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 To lerance When Used as an Ine rt Ingredient in Pesticide Formulations.

PC Code: 800664; CAS Reg. No: 1174627-68-9 ; Petition No. 2 E8010 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 ora l or dermal routs of exposure. LD 5 

### o va l ues 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 t reatment 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 Bac terial Reverse Mutation Assay with

Page 1 of I8Page 2 of 18 Salmonella typhimurium concluded Methyl

- 5 did not induce mutagenic activity. A Gene Mutation Assay with Chinese hamster cells showed no re producible 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 metaphase s 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 non

mutage nic. 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 Der ek 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 neurot oxic 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 toxici ty. 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 an d 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 do es not have a common mechanism of toxicity with other su bstances.

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 e xposure to residues of the Methyl 5

- (dimethyl amino)

- 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 (CASR N 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 pr oduct 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 solven t 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 C 9 H 17 NO 3 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/cm 3 at 20o C Vapor Pressure <0.01 Pa at 20o C Partition Coefficient (usually the Log P or Kow) Log K OW 0.39 (extrapolated)
Water Solubility Totally miscible 3

- 40o C >490 g/L at 24o C Adsorption Coefficient K OC <17.8 Log K OC <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 OPage 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. LD 50 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 tr eatment related effects on gestation, litter size, litter growth and development as compared to controls. There w as no systemic toxicity. The NOAEL for systemic toxicity was considered to be 1000 mg/kg bw/day. A Bacterial Reverse Mutation Assay with Sal monella 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 V itro 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 signifi cant decreases in the PCE/NCE ratio therefore Methyl

- 5 is considered to be negative for genotoxicity. Methyl

- 5 is considered non

mutagenic. 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 immu notoxicity 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 LD 50 > 2000 mg/kg IV
81

- 2 Acute Dermal

- rat 48784216 LD 50 > 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 w ere 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 LD 50 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. 4 40/2008. 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. T here 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 fi rst 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 o f 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 th e 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 ad ministered 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 remain ing 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 clini cal signs (i.e., erythema or oedema) were observed o n 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 A ssay
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) hexylcinnamal dehyde ( 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 cont rol, 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 4878 4219)

.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 tryptophan

requiring auxotroph strain of Esc herichia coli strain WP2 uvrA in the presence and absence of a post mitochondrial supernatant (S9) fraction prepared from rat livers of phenobarbital/β

naphthoflavone

- 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 i n 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 se cond 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. M ethyl

- 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 stati stically 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 maxim um 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 nor mochromatic (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 se e n 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 i n 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 statistical ly 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 syste m. 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 D EREK 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 “Plausib le”. 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 persi stent) even following acute exposure and the lack of mutagenicity the alert in the DEREK model for Methyl

- 5 is not considered predictivePage 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 (inclu ding 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 wer e 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 gr owth 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 relat ive 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 strai n 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.

Treat ment

- 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 hepatoc yte enlargement in males at the highest dose. These changes however, were not considered to be of toxicologicalPage 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 wa s 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 gen eral . 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 t o infants and children. The available toxicity studies suggest low toxicity of Methyl 5

- (dimethylamino)

- 2

- methyl

5

- oxopentanoate. The toxicity database for Methyl 5

- (dimethylamino)

- 2

- methyl

- 5

- oxopentanoate contains acute oral
, dermal
, and inhalation toxic ity studies; skin, eye, andPage 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 conce rn, 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 oc cur 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 contac t 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

- (dimethyl amino)

- 2

- methyl

- 5

- oxopentanoate was seen in the toxicity databases. Therefore, acute dietary risk assessments for Methyl 5

- (dimethyl amino)

- 2

- m ethyl

- 5

- oxopentanoate is not required.

ii. Chronic exposure

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

- (dimethyl amino)

- 2

- methyl

- 5

- oxopentanoate because no toxicological endpoint of concern was identified for chronic dietary exposure. The available stud ies/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 exp osure (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

o utdoor 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 (non

occupational) 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

- (dimethyl amino)

- 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

- (dimethyl amino)

- 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 exposu re assumptions described above , EPA has concluded that the combined sho rt

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

. Residential Postapplication Exposure

Assessments of Residential Post

- application exposure are not necess ary since there are no toxicological endpoints of concern at doses less than 1,000 mg/kg bw/day, the limit testing dose.

VIII. A GGREGATE 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 r isk 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 c oncern.

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 “ava ilable 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 Methyl

5 do es 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 fla sk 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 sou rces: 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 contr ol containing inoculum and the reference item sodium benzoate; an abiotic sterile control containing sterilizing agent CuSO 4 , Methyl

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

- 5 and sodium benzoate were tested concurrently to mon itor 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 Met hyl

- 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 activit y 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 c onsidered 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 a nalysis, 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 X I

. 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 a uthors 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 LC 50 value > 100 mg/L. 96 hr LC 0 (NOEC) 100 mg/L 96 h r LOEC >100 mg/L 96 hrLC 100 >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 mag na 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 co ntained twenty Daphnia . Each vessel contained approximately 40 ml test solution. In this test the results were: 24hr EC 50 value >100.0 mg/L 48hr EC 50 value >100.0 mg/L 48hr EC 0 (NOEC) 100.0 mg/L 48hr LOEC >100.0 mg/L 48hr EC 100 >100.0 mg/L Results we re 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. Sign ificant 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 10 4 cells/mL. The results were: 72hr E b C 50 (bio mass) >100.0 mg/L 72hr E r C 50 (growth rate) >100.0 mg/L 72hr E y C 50 (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 solut ion 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 r eference material, 3,5dichlorophenol. The results were that exposure to Methyl

- 5 indicate a 3 hour EC 50 of > 1000 mg/L. The No Observed EffectPage 15 of 18 Concentration (NOEC) after 3 hours was 1000 mg/L. The 3 hour EC 50 of the reference material as 6.9 mg/L. Stat istical analyses were considered unnecessary (MRID 48784214).

XI I

. 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

- (dimethyl amino)

- 2

- m ethyl

- 5

- oxopentanoate when used as an inert ingredient in pesticide formulations under 40 CFR 180. 910

.

XII I . 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 pes ticide 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 Individual s (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 softwar e 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 intentiona lly exposed to a pesticide.

XV

. I NTERNATIONAL 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) hasPage 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 rout s of exposure. LD 50 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 (th e 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 Mi cronucleus 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 non

mutagenic. There are no known data that directly suggest that Meth yl 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

- me thyl

- 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 sig ns 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 intermed iate 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 do es not have a common mechanism of toxicity with other substances.

Based on the lack of tox icological 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

- (dimethyl amino)

- 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 10 59 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 Guidelin e 870.5395. Rhodia Inc., CN 7500 8 Cedar Brook Dr. Cranbury, NJ 08512; MRID 48784224.

Clarke, N. Rhodiasolv Polarcl ean: 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 Propert ies. 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 83 5.3200

. 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 750 0 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.

Travas zi, 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:S7 958 :PY1:(703)305

- 5533: IIA B:7505P