relative liver weight was identified in 1,000 mg/kg 

bw/day males. Females at this dose level showed an increase (p < 0.05) in absolute 

and relative kidney weight in comparison with controls. Individual values all fell 

within the historical ranges for rats of the age and strain used. Treatment related 

microscopic findings were confined to minimal to slight centrilobular hepatocyte 

hypertrophy in four out of five males receiving 1,000 mg/kg bw/day. None of these 

changes were considered to be toxicologically significant, therefore the NOAEL for 

systemic toxicity was considered to be 1,000 mg/kg bw/day. No treatment-related 

systemic toxicity was detected in either sex at 30 and 300 mg/kg bw/day, therefore 

the NOEL for systemic toxicity was considered to be 300 mg/kg bw/day.

There were no treatment-related effects on mating, conception rate or gestational 

length in animals of either sex treated with 30, 300 or 1,000 mg/kg bw/day. Of the 

litters born, litter size at birth and subsequently on Day 1 and Day 4 post partum, as 

well as, offspring body weight gain and litter weights were comparable to controls. 

No adverse effects were detected in surface righting reflex on Day 1. No effect on the 

reproductive organs of parental animals was detected during post mortem or 

histopathological assessments. There was no evidence of any developmental effects 

observed in offspring from treated litters. The NOEL for reproductive toxicity was 

therefore considered to be 1,000 mg/kg bw/day.]

4. Subchronic toxicity. [Combined Repeat Dose Toxicity with 

Reproduction/Developmental Toxicity Screening Test 

The systemic toxicity and potential adverse effects of methyl 5-(dimethylamino)-2-

methyl-5-oxopentanoate on reproduction including offspring development was 

investigated in accordance with OECD Guideline 422 (1996). The study was 
10

performed in compliance with UK GLP standards [Schedule 1, Good Laboratory 

Practice Regulations 1999 (SI 1999/3106 as amended by SI 2004/0994] which are in 

accordance with the OECD Principles of Good Laboratory Practice 

[ENV/MC/CHEM(98)17].

The test item was administered by oral gavage to three groups, each of ten male and 

ten female Wistar HanTM:RccHanTM:WIST strain rats, for up to eight weeks 

(including a two week maturation phase, pairing, gestation and early lactation for 

females), at dose levels of 30, 300 and 1,000 mg/kg bw/day. A control group of ten 

males and ten females was dosed with vehicle alone (distilled water). Clinical signs, 

behavioral assessments, body weight change, food and water consumption were 

monitored during the study. Pairing of animals within each dose group was 

undertaken on a one male:one female basis within each treatment group on Day 15 

of the study, with females subsequently being allowed to litter and rear their 

offspring to Day 5 of lactation. During the lactation phase, daily clinical 

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

offspring weights and assessment of surface righting reflex. Extensive functional 

observations were performed on five selected males from each dose group after the 

completion of the mating phase, and for five selected parental females from each 

dose group on Day 4 post partum. Hematology and blood chemistry were evaluated 

prior to termination on five selected males and females from each dose group. Adult 

males were terminated on Day 43, followed by the termination of all females and 

offspring on Day 5 post partum. All animals were subjected to a gross necropsy 

examination and histopathological evaluation of selected tissues was performed.

There were no deaths during the study. Clinical findings were confined to transient 

episodes of increased salivation in one 300 mg/kg bw/day male on Day 17 and 

among animals of either sex at 1,000 mg/kg bw/day between Days 30 and 46. There 

were no treatment-related changes in the behavioral parameters measured, 

functional performance or sensory reactivity. Weight development in all test 

animals was comparable to that of the controls throughout the treatment period. No 

adverse effects on food consumption, food efficiency or water consumption were 

detected in test animals in comparison with controls.

There was no evidence of treatment-related changes in the hematological 

parameters measured and no convincing treatment-related adverse effects identified 

for the biochemistry profile. There were no macroscopic abnormalities detected. An 

increase (p < 0.01) in absolute and relative liver weight was identified in 1,000 mg/kg 

bw/day males. Females at this dose level showed an increase (p < 0.05) in absolute 

and relative kidney weight in comparison with controls. Individual values all fell 

within the historical ranges for rats of the age and strain used. Treatment related 

microscopic findings were confined to minimal to slight centrilobular hepatocyte 

hypertrophy in four out of five males receiving 1,000 mg/kg bw/day. None of these 

changes were considered to be toxicologically significant, therefore the NOAEL for 

systemic toxicity was considered to be 1,000 mg/kg bw/day. No treatment-related 
11

systemic toxicity was detected in either sex at 30 and 300 mg/kg bw/day, therefore 

the NOEL for systemic toxicity was considered to be 300 mg/kg bw/day.

There were no treatment-related effects on mating, conception rate or gestational 

length in animals of either sex treated with 30, 300 or 1,000 mg/kg bw/day. Of the 

litters born, litter size at birth and subsequently on Day 1 and Day 4 post partum, as 

well as, offspring body weight gain and litter weights were comparable to controls. 

No adverse effects were detected in surface righting reflex on Day 1. No effect on the 

reproductive organs of parental animals was detected during post mortem or

histopathological assessments. There was no evidence of any developmental effects 

observed in offspring from treated litters. The NOEL for reproductive toxicity was 

therefore considered to be 1,000 mg/kg bw/day.]

5. Chronic toxicity. [No experimental carcinogenicity study is available on 

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

methyl-5-oxopentanoate was assessed using the knowledge-based expert system 

DEREK for Windows (software version DfW 9.0.0,14_08_2006). The expert system 

DEREK has been designed for the qualitative prediction of the possible toxicity of 

chemicals and the following endpoints were searched for this structure: 

carcinogenicity, genotoxicity, HERG channel inhibition, irritation, respiratory 

sensitization, skin sensitization, thyroid toxicity, and miscellaneous endpoints. The 

toxicity assessments are based on the presence of specific substructures. The ester 

amide structure of methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate triggered 

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

“Plausible” [Structural alert 048: alpha-substituted propionic acid or ester; rules 47

and 243]. This prediction is associated with the methyl group being close to an ester 

link such that substituted propionic acid could be created, triggering an alert for 

gastrointestinal irritation based on the side effects documented in the knowledge 

database with propionic acid-based nonsteroidal anti-inflammatory drugs (NSAIDs) 

following administration by the oral and parenteral routes. Their irritancy is 

reported to be predominantly a consequence of physico-chemical disruption of the 

gastric intestinal mucosa. As an automatic consequence of triggering the structural 

alert for gastrointestinal irritation, the super-endpoint of carcinogenicity was also 

triggered with the same likelihood (Rule 704). 

In DEREK, the endpoint carcinogenicity can be triggered due to extrapolation from 

certain other endpoint alerts as opposed to specific, recognized, carcinogenic 

toxicophores. It is well-recognized in the scientific literature that gastrointestinal 

irritation is not necessarily relevant to predict cancer risk in humans. No other 

alerts were triggered. The other minor structures present as impurities in the 

substance (including the impurities methyl 4-(dimethylamino)-ethyl-4-oxobutanoate,

and N1,N1,N5,N5,2-pentamethylpentanediamide) did not trigger any alert in the 

DEREK model.

In the absence of significant findings in the gastrointestinal tract during 

macroscopic and histopathology examination in rats treated by oral gavage for up to 
12

eight weeks, and considering the absence of genotoxic effects in the available in vitro

and in vivo studies, the alert in the DEREK model is not considered predictive of a 

particular toxicological concern or carcinogenicity potential that would be relevant 

to the use conditions foreseen.]

6. Animal metabolism. [NA-Remove.]

7. Metabolite toxicology. [NA-Remove.]

8. Endocrine disruption. [There is no available evidence demonstrating that 

methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate is an endocrine disruptor in 

humans.]

C. Aggregate Exposure

1. Dietary exposure. [In examining aggregate exposure, section 408 of the 

Federal Food, Drug, and Cosmetic Act (FFDCA) directs EPA to consider available 

information concerning exposures from the pesticide residue in food and all other 

nonoccupational exposures, including drinking water from ground water or surface 

water and exposure through pesticide use in gardens, lawns, or buildings 

(residential and other indoor uses).

It is anticipated that methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate will be 

used as a solvent in EC formulations at a concentration no higher than 30%. Methyl 

5-(dimethylamino)-2-methyl-5-oxopentanoate is not expected to be persistent in the 

environment based on a PBT assessment of the substance. Further, methyl 5-

(dimethylamino)-2-methyl-5-oxopentanoate has a low toxicity profile as 

demonstrated through acute, subchronic, developmental, and mutagenicity testing. 

Therefore, dietary exposure to methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate

should not be of concern.

Methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate will not be applied directly to 

water. Agricultural practices minimize spray drift and typical end-use product 

labels prohibit direct application to water. Methyl 5-(dimethylamino)-2-methyl-5-

oxopentanoate is inherently biodegradable and is not expected to be persistent in the 

environment. Therefore, methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate as a 

solvent in EC formulations does not pose a risk to drinking water.

Overall, methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate is considered to be a 

low toxicity substance with a reasonable certainty of no harm from dietary exposure 

and all other nonoccupational sources of exposure.]

i. Food. [NA-Remove.]

ii. Drinking water. [NA-Remove.]
13

2. Non-dietary exposure. [NA-Remove.]

D. Cumulative Effects

[Section 408(b)(2)(D)(v) of the FFDCA requires that, when considering 

whether to establish, modify, or revoke a tolerance, the Agency consider “available 

information” concerning the cumulative effects of the particular pesticide’s residues 

and “other substances that have a common mechanism of toxicity.”

Rhodia has not found methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate to share 

a common mechanism of toxicity with any other substances, and methyl 5-

(dimethylamino)-2-methyl-5-oxopentanoate does not appear to produce a toxic 

metabolite produced by other substances. 

Resultant risks, separately and/or combined with other substances that may have a 

common mechanism of toxicity, should be low for methyl 5-(dimethylamino)-2-

methyl-5-oxopentanoate. Rhodia does not expect any adverse cumulative effects 

associated with the use of methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate.]

E. Safety Determination

1. U.S. population. [Methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate

exhibits a low toxicity profile, as demonstrated by the acute, subchronic, 

carcinogenicity, reproductive, and developmental studies summarized above. 

Further, methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate was not mutagenic in 

in vitro and in vivo studies. When methyl 5-(dimethylamino)-2-methyl-5-

oxopentanoate is used on raw agricultural commodities in accordance with good 

agricultural practice, it is expected to meet the reasonable certainty of no harm 

requirement. Based on the low toxicity profile of methyl 5-(dimethylamino)-2-

methyl-5-oxopentanoate, there is no reason to believe that adverse effects on the 

U.S. population will result from the use of this inert ingredient in pesticide 

formulations. In addition, there is no reason to believe that infants and children will 

be disproportionately at risk to the use of methyl 5-(dimethylamino)-2-methyl-5-

oxopentanoate in pesticide formulations.]

2. Infants and children. [NA-Remove.]

F. International Tolerances

[There are no known U.S. or international tolerances or tolerance 

exemptions for methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate.]