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

OF FICE OF CHEMICAL SAFETY

AND POLLUTION PREVENTION

December 16 , 2013

MEMORANDUM

SUBJECT: Petition IN

- 10520 ; Dimethyl esters of glutaric acid, succinic acid, and adipic acid ; Human Health Risk Assessment and Ecological Effects Assessment to Support Proposed Exemption from the Requirement of a Tolerance When Used as Inert Ingredients in Pesticide Formulations

.

All PC Code: Dimethyl Glutarate : 800696 Dimethyl Succinate : 877809 Dimethyl Adipate : 800095 DP Barcode: 009295288

Regulatory Action: Inert Tolerance Exemption; 40

CFR 180.910

Petition No: IN

- 10520 All CAS No : 1119

- 40

- 0,

106

- 65

- 0,

627

- 93

- 0

FROM: Deird r e Sunderland, Industrial Hygienist Inert Ingredient Assessment Branch (IIAB) Registration Division (7505P)

TO: PV Shah , Chief Inert Ingredient Assessment Branch (IIAB) Registration Division (7505P)2 Table of Contents Executive Summary.......................................................................................... ..................... 3

1.0 Background.........

.................................................................................... ....................... 6

2.0 Inert Ingredient Profile................................................................................. ...................... 6

2.1 Summary of Uses....................................................................................... ..................... 6 2.2 Physical and Chemical Properties..................................................................... .................... 7

2.3 Metabolis m and Pharmacokinetics..................................................................

.................. ... 9

3.0 Hazard Assessment..................................................................

......................................... 9

3.1 Summary of Toxicity Data...........................................................................

...................... 9 3.2 Toxicity Profile..........................................................................................

.................... 9

3.2.1 A cute Toxicity.......................................................................................

.................... 9 3.2.2 Dermal Absorption

... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... .. 12 3.2.3 Subchronic Toxicity.................................................................................

... ... ... ... ... ... 13 3.2.4 Reproductive and Developmental Toxicity......................................................

... ... ... ... ... ... 18 3.2.5 Neurotoxicity..........................................................................

.......... ... ... ... ... ... ... ... ... 21 3.2.6 Mutagenicity.......................................................................................

... ... ... ... ... ... ... 22 3.2.7 Carcinogenic Potential..............................................................................

... ... ... ... ... ... 22 3.3 Endpoint Selection and Levels of Concern......................................................

... ... ... ... ... ... ... . . 22 3.4 FQPA Safety Factor Considerations..................................................................

... ... ... ... ... ... 23

4.0 Ex posure Assessment..............................................................................

... ... ... ... ... ... ... ... . 24

4.1 Dietary Exposure.................................................................................

... ... ... ... ... ... ... ... . . 24

4.1.1 Acute Exposure..............................................................................

... ... ... ... ... ... ... ... .. . 24 4.1.2 Chronic Exposure...........................................................................

... ... ... ... ... ... ... ... ... 2 4

4.1.3 Cancer.......................................................................................

... ... ... ... ... ... ... ... ... . 26

4.2 Residential Exposure...........................................................................

... ... ... ... ... ... ... ... ... 2 6 4.3 Occupational Exposure........................................................................

... ... ... ... ... ... ... ... ... 27

5.0 Aggregate Risk and Determination of Safety.........................................................

... ... ... ... ... ... 27 5.1 Acute Dietary Risk.................................................................................

... ... ... ... ... ... ... ... . 27 5.2 Chronic Dietary Risk....................................

............................................. ... ... ... ... ... ... ... . 28 5.3 Cancer Risk for U.S. Population..................................................................

... ... ... ... ... ... ... ... 28

5.4 Short

- term/Intermediate Aggregate Risk............................................................

... ... ... ... ... ... .. 28

6.0 Cumulative Risk....................................................................................

... ... ... ... ... ... ... ... . 28

7.0 Environmental Fate..............................................................................

... ... ... ... ... ... ... ... ... 29

8.0 Ecologica l Effects.................................................................................

... ... ... ... ... ... ... ... .. 29 8.1 Acute Fish Toxicity..............................................................................

... ... ... ... ... ... ... ... .. . 29 8.2 Acute Invertebrate Toxicity.....................................................................

... ... ... ... ... ... ... ... .. 30 8.3 Acute Algal Toxicity..............................................................................

... ... ... ... ... ... ... ... . 30

9.0 Risk Characterization..............................................................................

... ... ... ... ... ... ... ... . 313 E XECUTIVE SUMMARY

On October 11, 2012, SciReg, Inc., on behalf of Rhodia Inc., submitted a petition to the Environmental Protection Agency, herein referred to as the agency or EPA, to amend 40 CFR 180.910 by establishing an exemption from the requiremen t of a tolerance for the use of the inert ingredients dimethyl esters of glutaric acid (i.e., dimethyl glutarate (DMG) , CAS Reg. No. 1119

- 40

- 0), succinic acid (i.e., dimethyl

succinate (DMG) , CAS Reg. No. 106

- 65

- 0), and adipic acid (i.e., dimethyl adipate (DMA)

, CAS Reg.

No. 627

- 93

- 0) ( collectively referred to as DMEGSA for ease of reading ) for use as solvents/co

- solvents in pesticide formulations applied to growing crops and raw agricultural commodities after harvest.

These three discrete compounds are s hort, straight

- chain dicarboxylic acid dimethyl esters differing by one carbon atom, from four to six carbons, in the dicarboxylic acid moiety. They are used as solvents, plasticizers, polymer intermediates, and as components in paint strippers, polishes, and lacquer thinne rs. A mixture of the three , known as dibasic esters (DBE) represented by CAS Reg. No. 95481

- 62

- 2

, is also approved for use as inert ingredients under 40 CFR 180.1277. DMEGSA are similar in structure, physicochemical properties and toxici ty responses among the category members. The three category members ( i.e., DMG, DMS, and DMA) and a mixture of the three (e.g., DBE) produce similar levels of acute and repeated

- dose toxicity in experimental animals, such that information on one category m ember is expected to represent the toxicity of the category as a whole.

DMEGSA is hydrolyzed to its corresponding monomethyl esters and subsequent dicarboxylic acid metabolites (i.e., adipic, glutaric, and succinic acid) by car bo x y l e st e ra s e s. Based on the expected similarity in toxicity and fate, this risk assessment relies upon available data for DBE, DMG, DMA, and DMS. In addition, the toxicological properties of their metabolites were also considered (qualitatively) and presented here to address potenti al exposure via the oral route.

A c ute to x i c i t y studi e s c ondu c t e d with DMEGSA d e monst ra t e low acute oral and dermal toxicity.

DME GSA showed minimal eye irritation, no dermal irritatio n, and no dermal sensitization. In addition

to a 14

- day dermal study, two oral rat stu dies have been conducted on DBE

- a 14

- day and a one month study. Animals in the 14

- day study showed reduced weight gain and food consumption at 1,684 mg/kg/day but showed no adverse effect at 842 mg/kg/day. Animals in the one month study showed no adverse effects at the limit dose of 1,000 mg/kg/day. In the dermal study mild skin irritation was noted; however, these effects were reversible and no systemic effects were observed at any dose tested up to the limit dose of 1,000 mg/kg/day.

Oral st udies on the metabolites were also used to support a safety finding for DMEGSA. Available repeat dose oral studies on the metabolites include a 13

- week study on succinic acid, two 90

- day studies on glutaric acid and a two year study on adipic acid. Succini c acid was shown to cause decreased body weight gain in rats at and above 2,500 mg/kg/day. Glutaric acid also caused a decrease in body weight gain in both rats and dogs at 1,000 and 750 mg/kg/day, respectively. Similarly, adipic acid was seen to

cause dec reased body weight gain and food consumption in rats at 2,250 mg/kg/day. The results of these studies indicate that the metabolites of DMEGSA are of low toxicity via the oral route of

exposure.

The majority of the repeat dose studies conducted on DBE an d/or DMEGSA are via the inhalation route of exposure. The available database includes three 90

- day inhalation studies. In the first study dose4 dependant degeneration of the olfactory epithelium was observed at and above 0.05 mg/L. Exposed

animals also show ed microscopic alterations in the liver (males) and lung (females) and hormonal changes in both sex. The significance of these findings is unclear because the decrease in male hormone levels should result in a decrease in sperm counts, yet the opposite eff ect was observed. The single study showing changes in estradiol was not observed in the other two studies. Furthermore, there were no functional parameters such as estrous cycle and sperm motility or morphology affected. A reproductive study was conducted with DBE and there were no effects on fertility, viability of pups at birth, and the ability of the mothers to lactate.

Two other 90

- day rat studies tested DBE and again, degeneration of the olfactory epithelium was noted at all doses tested (0.02

- 1.0 mg/ L). In both studies decreases in liver weight were observed but no histopathological findings were evident. At high doses slight increases in relative heart and testes weights in males and a slight decrease in absolute spleen weight in females were observe d. These slight organ weight changes were not accompanied by any histopathological changes and are therefore

, considered to be of minimal biological significance. No other significant effects were observed.

Like much of the repeat dose testing, inhalatio n was also the ro ute of exposure used in the reproductive and developmental studies. Depressed pup weights were observed in a on e

- g e n era tion r e p r o d u c tion

inh a l a tion toxi c i t y stu d y with D B E at 1.0 mg/L but were only seen in the presence of maternal toxicity

. In two developmental inhalation studies no developmental effects were observed. Similarly, no adverse developmental effects were observed in oral studies on the metabolites glutaric acid and adipic acid at doses up to and including 1,300 mg/kg/day.

Repe at dose inhalation studies have demonstrated the chemicals potential to affect the olfactory mucosa in the nasal passage of rats. T h ese local e f f

e c ts ar e believed to b e re l a t ed to the h y d r o l y sis of DMEGSA

b y car bo x y l e st e ra s e s lo c a t e d in the n a s a l/ol fac to r y e pith e lium to the ir di c a r bo x y l i c a c id m e t a bolit e s. T h e

e f

f

e c ts on the ol f ac to r y e pith e lium ar e e x p ec t e d t o be of mu c h low e r imp a c t in hum a ns due to m a jor

p h y si o l o g i ca l d i f f

ere n ce s b etw ee n r a ts an d hu m a n s.

No n e u r op a tholo g i ca l c h a n g e s o r e f fe c ts on t he f un c tion a l obs er v a tion b a tt e r y p ara m e t er s w er e re p o r t e d in any of the studies. The agency does not believe DMEGSA will be neurotoxic. Based on study results

DMEGSA is n ot expected to be mutagenic or g enotoxic. C h r oni c / carc in o g e ni c i t y studi e s c ould not be

id e nti f i e d f or DMEGSA. A DE R EK e v a lu a tion f or DMG a nd D M S w a s c ondu c t e d a nd did not show a n y

s p ec i a l a l er ts. I n a dd i ti on
, carcinogenicity stu d ies were c ondu c t e d with a dipic a c id and monosodium

succinate in ra ts and no carc in o g e n i c e f f

e c ts w er e obs er v e d. Ther efore, the agency does not expect DMEGSA to be carcinogenic in humans.

Repeated exposures to DMEGSA via inhalation show local effects (likely a result of irritation at the point of contact in the nasal region) as well as some changes in hormone levels t hat, although consistently observed, are not considered to be toxicologically significant. The point of departure for the risk assessment for chronic oral routes of exposure was from the 14

- day oral toxicity study in rats. The

no observed adverse effect le vel ( NOAEL ) was 842 mg/kg/day and the lowest observed adverse effect

level ( LOAEL ) was 1684 mg/kg/day based on reduced weight gain and food consumption. A 1000 fold uncertainty fa ctor was used for chronic exposure (10X interspecies extrapolation, 10X for i ntraspecies variability and 10X FQPA safety factor )

.5 Exposure to DMEGSA will be pr imarily through the oral route from consuming food treated with pesticide products containing the chemical. EPA’s highly conservative I

- DEEM model was used to

estimate oral exposure. I

- DEEM showed the exposure from the use of this inert ingredient in pesticide formulations (including exposure through drinking water) would result in acceptable risk to all subpopulations. The most highly exposed subpopulation was children 1

- 2 years old at 83.9% of the

cPAD (chronic Population Adjusted Dose)

.

Residential exposure to outdoor pesticide products was evaluated using a gency approve d models to

estimate the risk of residential post

- applica tion exposure to treated lawns . All exposure s cenarios resulted in acceptable levels of risk to all subpopulations evaluated. Exposure to DMEGSA inert ingredients via paint, residential antimicrobials, and pet products were not evaluated in this risk

assessment. When oral residential and dietary expos ures were combined exposure did not exceed the acceptable level of risk.

Similarly, occupational exposure would be expected via the dermal and inhalation routes of exposure; however, because no endpoints of concern were identified for these routes of exp osure, a qualitative occupational assessment was conducted.

Based on ecological (i.e., fish, invertebrates, and algae) and fate studies the agency concluded that

DMEGSA does not pose an ecological risk to terrestrial or aquatic species. DMEGSA is not exp ected to persist in the environment and the potential for bioaccumulation is low.

In assessing an inert ingredient for use in pesticide products the agency takes into account all available information regarding the toxicity, fate, and use of the inert i ngredient. In the case of DMEGSA many of the studies showed olfactory effects in rats following inhalation exposure. While these effects were observed in rats, it is unlikely that the same effects will be seen in humans due to physiological and

chemical di fferences between the species. In addition, some studies showed hormonal changes which were not replicated in other studies and organ effects were most often not accompanied by histological changes. The implications of these effects are unknown but due to their use in food products and the low toxicity observed in oral and dermal studies c oupled with the expected exposure from the use of these chemicals as inert ingredients in pesticide products, EPA concludes that there is a reasonable certainty

that no ha rm will result to the general population, including infants and children, from aggregate

exposure to residues of DMEGSA when used as an inert ingredients in pesticide formulations under 40

CFR 180. 910

.6 1.0 B ACKGROUND

On October 11, 2012, SciReg, Inc., on behalf of Rhodia Inc., submitted a petition to the Environmental Protection Agency, herein referred to as the agency or EPA, to amend 40 CFR 180.910 by establishing an exemption from the requirement of a tolerance for the use of the inert ingredients dimethyl esters of glutaric acid (i.e., dimethyl glutarate, CAS Reg. No. 1119

- 40

- 0), succinic acid (i.e., dimethyl succinate, CAS Reg. No. 106

- 65

- 0), and adipic acid (i.e., dimethyl adipate, CAS Reg. No. 627

- 93

- 0) for use as

solvents/co

- solven ts in pesticide formulations applied to growing crops and raw agricultural

commodities after harvest.

Throughout this document various names/acronyms are used to describe dimethyl glutarate (DMG), dimethyl adipate (DMA), and dimethyl succinate (DMS). As a point of clarification, dimethyl esters of glutaric acid, succinic acid, and adipic acid (DME GSA ) is used to collectively refer to the these

individual chemicals whereas dibasic esters (DBE), CAS Reg. No. 95481

- 62

- 2

, is a chemical mixture of approximatel y 55

- 75% dimethyl glutarate, 15

- 27 % dimethyl succinate, and 10

- 25 % dim ethyl adipate

.

In 2008 the EPA published a “Screening

- Level Hazard Characterization: Dibasic Esters (DBE) Category” document that outlined EPAs determination that information on one o f the individual components of DBE or DBE itself would be representative of this group and subsequently can be used as surrogate or read across data for all members of the group:

The basis for the category is similarity in structure, physicochemical prope rties and toxicity responses among the category members. The three discrete compounds are short, straight

- chain dicarboxylic acid dimethyl esters differing by one carbon atom, from four to six carbons, in the dicarboxylic acid moiety. The three category me mbers and the mixture produce similar levels of acute and repeated

- dose toxicity in experimental animals, such that information on one category member is expected to represent the toxicity of the category as a whole.

This 2008 document also associates thi s chemical category to the metabolites of DMEGSA “...this category is related to another, similar category called the dicarboxylic acids (which consists of succinic acid, glutaric acid and adipic acid).”

Based on the expected similarity in toxicity and fate, t his risk assessment relies upon available data for
DBE, DMG, DMA, and DMS. In addition, the toxicological properties of their metabolites were also considered (qualitatively) and presented here to support the toxicological profile of DMEGSA, in particula r to address the potential exposure via the oral route.

To access the Office of Chemical Safety and Pollution Prevention ( OCSPP ) test guidelines referenced in this document electronically, please go to http://www.epa.g ov/ocspp and select “Test Methods and

Guidelines.”

2.0 INERT INGREDIENT PROFILE

2.1 Summary of Uses7 Di basic esters are used as solvents, plasticizers, polymer intermediates, and as components in paint strippers, polishes, and lacquer thinners

. In addition, dimethyl s uccinate (DMS) has been approved by

the US F ood and D rug A dministration (FDA) as a direct food additive under 21 CFR 172.515 as a synthetic flavoring agent and adjuvant. DBE is currently exempt from the requirement of tolerance as an inert ingredient under 40 CFR 180.1277 when used as a solvent and/or anti

- freeze at 10% w/w or less in microencapsulated pesticide formulations with the active ingredient cyfluthrin.

Me tabolites of DBE are naturally o ccurring dicarboxylic acids: succi nic, glutaric, and adipic acids

. Adipic acid, for example, can be found in edible plant parts such as beet, ripe fruits of Morinda citrifolia,

and rice straw. (OECD, 2006) A dipic and succinic acids are classified as Generally Recognized As Safe (GRAS) by t he U.S. Food and Drug Administ rat ion (FDA) for substances directly added to human food (21 CFR 184.1 009 and 21 CFR 582.1009

, and 21 CFR 184.1091 and 21 CFR 582.1091, respectively ).

Methanol , a metabolite of DMEGSA, is an approved food use inert ingredien t in pesticide formulations

under 40 CFR Part 180.910 and 180.920 as a solvent and 180.930 as a solvent/co

- solvent.

2.2 Physical and Chemical Properties

Some of the physical and chemical characteristics of dimethyl adipate, dimethyl glutarate

, and d imethyl

succinate along with their structure and nomenclature, are found in the tables below.

Table 1. Physical and Chemical Properties of Dimethyl Adipate

Parameter Value Reference

Structure ChemIDPlus, 2013

CAS # 627

- 93

- 0 ChemIDPlus 2013

Molecular Formula C8

- H14

- O4 ChemIDPlus 2013 Molecular Weight 174

Common Names Hexanedioc acid, dimethyl ester; dimethyl hexanedioate; adipic acid, dimethyl ester ChemIDPlus, 2013

Melting Point 8.5°C SOCMA 2002 * Boiling Point 230. 9°C SOCMA 2002 * Density 1.062 g/cm 3 SOCMA 2002 *

Vapor Pressure 0.47 Pa @ 25 oC (4 x10
- 3 mm Hg) MRID 48968810 ; OSCPP 830.7 95 0

Log K

ow 1.4 @ 22 oC MRID 48968808

, OSCPP 830.7550

Water Solubility 4.0 g/L @ 20oC MRID 48968809 ; OSCPP 830.7840

Henry' s Law Constant 2.31 x 10
- 6 atm

- m 3 /mole @ 25oC ; 9.77 x 10

- 7

atm

- m 3 /mole ChemIDPlus 2013; HSDB

2013

* Referenced in EPA’s 2008 “Decision Document for Petition #5E4442; Dibasic Esters (DBE; CAS Reg. No. 95481

- 62

- 2)”. The source of the information is the Sy nthetic Organic Chemical Manufacturers Association Dibasic Esters Group (SOCMA DBE Group) who submitted data on DBE and its components as part of the TSCA Section 4 Enforceable Consent Agreement with the EPA initiated on August 8, 1999.8 Table 2. Physic al and Chemical Properties of Dimethyl Glutarate

Parameter Value Reference

Structure ChemIDPlus 2013

CAS # 1119

- 40

- 0 ChemIDPlus 2013

Molecular Formula C7

- H12

- O4 ChemIDPlus 2013 Molecular Weight 160 SOCMA 2002 *

Common Names Dimethy l glutarate; dimethyl p entanedioate; glutaric acid , dimethyl ester; pentanedioic acid, dimethyl ester ChemIDPlus, 2013

Melting Point

- 37 °C SOCMA 2002 * Boiling Point 213.5

- 214°C SOCMA 2002 * Density 1.0876 g/cm 3 @ 20oC SOCMA 2002 *

Vapor Pressure 8 .5 Pa @ 25 oC (6.4 x10
- 2 mm Hg) MRID 48968810 ; OSCPP 830.7 95 0

Log K

ow 1.0 @ 22oC MRID 48968808 ; OSCPP 830.7550

Water Solubility 40.5 g/L @ 20oC MRID 489688 09 ; OSCPP 830.7840 Henry's Law Constant 6.43 x 10
- 7 atm

- m 3 /mole @ 25oC ChemIDPlus 20 13

* Refe renced in EPA’s 2008 “Decision Document for Petition #5E4442; Dibasic Esters (DBE; CAS Reg. No. 95481

- 62

- 2)”. The source of the information is the Synthetic Organic Chemical Manufacturers Association Dibasic Esters Group (SOCMA DBE Group) who submitted da ta on DBE and its components as part of the TSCA Section 4 Enforceable Consent Agreement with the EPA initiated on August 8, 1999.

Table 3. Physical and Chemical Properties of Dimethyl Succinate

Parameter Parameter Reference

Structure ChemIDPlus 2013

CAS # 106

- 65

- 0 ChemIDPlus 2013

Molecular Formula C6

- H10

- O4 ChemIDPlus 2013 Molecular Weight 146 SOCMA 2002 *

Common Names Dimethyl succinate; dimethyl butanedioate;

butanedioic acid , dimethyl ester ChemIDPlus 2013

Melting Point 19 °C SOCMA 2002 * Boiling Point 196°C SOCMA 2002 * Density 1.11 g/cm 3 @ 25°C SOCMA 2002*

Vapor Pressure 9.4 Pa @ 25°C (7.1 x 10
- 2 mm Hg) MRID 48968810 ; OSCPP 830.7 95 0

Log K

ow 0.6 @ 22°C MRID 48968808 ; OSCPP 830.7550

Water Solubility 26.0 g/L @ 20 o C MRID 4896880 9 ; OSCPP 830.78409 Table 3. Physical and Chemical Properties of Dimethyl Succinate

Parameter Parameter Reference

Henry's Law Constant 6.4 x 10
- 8 atm

- m 3 /mole @ 25°C ChemIDPlus 2013, HSBD

2013

* Referenced in EPA’s 2008 “Decision Document for Petition #5E4442; Dibasic Esters (DBE; CAS Reg. No. 95481

- 62

- 2)”.

The source of the informati on is the Synthetic Organic Chemical Manufacturers Association Dibasic Esters Group (SOCMA DBE Group) who submitted data on DBE and its components as part of the TSCA Section 4 Enforceable Consent Agreement with the EPA initiated on August 8, 1999.

2.3 Metabolism and Pharmacokinetics

Various studies ha ve show n that DBE undergo es carbo xylesterase

- mediated hydrolysis in rodent nasal

mucosa to form monomethyl esters (i.e., monomethyl glutarate, monomethyl succinate, and monomethyl adipate)

, and subsequently dicarboxylic acid s (i.e., glutaric acid, succinic acid, and adipic acid) and

methanol (Trela, 1991; US CPSC, 1994). M ammalian carboxylesterases are localized in the endoplasmic reticulum of ma n y tissues (e.g., liver, kidney, bra in, testis , gastrointestinal tract, etc. ), with the highest levels of activity found in the liver of many species. (M RID 48968830; 48968831) Although different areas of the body may be more efficient at metabolizing DBEs, following oral exposure, dimethyl esters a re expected to be metabolized by carboxylesterase in the body similar to those seen in

rodent nasal mucosa studies following inhalation exposure.

3.0 H AZARD ASSESSMENT

3.1 Summary of Toxic ity Data

This risk assessment relies upon av ailable data for the individual components dimethyl glutarate (DMG), dimethyl adipate (DMA), and dimethyl succinate (DMS) as well as studies on dibasic esters (DBE) under CAS Reg. No. 95481

- 62

- 2 and a mixture of DMEGSA chemicals similar in composition to D BE

. In addition, data on the dicarboxylic acids metabolites glutaric acid, succinic acid (as monosodium succinate) , and adipic acid are used to support the toxicological profile of DMEGSA. See Table 4 for a summar y of the

acu te toxicity profile, Table 5 fo r re peat dose studies (including reproductive and developmental) , and

Table 6 for studies on DMEGSA metabolites

.

3.2 Toxicity Profile

3.2.1 Acute Toxicity

Acute Oral Toxicity Sprague

- Dawley rats (5/sex/dose) were administered DMS via g avage at 500 and 5000 mg/kg and observed for 14 days. No mort alities occurred at 500 mg/kg and a ll animals died at 5000 mg/kg

. (EPA,

2008 b )

LD 50 > 500 and < 5000 mg/kg

Sprague

- Dawley rats (5/se x /dose ) were administered DMG via gavage at 5000 mg/kg and observed for 14 days. All animals survived to 14 days. (EPA

, 2008b )

LD 50 > 5000 mg/kg10 Sprague

- Dawley rats (5/sex/dose) were a dministered DMA via gavage at 500 and 5000 mg/kg and observed for 14 days. No mort alities occurred at 500 mg/kg and t wo animals died at 500 0 mg/kg

. (EPA,

2008 b )

LD 50 > 5000 mg/kg

Sprague

- Dawley Crl:CD (SD) BR rats (5/sex) were administered a single oral dose of 2,000 mg/kg of a test substance comprised of a mixture of DMG

, DMS

, and DMA (OSCPP 870.1100)

. No mortality or clinical signs were o bserved during the 14 day observation period. All animals were euthanized and necropsied at the end of the study. At necropsy, a macroscopic examination revealed no abnormalities. (MRID 48968813)

LD 50 >2,000 mg/kg

Acute Dermal Toxicity

New Zealand White rabbits (5/sex /chemical ) were administered a single dose (5000 mg/kg) of either

DMS , DMA, or DMG, applied directly to the skin for 24 hours and were observed for 14 days after removal of excess test substance. No mortalities occurred. (EPA, 2008 b )

LD 50 > 5 000 mg/kg

New Zealand White rabbits (5/sex) were administe red a single dose (5000 mg/kg) of DBE applied directly to the skin for 24 hours and were observed for 14 days after removal of excess test substance.

No mortalities occurred. (EPA, 2008 b )

LD 50 > 50 00 mg/kg

Sprague Dawley rats (5/sex) were administered a single dermal dose of 2,000 mg/kg of a test substance comprised of a mixture of DMG, DMS, and DMA applied to a clipped area skin (5 x 7 cm) for 24 hours

under a semi

- occlusive dressing (OSCPP 870.12 00)

. Examinations for mortality, clinical signs, and body weight gain were performed during the 14

- day study period. No deaths occurred and no clinical signs were observed during the observation period. All surviving animals were euthanized and necropsied at the end of the observation period . M acroscopic examination reveale d no abnormalities. (MRID 48968814)

LD 50 > 2,000 mg/kg

Acute Inhalation Toxicity

C r l:C D ra t s ( 5 / s e x /dose ) w e re ex p ose d n o se

- o n ly f o r a sin g l e 4

- h o u r p er i o d t o ae r o s o l/ v a p o r m i x t u r e s o f

DBE i n ai r a t 5.6 a n d 1 1 m g / L a n d o b se r v e d fo r 1 4 d a ys

. T r a n sie n t cli n ica l signs o b s e rv e d at

c o ncen t rations o f 5

. 6 m g /L o r greater i n clude r e d o c ular or n a sal d i scha r g e, let h a r g y
, la bo red b r e at h i n g

o r h un c hed p o s ture, a n d sli g ht to sev e r e w ei g ht l o s s . Op h t h al m o l og i c e x a m i n ati o n re v ealed m ild

c h e m o sis (swe l li ng ) in t h e bu l b ar con j u n ctiva. No m o rtalit i es o cc u rre d . (EPA, 2008 b )

L D 50 > 11 mg / L

Primary Eye Irritation

A test substance comprised of a mixture of DMG, DMS, and DMA was tested for acute ocular irrit ation by applying a single dose of 0.1 mL, into the conjunctival sac of three male New Zealand White rabbits (OSCPP 870.2400) . One eye remained untreated and served as a control. The eyes were not rinsed. Ocular examinations were performed at 1, 24, 48, an d 72 hours after instillation. The interpretation of

the results was based on Kay and C alandra’s modified scale.11 A slight corneal opac ity (score 1) was observed 24 hours after instillation in one of the three animals. No iritis was observed throughout th e observation period in any of the animals. Conjunctival redness was observed at 1 hour in all animals (score 2 or 3), and in two animals 24 hours after instillation (score 1). Chemosis (score 1 or 3) was observed in two of three animals at 1 hour after in st illation. In addition, discharge was noted at 1 hour for all animals . All effects cleared by 48 hours post ins tillation . Based on the results of this study DME is considered mildly irritating . (MRID 48968815)

According to the EPA ’s previous assessments (EPA, 2008a; EPA, 2008b ) when tested individually or in a mixture, that these chemicals cause mild to moderate eye irritation. All effects cleared by Day 7 of

observation.

Primary Dermal Irritation 1) DMA, DMG, and DMS were individually administered to N ew Zealand White rabbits (3/sex/chemical) as a single dose applied directly to two 1 x 1 inch areas of skin on the back and held in place with semi

- occlusive dressings for 4 hours. Animals were observed for subsequent 3 days and

treated areas were observed at 30 minutes and 24, 48, and 72 hours. No dermal irritation was observed for DMA, DMG, or DMS. (EPA, 2008 b )

2) A test substance comprised of a mixture of DMG, DMS, and DMA was tested for acute skin irritation

when a single dermal dose of 0.5 mL was appl ied to a clipped area of the skin (6 cm 2 ) of three male

New Zealand White rabbits for four hours (OSCPP 870.2500)

. Cutaneous examinations were performed at 1, 24, 48, and 72 hours after removal of dressing. No cutaneous reactions were observed in any of th e animals, throughout the observation period. (MRID 48968816)

The mixture was not considered a skin irritant

.

NOTE: According to the Agency’s 2008 “Decision Document for Petition #5E4442; Dibasic Esters (DBE; CAS Reg. No. 95481

- 62

- 2)”

Dermal irritation from DBE exposure varies depending on duration of exposure. For example, in the

dermal I rritation study in rabbits submitted by the petitioner (Sarver 1989), 24 hours of exposure to

DBE caused mild to moderate irritation at 24 and 48 hours post exposure. One rabbit had slight

edema and severe erythema at 72 hours, but no edema and no moderate to mild erythema were observed in the remaining rabbits. In other rabbit dermal irritation studies, four hours exposure to

DBE or its components DMA, DMG and DMS we re considered non

- irritating to rabbits (SOCMA 2002). DBE was also found to be non

- irritating to the skin of guinea pigs, however the duration of

exposure was not provided (SOCMA 2002). DBE was also not considered to be a skin

- sensitizer in guinea pigs.

Dermal Sensitization

A test substance comprised of a mixture of DMG, DMS, and DMA was assessed for dermal

sensitization in female CBA/CaOlaHsd mice, using the Local Lymph Node Assay (OSCPP 870.2600)

. A preliminary test was conducted in two mice with the selected concentrations of 10, 25, and 50% (w/v) and 100% (undiluted) to assess potential local irritation. After 24 hours, no irritating effects were observed at these concentrations following a single application. In the main assay, five treated groups o f

four animals each received the test item to the dorsum of each ear lobe for three consecutive days at12 concentrations of 5, 10, 25, or 50% (w/v) in the vehicle acetone/olive oil (4/1, v/v), or 100% (undiluted). In addition, a control group of four anim als received the vehicle alone

.

No clinical signs were observed in any animals of the control group, Group 2 (5%), Group 3 (10%) or Group 4 (25%). On the second application day, a slight to moderate ear e rythema was observed at both dosing sites in all mice of Group 5 (50%) and Group 6 (100%, undiluted), persisting for a total of two days

. (MRID 48968817 ) Based on the results of this study, the mixture was not considered to be a

dermal sensitizer

.

Table 4. Summa r y of Acute Toxicity Data Endpoint DMS DMG DMA DMA, DMG,

and DMS

Mixture Toxicity Category

Acute Oral

LD 50 (mg/kg) >500 and

<5000 >5000 >5000 > 2000 and

>5000 III

- IV

Acute Dermal

LD 50 (mg/kg) >5000 >5000 >5000 > 2000 and

>5000 III

- IV

Acute

Inhalation LD 50 (mg/L) No Data No Data No Data >11 IV

S kin Irritation (4 hour exposure) Not a skin

irritant Not a skin

irritant Not a skin

irritant Not a skin

irritant IV

Eye Irritation Mild to

moderate Mild to

moderate Moderate Mild to

moderate III

3.2.2 Dermal Absorption

An in vitro OECD 428 stud y on the individual DBE homologues, DMS, DMG, and DMA, and for the homologues in a 1:3:1 (DMS:DMG:DMA) blend examined the dermal kinetic parameters of penetration rate, lag time, and permeability coefficient (Kp) for rat ( 

### males of the Sprague

- Dawley strain

, Crl:CD®(SD)IGS 

### BR ) and human skin.

An infinite dose (150 μL) of the test solvent was applied to the epidermal surface of six skin replicates per species. Under occlusive conditions, receptor chamber effluent samples were collected hourly for each replic ate until six hours postapplication. Following application of the individual dibasic ester homologues the penetration rates for each homologue were comparable within a species and ranged from 3,131.8 to 4,542.4 μg/cm 2 /h for rat skin and from 79.5 to 113.0 μg/cm 2 /h for human skin. In contrast, when the DBE blend containing DMS, DMG, and DMA was applied to rat skin, the penetration rate for DMS (571.7 μg/cm 2 /h), DMG (1,571 μg/cm 2 /h), and DMA (507.0 μg/cm 2 /h) was slower compared to the penetration rates observ ed when the individual homologues were applied alone as a single solvent system. The permeability coefficients (Kp) were comparable for each homologue within a species and higher for rat skin compared to human skin. The Kp values for rat and human skin ran ged

from 2.12 x 10

- 3 to 4.18 x 10

- 3 cm/h and from 6.81 x 10 - 5 to 1.69 x 10 - 4 , respectively. (Fasano, 2003)13 3.2.3 Subchronic Toxicity

Table 5

. Summary of Toxicological Endpoints for DMEGSA Inert Ingredients for Use in

Human Health Risk Assessments
Study Test Substance Toxicological Effect Reference

14

- Day Oral (Rat) DBE NOAEL= 842 mg/kg/day LOAEL= 1,684 mg/kg/day; reduced weight gain and food consumption MRID 45740506

1

- Month Oral (Rat) DBE NOAEL= 1,000 mg/kg/day (Highest Dose Tested (HDT))

LOA EL not established EPA , 2008 b

14

- Day Dermal (Rat) DBE, DMA, DMG, DMS Systemic NOAEL= 1,000 mg/kg/day (HDT) Systemic LOAEL not established Kirkpatrick,

2000

90

- Day Inhalation (Rat) DMS NOAEL not established LOAEL=0.4 mg/L ; effects on nasal tissue, decreas es in estradiol concentration in females and increased epididymal sperm count in males.

Bamberg, 2000 DMG NOAEL= 0.01 mg/L LOAEL= 0.05 mg/L; effects on nasal tissue, decreased serum LH and testosterone concentrations, increased epididymal sperm counts.

DMA NOAEL not established LOAEL= 0.4 mg/L; effects on nasal tissue, increased CP in liver, lungs, and nose.

90

- Day Inhalation (Rat) DBE NOAEL not established LOAEL= 0.16 mg/L; effects on nasal tissue MRID 45740503

90

- Day Inhalation (Rat) DBE NOAEL not established LOAEL= 0.02 mg/L; effects on nasal tissue MRID 48968819

Reproductive and Developmental

Inhalation (Rat) DBE Maternal NOAEL= 0.4 mg/L Maternal LOAEL= 1 mg/L; depressed body weight Reproductive NOAEL= 0.4 mg/L Reproductive LOAEL= 1 mg/L; depres sed pup weight Developmental NOAEL= 1 mg/L (HDT) Developmental LOAEL not established MRID 48968822

Developmental

Inhalation (Rat) DMG Maternal NOAEL= 0.1 mg/L Maternal LOAEL= 0.3 mg/L; body weight gains and

clinical observations Developmental NOAEL= 1 mg/ L (HDT) Developmental LOAEL not established Munley, 2003

Developmental

Inhalation (Rat) DBE Maternal NOAEL= 0.16 mg/L Maternal LOAEL= 0.4 mg/L; food consumption and body weight gain Developmental NOAEL= 1 mg/L Developmental LOAEL not established MRID 4896 8820

O RAL

(DBE) 14

- D ay (rat) Oral

DBE was tested in a 14

- day oral toxicity study on Crl:CD male rats fed c oncentrations of 10,000, 20,000, or 50,000 ppm (~842, 1684, or 4

, 210 mg/kg/day) in the diet

. Daily weights and clinical

observations were recor d ed

. On the 14th test day, half of the rats of each test group were sacrificed. The

re maining half was maintained on the regular diet for 14

- days (recovery group). The animals in the

recovery group were weighed every other day, observed for a 14

- day recovery period, and sacrificed 1414 days later. All rats were examined grossly, selected tissues were weighed, and selected tissues and organs evaluated histologically.

No gross or microscopic pathologic changes that could be att ributed to exposure of DBE were dete cted.

No deaths were observed. No clinical signs other than initial and sporadic weight loss were seen . The rate of body weight gain was reduced in rats of the mid

- and high

- dose group s with lower food intake

also seen by these rats. During the recovery pe riod, test rats in these two groups gained slightly more weight than the controls although the high

- dose rats (4

, 210 mg/kg/day) weighed approximately 7% less at the end of the recovery period. (MRID 45740506) No observed adverse effect level (NOAEL) = 842 mg/kg/day Lowest observed adverse effect level (LOAEL) = 1684 mg/kg/day based on reduced weight gain and food consumption.

(DBE) 1 month (rat) O ral

In an oral gavage toxicity study, male and female Sprague

- Daley rats were dose d with DBE daily at 0,

100 , 300 or 1000 mg/kg /day for 1 month. Clinical observations included mortality, body weights, food consumption, and clin ic opathological measurements. Except for a small decrease in urine pH (not statistically significant) in male and fe male rats at 1000 mg/kg /day, no other systemic toxicity was

evident. (EPA , 2008 b ) NOAEL = 1000 mg/kg /day (highest dose tested)

LOAEL not established

Stud ies on metabolites (oral )

- See Table 6

(Succinic acid) 13 week (rat) Oral

In a 13

- week study, groups of male and female F344 rats were administered succinic acid (as monosodium succinate) at 0, 0.3, 0.6, 1.25, 2.5, 5 and 10% (approximately 0, 300, 600, 1250, 2500, 5000 and 10,000 mg/kg/day) in their drinking water. All animals in the 10% group were severely

emaciated and di ed within the first 4 weeks. The decreased body weight gain was also seen at and above 2.5%. No effects were seen on hematological or biochemical parameters. Although atrophy of organs was observed, n o treatment

- related histological lesions were seen in an y organ

. (EPA, 2008 c ) NOAEL = 1.25% (~1250 mg/kg/day) LOAEL = 2.5% (~2500 mg/kg/day); based on decreased body weight gain

(Glutaric acid) 90 day (rat) Oral Groups of male and female Sprague

- Dawley rats were fed glutaric acid at 0, 0.5, 1.0 and 2.0% (appr oximately 0, 250, 500 and 1000 mg/kg/day) for 90 days. Body weight gain was markedly decreased in the 2% group in both sexes. No effects were seen on food consumption, hematology, clinical chemistry, urinalysis, absolute or relative organ weights or histop athology. No difference between control and treatment groups was observed in absolute or relative testes and ovary weights. Histopathological examination of testes, semi nal vesicles, ovaries and uteri did not reveal any treatmen t

related effects. (EPA , 200 8 c ) NOAEL = 1% (~500 mg/kg/day) LOAEL = 2% (~1000 mg/kg/day) ; based on decreased body weight gain15 (Glutaric acid) 90 day (dog) Oral

In a 90

- day study, groups of male and female Beagle dogs were fed diets containing 0, 1, 3 and 5% glutaric acid for days 1

– 10 and 0.5, 1, and 2% glutaric acid for days 11

– 90. Body weight loss was seen in male and females in the 5% group and in females of the 3% group after 10 days. The dogs in the high

- dose group did not gain weight during the study whereas the body weight gain for all other animals was comparable to the control group. No changes to other parameters, including histology of testes or

ov aries, were noted. (EPA , 2008 c ) NOAEL = 2% (~500 mg/kg/day) LOAEL = 3% (~750 mg/kg/day) ; based on decreased body weight gain

(Adipic acid) 2 year (rat) Oral

In a 2

- year chronic feeding study, male and female Carworth Farms rats were fed diets containing 0, 0.1, 1.0, 3.0 and 5.0% (males) or 0 and 1% (females) adipic acid (approximately 0, 75, 750, 2250, and 3750 mg/kg/day, resp ectively). In males, body weight gain was suppressed in the 3 and 5% dose groups and there was a slight but consistent reduction in food consumption in the 5% exposure group. Wheezing, bloody crust about eyes and nose and body sores were noted in all group s (including control animals). There was a lower incidence of signs indicative of respiratory infection and body sores in animals from the 5% exposure group. No marked differences between control and treated groups were noted in organ weights or microscopi c examination. In females, body weight gain and food consumption were not affected by treatment. (H orn , 1957) NOAEL = 1% (~750 mg/kg/day) LOAEL = 3% (~2250 mg/kg/day), based on decreased body weight gains and food consumption in

males )

DERMAL

(DBE, DMA , DMG, DMS) 14

- Day (rat) Dermal Undiluted DBE, DMA, DMG, or DMS was applied to the shaved intact dorsal skin of rats (Crl:CD (SD) IGS BR) at doses of 100, 300 or 1000 mg/kg/day for seven days a week for two weeks. No mortality or

clinical effects were obs erved. There was a low incidence of slight erythema and/or edema in rats exposed to DBE, DMA, DMG, or DMS. Minimal to mild erythema was observed in males and females treated with DBE, DMA and DMG. Generally minimal to mild dermal irritation in the form of focal eschar (scabbing) formation and desquamation was observed in rats treated with DBE, DMA, DMG, and DMS. All observed effects were reversible. (Kirkpatrick, 2000) Systemic Effects NOAEL= 1000 mg/kg/day (highest dose tested) Systemic Effects LOAEL not e stablished

INHALATION

(DMS , DMG, DMA) 90

- Day (rat) I nhalation (Bamberger, 2000) *

- (Presented separately for ease of reading):

DMS

* Summary Taken directly from EPA’s 2008 “Supporting Documents for Initial Risk

- Based Prioritization of High Production

Volume Chemicals” for Dibasic Esters.16 Sprague

- Dawley rats were exposed to DMS via inhalation at 0 or 400 mg/m 3 (0.4 mg/L), 6 hours/day, 5 days/week for 90 days. A 1

- month recovery group was included in the study. Neurobehavioral test battery; evaluation of male reproductive organs including sperm count, motility and morphology; cell proliferation (CP

— hepatic, lung, and nasal tissues); female estrous cycle determin ation; and hormonal analysis (serum leutenizing hormone (LH), follicle stimulating hormone (FSH) and testosterone in males and serum estradiol and progesterone concentrations in females) were included in the test. Test

substance

- related effects seen in the noses of male and female rats at 400 mg/m 3 DMS included degeneration/atrophy and focal respiratory metaplasia of the olfactory mucosa with minimum to mild severity. Degeneration/atrophy of the olfactory mucosa was evident in recovery animals in the same

l ocations as observed in the animals examined after 90 days of exposure. Male rats exposed to 400 mg/m 3 showed marked increase in CP in the liver and the females had greater CP in the nose level III relative to controls. Females showed a statistically signi ficant decrease (43% of control) in serum estradiol concentrations; h owever, the change in estradiol was not observed in the other two studies therefore, it was not considered adverse. In male rats, epididymal sperm counts were significantly increased (141

– 153% of control) but other sperm parameters were not affected. Hence, the chang es in epididymal sperm count were not considered as adverse

. NOAEL not established LOAEL = 400 mg/m 3 (0.4 mg/L) ; based on effects on nasal tissues, decrease in estradiol conc entration in females and increased epididymal sperm counts in males

DMG Sprague

- Dawley rats were exposed to DMG via inhalation at 0, 10, 50 or 400 mg/m 3 (0, 0.01, 0.05 or 0.4 mg/L), 6 hours/day, 5 days/week for 90 days. A 1

- month recovery group was includ ed in the study. Neurobehavioral test battery; evaluation of male reproductive organs including sperm count, motility and morphology; cell proliferation (CP

— hepatic, lung, and nasal tissues); female estrous cycle determination; and hormonal analysis (serum LH, FSH and testosterone in males and serum estradiol and progesterone concentrations in females) were included in the test. Male rats exposed to 400 mg/m 3
showed lower mean body weight and body weight gains during the study and male and female rats had

l ower food consumption. Test substance

- related effects seen in the noses of male and female rats at 400 mg/m 3 DMG included degeneration/atrophy and focal respiratory metaplasia of the olfactory mucosa with minimum to mild severity. Degeneration/atrophy of t he olfactory mucosa was evident in recovery animals in the same locations as observed in the animals examined after 90 days of exposure. Male and female rats exposed to 400 mg/m 3 DMG showed marked increase in CP in the nose level III. Male rats

showed a st atistically significant decrease in serum testosterone levels at 50 and 400 mg/m 3 (59 and 50% of control, respectively). Serum LH concentration was decreased in a dose

- dependent manner and was statistically significant at 400 mg/m 3 (71% of control). In add ition, a significant increase in epididymal sperm count was seen in the animals exposed to 50 and 400 mg/m 3 (124 and 131% of control, respectively) ; however, other sperm parameters were not affected

. NOAEL = 10 mg/m 3 (0.01 mg/L) LOAEL = 50 mg/m 3 (0.05 mg/L ) , based on decrease in serum LH concentration in a dose

- dependent manner, decrease in testosterone concentration, effects on nasal tissues, increased epididymal sperm counts at 50 mg/m 3 and above in males

DMA Sprague

- Dawley rats were exposed to DMA via inhalation at 0 or 400 mg/m 3 (measured as 390 mg/m 3 ; 0.39 mg/L), 6 hours/day, 5 days/week for 90 days. A 1

- month recovery group was included in the study.17 Neurobehavioral test battery; evaluation of male reproductive organs including sperm count, motility, and morphology; cell proliferation (CP

— hepatic, lung, and nasal tissues); female estrous cycle determination; and hormonal analysis (serum LH, FSH and testosterone in males and serum estradiol and progesterone concentrations in females) were included in t he test. Test

- substance

- related effects seen in the noses of male and female rats at 400 mg/m 3 DMA included degeneration/atrophy and focal respiratory metaplasia of the olfactory mucosa with minimum to mild severity. Degeneration/atrophy of the olfactory m ucosa was evident in recovery animals in the same locations as observed in the animals examined after 90 days of exposure. Male rats exposed to 400 mg/m 3 showed marked increase in CP in the liver and had greater CP in the nose level II relative to controls . Female rats exposed to 400 mg/m 3
had greater CP in the lungs relative to controls. In male rats, although not statistically significant, an increase in epididymal sperm counts was noted.

NOAEL not established LOAEL = 400 mg/m 3 (0.4 mg/L); based on effect s on nasal tissues, increase in CP in liver, lungs and

nose

(DBE) 90

- Day (rat) Inhalation

In a 90

- day inhalation toxicity study, CRL:CD®BR rats were exposed to DBE aerosol

- vapor mixture at 160, 400 or 1000 mg/m 3 (~0.160, 0.400 or 1.0 mg/L) 6 hours/day, 5 days/week for approximat ely 14 weeks. Microscopic examination of nasal tissues showed degeneration of the olfactory epithelium in all

DBE

- exposed groups. Effects were of minimal severity in the 160 mg/m 3 group and mild to moderate at

the mid

- and high

- conc entrations. Dose

- dependent decreases in absolute and relative liver weights were observed in female rats in all exposed groups and males exposed to 1000 mg/m 3

. However, a histopathologic examination revealed no toxic effects in the liver and therefore, the biological significance of the red uced liver weights is unknown. Other statistically significant differences between test and control rats in the 1000 mg/m 3 group included slight increases in relative heart and testes weights in males and a slight decreas e in absolute spleen weight in females. These slight organ weight changes were not accompanied by any histopathological changes and are therefore

, considered not
adverse . There were also slight decreases in blood sodium concentrations in both male and fema le rats exposed to 1.0 mg/L DBE, and slight increases in blood calcium concentrations in female rats exposed to 0.40 mg/L and 1.0 mg/L of DBE. These slight changes in blood sodium and calcium levels were not
considered to be adverse since these changes we re minor in magnitude and there was no clear dose

response

. (MRID 45740503)

NOAEL not established LOAEL = 160 mg/m 3 (0.16 mg/L); based on degeneration of olfactory epithelium

(DBE) 90

- Day (rat) Inhalation

In another 90

- day inhalation toxicity study (OSCP P 870.3465)

, Crl:CD/BR male and female rats were exposed to DBE at 20, 76 or 390 mg/m 3 (0.02, 0.076 or 0.39 mg/L) for 13 weeks. The results indicated degeneration of olfactory epithelium in male rats exposed to 76 or 390 mg/m 3 and in female rats exposed to all test concentrations. At the end of the 6

- week recovery period, these effects were still

visible in affected animals. Absolute liver weights in female rats exposed to 390 mg/m 3 were decreased,

but the liver

- to

- body weight ratios were not different from the controls. Liver weights were normal after the six week recovery period and there were no toxic effect s observed histopathologically. A slight

decrease in sodium levels was evident in all female exposure groups and males exposed to 76 and 390 mg/m 3

. Af ter 6 weeks of recovery, the sodium level was still low in animals exposed to 390 mg/m 3

.18 These changes were slight and generally within the range of biological variation and therefore, not considered to be toxicologically relevant. ( MRID 48968819)

NOAEL no t established LOAEL = 20 mg/m 3 (0.02 mg/L); based on degeneration of olfactory epithelium



### 3.2.4 Reproductive and Developmental Toxicity

(DBE) Reproductive and Devel opmental Toxicity (rat) Inhalation

In a combined study, thirty Sprague Dawley rats of each sex were exposed to dibasic esters for 6 hours a day, 5 days a week for 15 weeks to 0, 160, or 400 mg/m 3 of DBE vapor or to 1000 mg/m 3 of DBE

aerosol

- vapor mixture. Ten rats/sex/group w ere necropsied after 15 weeks. The remaining 20 rats/sex/group were exposed in the reproduction study through breeding, gestation and lactation periods. Ten pups/sex/group were necropsied at age 21 days. In the teratology part of the study 24 pregnant rats per group were exposed to DBE o n gestation days 7

- 16 and eutha nized on day 21. Effects seen after 15 weeks were slightly depressed body weights and depressed male liver weights at 1000 mg/m 3 and dose

related depressed liver weights in all exposed females. There were no histological findings other than a

dose

- related mild degeneration of the olfactory epithelium in all DBE exposed groups. There were no reproductive effects except for depressed pup weights in the 1000 mg/m 3 group, and no effects in the teratology study except for an increased incidence of delayed renal papillary development which was not considered to be compound related instead a result of an unusually low control group value relative to

the relevant historical control values

. ( MRID 48968822) Maternal NOAEL= 400 mg/m 3
Maternal LOAEL= 1000 mg/m 3 based on depressed body weight Reproductive NOAEL= 400 mg/m 3
Reproductive LOAEL= 1000 mg/m 3 based on depressed pup weight Developmental NOAEL = 1000 mg/m 3 (highest dose tested) Developmental LOAEL not established

(DMG) Developmental Toxicity (rabbit) Inhalatio n A developmental inhalation study was carried out on Hra:(NZW)SPF rabbits exposed to Dimethyl glutarate (DMG) for approximately 6 hours each day on gestation days 7 through 28 at concentrations of 30, 100, 300, or 1000 mg/m 3 . Maternal body weight, food co nsumption, and clinical observation data were collected daily. Animals were euthanized on day 29 of gestation and subjected to a gross external and internal postmortem examination. Gravid uteri were removed, weighed, and dissected and the

uterine contents were evaluated. Each live fetus was weighed, sexed, and examined for external, visceral, and skeletal alterations.

There was no evidence of maternal toxicity at 30 or 100 mg/m 3 and there was no evidence of developmental toxicity at any level tested. At 1 000 mg/m 3 one animal was found dead on gestation day

13 and one animal was sacrificed in extremis on gestation day 22

. Among survivors there were reductions in maternal body weight gains and food consumption and there were compound

- related

clinical observa tions (ocular discharge and wet fur). At 300 mg/m 3 , evidence of maternal toxicity was limited to reduced maternal body weight gains and increased clinical observations (ocular discharge). There was a significant decrease in sternal ossifications at 1000 mg /m 3 ; however, it was not considered to be compound related rather the result of an unusually low control group value relative to historical control group data. (Munley, 2003)19 Maternal NOAEL = 100 mg/m 3

Maternal LOAEL = 300 mg/m 3 based on body weight gains an d clinical observations Developmental NOAEL = 1000 mg/m 3 (highest dose tested) Developmental LOAEL not established

(DBE) Developmental Toxicity (rat) Inhalation A group of pregnant female Crl:CD®BR rats were exposed to either 0.16, 0.4, or 1.0 mg d ibasic esters (DBE)/L (160, 400 or 1000 mg/m 3 ) by inhalation for 6 hr/day from Days 7 through 16 of gestation (OSCPP 870.3700) . A suppression of both food consumption and the rate of body weight gain was seen in the 0.4 and 1.0 mg/L groups during the first 6 expo sure days. Staining on the fur and perineal area was seen in rats exposed to 1.0 mg/L and liver weight decreases, although not statistically significant, occurred in the 2 high exposure groups. All female rats were euthanized on gestation Day 21 and the

fe tuses were examined. None of the reproductive parameters were altered in any of the groups and no fetal effects were observed. DBE was not observed to be a developmental toxin in the rat following inhalation exposures as high as 1.0 mg DBE/L (1000 mg/m 3 )

. ( MRID 48968820)

Maternal NOAEL = 160 mg/m 3

Maternal L OAEL = 400 mg/m 3 based on food consumption and body weight gain Developmental NOAEL = 1000 mg/m 3 (highest dose tested) Developmental LOAE L not established

R EPRODUCTIVE AND DEVELOPMENTAL TOXICITY Studies on Metabolites

– See Table 6

( Glutaric acid ) Developmental Toxicity (rat) Oral Groups of pregnant female CD rats were administered doses of glutaric aci d a t 0, 125, 400 and 1300 mg/kg/ day via gavage on gestation days 6

– 15 . A nimals were sacrificed on ge station day 20 and examined for any gross patho logical changes. At 400 mg/kg /day and higher, clinical signs such as salivation, rales

, and nasal discharge were observed. Mean body weight gain was decreased at 1300 mg/kg /day during the dosing period, but th ey were comparable to control animals during post

- dosing (GD 15

– 20). Animals dosed with 1,300 mg/kg also exhibited slight inactivity, labored breathing, decreased body temperature, soft stool, and staining around the mouth, nares, and anogenital area. At 1300 mg/kg /day, one female died and one was sacrificed on gestation day 13. No changes were seen in reproductive status. There were no effects on the number of corpora lutea, implantation sites, number of live and dead fetuses or fetal body weights. No di fferences were seen in visceral and skeletal abnormalities between the control and the treatment groups. No adverse effects on pregnancy and no teratogenic effects were observed. A marked increase in the number of resorption s was observed at 1300 mg/kg /day

. The number or resorptions was within normal expected limits; therefore, the increase was not considered biologically meaningful. (EPA , 2008 c )

Maternal NOAEL = 125 mg/kg/day

Maternal LOAEL = 400 mg/kg /day based on salivation, rales, and nasal discharge

De velopmental NOAEL = 1300 mg/kg/day Developmental L OAEL not established

(Glutaric acid) Developmental Toxicity (rabbit) Oral Groups of pregnant female New Zealand White rabbits were administered glutaric acid at 0, 50, 160 and 500 mg/kg /day via gavage on d ays 6

– 18 of gestation; females were sacrificed on gestation day 29 and20 examined for gross pathological changes. No changes were seen in reproductive status. There were no effects on the number of corpora lutea, implantations, number of live and dead fetu ses, resorptions, fetal body weights or external, visceral and skeletal abnormalities. There were no adverse effects on pregnancy and no embryotoxic or teratogenic effects were observed. (EPA , 2008 c )

Maternal NOA EL = 500 mg/kg /day (highest dose tested)

Mat ernal LOAEL not established Developmental NOAEL = 500 mg/kg /day (highest dose tested) Developmental LOAEL not established

(Adipic acid) Developmental Toxicity (rat) Oral Groups of pregnant female Wistar rats were administered adipic acid via gavage at 0, 2.9, 13, 62 and 288 mg/kg /day during gestation days 6

– 15. Females were sacrificed on gestation day 20 and were examined for any gross pathological changes. There were no effects on the number of corpora lutea, implantations, number of live and dead fetus es, resorptions, fetal body weights, or external, visceral and

skeletal abnormalities. (EPA , 2008 c ) Maternal NOAEL = 288 mg/kg/day (highest dose tested)

Maternal LOAEL not established Developmental NOAEL = 288 mg/kg/day (highest dose tested) Developmental LOAEL not established

(Adipic acid) Developmental Toxicity (rat) Oral Groups of pregnant female Dutch

- belted rabbits were administered adipic acid a t 0, 2.5, 12, 54 and 250 mg/kg/ day via gavage on gestation days 6

- 18; females were sacrificed on gestation day 29 and examined for gross pathological changes. No changes were seen in reproductive status. There were no effects on the number of corpora lutea, implantations, number of live and dead fetuses, resorptions, fetal body weights, and external, visceral a nd skeletal abnormalities. There were no adverse effects on pregnancy and no embryotoxic or teratogenic effects were observed. (EPA , 2008 c ) Maternal NOAEL = 250 mg/kg/day (highest dose tested)

Maternal LOAEL not established Developmental NOAEL = 250 mg/kg/ day (highest dose tested) Developmental LOAEL not established

(Adipic acid) Developmental Toxicity (mouse) Oral Groups of pregnant female CD

- 1 mice were administered adipic acid via gavage at 0, 2.6, 12, 56 and 263 mg/kg/day during gestation days 6

– 15. There were no effects on the number of implantations, number of live and dead fetuses, resorptions, fetal body weights, or external, visceral and skeletal

abnormalities. (OECD, 2006) Maternal NOAEL = 263 mg/kg/day (highest dose tested)

Maternal LOAEL not e stablished Developmental NOAEL = 263 mg/kg/day (highest dose tested) Developmental LOAEL not established21 Table 6. Summary of Toxicological Endpoints for Metabolites of DMEGSA: Glutaric Acid, Adipic Acid, and Succinic Acid

Study Test Substance Toxicologi cal Effect Reference

13

- Week Oral (Rat) Succinic Acid (as

Monosodium

Succinate) NOAEL= ~1,250 mg/kg/day LOAEL= ~2,500 mg/kg/day; decreased body weight gain EPA , 2008 c

90

- Day Oral (Rat) Glutaric Acid NOAEL= ~500 mg/kg/day LOAEL= ~1,000 mg/kg/day; decre ased body weight gain EPA, 2008c

90

- Day Oral (Dog) Glutaric Acid NOAEL= ~500 mg/kg/day LOAEL= ~750 mg/kg/day; decreased body weight gain EPA, 2008c

2 Year Oral (Rat) Adipic Acid NOAEL= ~750 mg/kg/day

LOAEL = ~2,250; decreased body weight gain

and food consumption Horn, 1957

Developmental

Oral (Rat) Glutaric Acid Maternal NOAEL= 125 mg/kg/day Maternal LOAEL= 400 mg/kg/day; salivation, rales, and nasal discharge Developmental NOAEL= 1,300 mg/kg/day (HDT) Developmental LOAEL not established EPA, 2008c

Developmental

Oral (Rabbit) Glutaric Acid Maternal NOAEL= 500 mg/kg/day (HDT)

Maternal LOAEL not established Developmental NOAEL= 500 mg/kg/day (HDT) Developmental LOAEL not established EPA, 2008c

Developmental

Oral (Rat) Adipic Acid Maternal NOAEL= 28 8 mg/kg/day (HDT)

Maternal LOAEL not established Developmental NOAEL= 288 mg/kg/day (HDT) Developmental LOAEL not established EPA, 2008c

Developmental

Oral (Rat) Adipic Acid Maternal NOAEL= 250 mg/kg/day (HDT)

Maternal LOAEL not established Developmental NOAEL= 250 mg/kg/day (HDT) Developmental LOAEL not established EPA, 2008c

Developmental

Oral (Mouse) Adipic Acid Maternal NOAEL= 263 mg/kg/day (HDT)

Maternal LOAEL not established Developmental NOAEL= 263 mg/kg/day (HDT) Developmental LOAEL not establishe d OECD, 2006

3.2.5 Neurotoxicity

In the previously reviewed 90

- day inhalation studies (Bamberger, 2000) described above

, DMA, DMG, and DMS did not induce neurotoxicity in rats at doses up to 0.4 mg/L

. There were no microscopic neuropathological ch anges that could be attributed t o exposure to these chemicals. In addition, no test
substance

- related effects on functional observational battery parameters in male and female rats exposed

to DMA, DMG, or DMS were observed

.

The a gency concluded that based on the lack of neurotoxicity seen in any of the reviewed studies on the chemicals or their metabolites and the common use of the chemicals in food products it is unlikely that

these chemicals would be neurotoxic.22 3.2.6 Mutagenicity

The following p aragraph is a taken from the previous 2008 EPA’s “Decision Document for Petition

#5E4442: Dibasic Esters” . References have been added for clarification

...submitted studies indicating that DBE was non

- mutagenic in most assays ( Salmonella /microsome (MRID 457 40505)

, Salmonella /suspension and microforward (MRID 45740509) , and mouse bone marrow micronucleus assays (MRID 45740507 ), but caused chromosomal aberrations at concentrations greater than 0.3% in the chromosome aberration test. The Agency agrees that DBE is negative for mutagenicity in most tests, but positive for dose

dependent increases in chromosomal aberrations in lymphocites. (MRID 45740508)

The Agency reviewed additional mutagenicity studies sponsored by SOCMA when originally assessing the mutage nic potential for DBEs. DMA and DMG did not induce chromosome damage or bone marrow toxicity in male rats treated for two six

- hour periods of whole body inhalation exposure to DMA or DMG at dose levels of 0.50, 1.0, or 2.0 mg/L (500 mg/m 3 , 1000 mg/m 3 , or 2 000 mg/m 3 ). ( Mason

, 2001) DMG did not demonstrate mutagenic potential in an in vitro hypoxanthine

- guanine phosphoribosyl transferase (HPRT) cell mutation assay, either in the presence or absence of S9 metabolic activation

. (Clare

, 2002) Although DBE test ed positive for dose dependent increases in chromosomal aberration in lymphocytes , it was negative in the in vivo micronucleus for chromosomal aberrations.

Table 7. Summary of Genoto xicological Endpoints for DMEGSA Inert Ingredients for Use

in Human Hea lth Risk Assessments
Study Test Substance Toxicological Effect Reference Mutagenicity: Microsome Assay (Salmonella) DBE Negative MRID 45740505

Chromosome Abberation DBE S9(

- ): Negative S9(+): Positive MRID 45740508

Genotoxicity Mouse Micronucleus DBE N egative MRID 45740507

R at m ic ro nu cl e u s

- i nh a lati o n DMG Negative Mason, 2001

3.2.7 Carcinogenic Potential

No carcinogenicity studies are available on DMEGSA or DBE chemicals. In the absence of quantitative data a qualitative structure activity rel ationship (SAR) database, DEREK Version 11, was used to determine if there were structural alerts suggestive of carcinogenicity. No structural alerts were identified for DMG and DMS. In addition, the metabolites succinic acid and adipic acid have been

eval uated for carcinogenicity in chronic studies and there was no increase in the incidence of tumors over that in the corresponding control group . (MRID 48968818; OECD, 2006)

3.3 Endpoint Selection and Levels of Concern

Repe ated exposures to DMEGSA vi a inhalation show local effects (likely a result of irritation at the point of contact in the nasal region) as well as some changes in hormone levels that, although consistently observed, are not considered to be toxicologically significant. Although t hese studies showed changes in the cells of the nasal region (degeneration/atrophy with minimum to mi ld severity) in23 animals exposed daily for 90 days via th e inhalation route of exposure , t h ese e f f

e c ts on the ol f ac to r y

e pith e lium ar e e x p ec t e d t o be of mu c h lo w e r imp a c t in hum a ns due to m a jor anatomical and

p h y si o l o g i ca l d i f f

ere n ce s b etw ee n r a ts an d hu m a n s. R a ts h a v e a l a r g er s u r f ac e o f n a s al e pith e lium a nd

di ffe r e nt a ir f low a nd b rea thi n g p a tt er n c omp a r e d to hum a n s ( MRID 48968834; 48968835 ) . The a i r f low

is not di rec t e d to t h e o l fac t o r y e pith e lium to the s a me e x t en t in t h e hu m a n n a s a l cav i t y so t h e l o c al

e x posu r e will th eref o r e b e si g ni f i c a nt l y lo w e r in h um a ns. In addition, rodents are ob ligate nasal

breathers while humans breathe through both the mouth and nose

. R a ts a lso h a v e g r ea t er carbo x y l e st e ra se ac ti v i t y in n a s a l/ o l fac t o r y ep i t h el i u m th a n do hum a ns ( MRID 48968828; 48968832)

. “Preliminary in vitro experiments with human nasal tissue homogenates suggest that DBE metabolism

in human nasal tissue is 100 to 100 0 times less active that rat nasal tissue.” (US CPSC, 1994 ) T h e ref o re
, hu m an s a r e e x p e c t e d t o b e much less s e nsitiv e

.

Exposed animals also showed microscopic alterations in the liver (males) and lung (females).The hormonal changes observed in these studie s with DMS, DMA, and DMG were: an increase in sperm counts (2/3 studies), a decrease in testosterone levels (1/3 studies), and a decrease in leutenizing

ho rmone levels (1/3 studies) in males and a decrease in estradiol levels in females (1/3 studies). The significance of these findings is unclear because the decrease in male hormone levels should result in a decrease in sperm counts, yet the opposite effect was observed. The single study showing changes in

estradiol was not observed in the other two studies

. Furthermore, there were no functional parameters

such as estrous cycle and sperm motility or morphology affected. In addition, a reproductive study was conducted with DBE and there were no effects on fertility, viability of pups at birth, and the ability of

the mothers to lactate. For these reasons t he point of departure for the risk a ssessment for chronic oral routes of exposure was from the 14

- day oral toxicity study in rats. The NOAEL wa s 842 mg/kg/day

and the LOAEL was 1684 mg/kg/day based on reduced weight gain and food consumption. A 100 0 fold uncertainty factor was used for the chronic exposure (10X interspecies extrapolation, 10X fo r intraspecies variability and 1 0 X FQPA factor (See Section 3.4 for more information on the FQPA safety factor)).

Th e dermal study did not result in an endpoint o f concern

. Therefore, quantification of dermal risk is n ot

necessary. Adverse local olfactory effects were observed in inhalation toxicity studies; however, due to anatomical and physiological difference betwee n study animals and humans, the effects are likely to be less severe in humans and subsequently of minimal toxicological concern. No systemic endpoint of concern was identified in the available inhalation toxicity studies; therefore, quantification of inha lation risk is not necessary. The study and endpoint of concern used for estimation of chronic RfD was used

for short

- term and intermediate

- term incidental oral estimation. The residential and aggregate level of concern (LOC) is for margins of expos ure (MO E) that are less t han 100 0 and is based on 10X interspecies extrapolation, 10X for intraspecies variabilit y and a 10X FQPA safety factor. No in vivo dermal absorption studies are available for DBEs: however, the dermal absorption estimation was not

necessa ry to quantify dermal exposure base on lack of a dermal endpoint of concern.

3.4 FQPA Safety Factor C onsiderations

FFDCA section 408 provides that EPA shall apply an additional tenfold margin of exposure (safety) for

infants and children in the ca se of threshold effects to account for prenatal and postnatal toxicity and the completeness of the data base unless EPA determines that a different margin of exposure (safety) will be

safe for infants and children. EPA concludes that the FQPA safety factor of 10X fo r DMEGSA should24 be retained because of the need to extrapolate from a subchronic study for a chronic risk assessment. Although the 10X FQPA safety factor has been retained due to the lack of a chronic oral study the following conditions have been met :

i. The toxicity database for DMEGSA and their metabolites includes several subchronic and chronic studies, several developmental and reproductive toxicity studies, and mutagenicity

studies

. No chronic studies are available on DBEs; however, chronic toxicity studies on metabolites are available to characterize long term toxicity potential of DBEs.

ii

. I ncreased incidence of delayed renal papillary development and decreased pup weights were observed in reproductive / developmental inhalation toxicity studies at 1000 mg/m 3 ; however, these effects were only observed in the presence of depressed maternal body weight. In addition, there were no systemic effects seen in o ral studies at doses up to and including the limit dose of 1000 mg/kg/da y indicating no evidence of increased susceptibility.

i ii

. There is no indication that DMEGSA are neurotoxic chemicals

. Although no neurotoxicity studies are available in the databa se, no clinical signs of neurotoxicity were

observed in the available subchronic and chronic studies. Therefore, there is no need for a developmental neurotoxicity study or additional UFs to account for neurotoxicity.

v i

. The dietary food exposure ass essment utilizes proposed tolerance level or higher residues

and 100% CT in formation for all commodities. By using these screening

- level assessments, chronic exposures/risks will not be underestimated.

In conclusion, b ased on the absence of developmental toxicity for DBE in inhalation studies at maternally toxic doses and the higher developmental NOAEL for DMG there is no concern, at this time, for increased sensitivity to infants and children to DBE when used as an inert ingredient in pesticide

for mulatio ns. However, due to the lack of a chronic oral toxicity study the 10X FQPA safety factor has been retained to protect infants and children.

4.0 EXPOSURE ASSESSMENT

4.1 Dietary Exposure:

4.1.1 Acute exposure

No adverse effect attributable to a single exposure of DMEGSA was seen in the database

. Therefore, an acute dietary risk assessment for DMEGSA is not required.

4.1.2 Chronic exposure

In conducting the chronic dietary exposure assessment using the Dietary Exposure Evaluation Model

DEEM

- FCID TM , Ve rsion 3.16 , EPA used food consumption information from the U.S. Department of Agriculture’s National Health and Nutrition Examination Survey, What we eat in America, (NHANES/WWEIA). This dietary survey was conducted from 2003 to 2008 . As to residue levels in food, n o residue data were s ubmitted for DMEGSA

. In the absence of specific residue data, EPA has25 developed an approach which uses surrogate information to derive upper bound exposure estimates for

the su bject inert ingredient. E xposure estimates are ba sed on the highest tolerance for a given commodity from a list of high

- use insecticides, herbicides, and fungicides. A complete description of the general approach taken to assess inert ingredient risks in the absence of residue data is contained in the

me morandum entitled “Alkyl Amines Polyalkoxylates (Cluster 4): Acute and Chronic Aggregate (Food and Drinking Water) Dietary Exposure and Risk Assessments for the Inerts.” (D361707, S. Piper, 2/25/09) and can be found at http://www.regulations.gov in docket ID number EPA

- HQ

- OPP

- 2008

- 0738.

In the dietary exposure assessme nt, the a gency assumed that the residue level of the inert ingredient would be no higher than the highest to lerance for a given commodity. Implicit in this assumption is that there would be similar rates of degradation (if any) between the active and inert ingredient and that the concentration of inert ingredient in the scenarios leading to these highest of tolerances would be no higher than the concent ration of the active ingredient.

The a gency believes the assumptions used to estimate dietary exposures lead to an extremely conservative assessment of dietary risk due to a seri es of compounded conservatisms. First, assuming

that the level of residue for an inert ingredient is equal to the level of residue for the active ingre dient will overstate exposure. The concentration of active ingredients in agricultural products is generally at least 50 percent of the product and often can be much higher. Furt her, pesticide products rarely have a single inert ingredient; rather there is generally a combination of different inert ingredients used which additionally reduces the concentration of any single inert ingredient in the pesticide product in relation

to t hat of the active ingredient.

Second, the conservatism of this methodology is compounded by EPA’s decision to assume that, for each commodity, the active ingredient which will serve as a guide to the potential level of inert ingredient residues is the ac tive ingredient wit h the highest tolerance level. This assumption overstates residue values because it would be highly unlikely, given the high number of inert ingredients, that a single inert ingredient or class of ingredients would be present at the leve l of the active ingredient in the highest tolerance for every commodity. Finally, a third compounding conservatism is EPA’s assumption that all foods contain the inert ingredient a t the highest tolerance level. In other words, EPA assumed 100 percent of al l foods are treated with the inert ingredient at the rate and manner necessary to produce the highest residue legally poss ible for an active ingredient. In summary, EPA chose a very conservative method for estimating what level of inert residue could be on food, and then use this methodology to choose the highest possible residue that could be found on food and assumed that al l food contained this

residue. No consideration was given to potential degradation between harvest and consumption even though monito ring data shows that tolerance level residues are typically one to two orders of magnitude higher than actual residues in food when distributed in commerce.

Accordingly, although sufficient information to quantify actual residue levels in food is not ava ilable, the compounding of these conservative assumptions will lead to a significant exa ggeration of actual

exposures. EPA does not believe that this approach underestimates exposure in the absence of residue

data.26 Table 8

. Summary of Chronic Dietary Exp osure and Risk for APG

Population Subgroup cPAD (mg/kg/day) Chronic Exposure (mg/kg/day) % cPAD General U.S. Population

0.842 0.189 22.6 All Infants (<1 year old) 0.394 46.8

Children 1

- 2 years old 0.706 83.9

Children 3

- 5 years old 0.486 57.7

C hildren 6

- 12 years old 0.251 29.8

Youth 13

- 19 years old 0.135 16.0

Adults 20

- 49 years old 0.145 17.2 Adults 50+ years old 0.152 18.0

Females 13

- 49 years old 0.146 17.4

Based on analyses of estimated dietary risks for the general U.S. population and various population subgroups, the chronic dietary exposure e stimates for DMEGSA are below the a gency’s level of concern for all supported commodities. The chronic dietary exposure estimate for the highest exposed population subgrou p, children 1

- 2 years old, is 8 3.9 % of the chronic population adjusted dose (cPAD).

4.1.3 Cancer

Although there are no animal carcinogenicity studies available in the database, DMEGSA tested negative in mutagenicity and clastogenicity assays and no evidence of specific t arget organ toxicity was observed in any of the repeat dose studies. A qualitative structure activity relationship database, DEREK Version 11, was used to determine if there were structural alerts suggestive of carcinogenicity. No

structural alerts were i dentified for DMG and DMS. Additionally, no evidence of carcinogenicity was observed in a two year feeding study on the metabolite adipic acid and monosodium succinate. The Agency does not anticipate DMEGSA to be carcinogenic; therefore, a carcinogenicity assessment was not performed.

4.2 Residential Exposur e

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 ). DMEGSA may be used as inert ingredients in

pest icide products t hat are registered for uses that may result in residential exposures. The major route s of exposure from residential uses are expected to be inhalation and dermal exposure; however

, there is

a lso a potential for incidental oral exposure in c hildren exposed to areas that have been treated with pesticides containing the inert ingredient. Since no endpoint of concern was identified in the dermal study and the result seen in the inhalation studies were not expected to be significant in humans

, on ly

incidental o ral exposure scenarios in children were conducted. Subsequently, residential handler

scenarios were not assessed. A screening level residential exposure assessment was conducted to
represent worst

- case re sidential exposure and high end

- use p roduct application methods . The assessment methodologies were taken from: Standard Operating Procedures for Residential Pesticide Exposure Assessment. EPA/OPP/Health Effects Division February 2012.27 Table 9 . Residential Post

- application Short

- and Inter mediate

- term Exposures and Risks for DMEGSA Inert Ingredients Exposure Scenario Application Rate 1 Exposed Population & Exposure Duration 2 Daily Dose (mg/kg/day) MOE

Outdoor Products

Hand

- to

- Mouth from

Treated Lawn 1.8 lb/day Child ST 0.034 25000

Chi ld IT 0.016 53000 Object

- to

- Mouth from

Treated Lawn Child ST 0.008 100000 Child IT

Soil Ingestion Child ST 0.0001 7500000 Child IT

1 Application rates are based on high end rates for similar products.

2 ST and IT indicate short

- or intermed iate

- term exposure durations

EPA has calculated the residential post

- application exposures for children expos ed via hand

- to

- mouth or by placing nonfood objects that have come into contact with pesticides containing the inert ingredient in

their mouth. Currently, there are no current or proposed residential pesticide uses for this inert ing redient; however, the agency evaluated this high level screening model in the event that future uses of this inert ingredient result in nonfood residential oral exposures to children. Of the three scenarios evaluated, the highest daily dose f rom exposure to treated lawns is from short

- term and intermediate

term hand

- to

- mouth exposure scenarios at 0.034 and 0.016 mg/kg/day, respectively

. The short

- term
MOE was calculated to be 25

, 000 and the intermediate

- term MOE was 53

, 000 . As the level of concern

is for MOEs that are lower than 100 0 , these MOEs are not of concern.

4.3 Occupational Exposure

As stated in Sec t ion 3.3 of the document, repeated exposures to DMEGSA via i nhalation show local effects (likely a result of irritation at the point of contact in the nasal region) as well as some changes in hormone levels that, although consistently observed, are not considered to be toxicologically significant. Expected exposure from occupational use of DMEGSA is via the dermal and inhalation routes of exposure. Because no endpoints of concern have been identified in dermal or inhalation studies a qualitative occupational assessment was conducted.

5.0 A ggregate Risk and Det ermination of Safety

Acute and chronic pesticide exposures are evaluated by the agency by comparing aggregate exposure

estimates to the acute and chronic population adjusted dose ( aPAD

, cPAD ) . The aPAD and cPAD represent the highest safe exposures, taki ng into account all appropriate safety factors (SFs). EPA calculates the aPAD and cPAD by dividing the POD by all applicable UFs. For linear cancer risks, EPA calculates the probability of additional cancer cases given the estimated aggregate exposure. Short

- , intermediate

- , and chronic

- term risks are evaluated by comparing the estimated aggregate food, water, and residential exposure to the POD to ensure that the MOE called for by the product of all applicable

UFs is not exceeded.

5.1 Acute Dietary Risk

.

No hazard attributable to a single exposure seen in the toxicity database for the DMEGSA; therefore an acute aggregate risk assessment was not conducted.28 5.2 Chronic Dietary Risk.

A chronic dietary risk assessment takes into account exposure estimates from chronic dietary consump

tion of food and drinking water using the exposure assumptions discussed in section 4.1.2 for chronic exposure. The chronic analysis was based on a toxicity study in rats with a NOAEL of 842 mg/kg/day

and LOAEL of 1684 mg/kg/day based on body weight gain and food consumption. A 1000

- f old uncertainty factor (UF) (10X for intersp ecies extrapolation, 10X for intraspecies variation , and 10X FQPA safety factor ) was incorporated. The chronic dietary exposure from food an d water to DMEGSA

is 22.6 % of the cPAD for the U.S. population and 83.9 % of the cPAD for children 1

- 2 yrs old, the most highly exposed population subgroup.

5.3 Cancer Risk for U.S. Population

.

The Agency has not identified any concerns for carcinogenic ity relating to DMEGSA; therefore, a cancer dietary exposure assessment was not performed and an aggregate risk assessment is not a

concern.

5.4 Short

- Term/Intermediate Aggregate Risk

.

Short

- term aggregate exposure takes into account short

- term residen tial oral exposure plus chronic exposure to food and water (considered to be a background exposure level). DMEGSA could be used as an inert ingredient in pesticide products that could result in short

- term and intermediate

- term residential

exposure

. Using t he exposure ass umptions described in section 4.1.2 , EPA has cal culated the combined

short

- and intermediate term aggregated food, water, and residential oral exposures. EPA has concluded

the combined short

- term and intermediate aggregated food, water, and residential oral exposures for

children result ed in an aggregate MOE s of 1 45 0 and 1 5 00, respectively . As the level of concern is for

MOEs that are lower than 100 0 , these MOEs are not of concern.

Table 10. Short

- Term and Intermediate

- Term Aggregate Risk f or DMEGSA

Population LOC for Aggregate

Risk 1 mg/kg/day; ( MOE )

food & water 2 mg/kg/d ay; ( MOE )

residential 3 Aggregate MOE (food and residential) 4

Short

- Term

Child 1000 0.547; (150 0) 0. 034 ; ( 25000 ) 1 45 0

Intermediate

- Term

Child 1000 0.547; (15 00) 0.0 08 ; ( 100 000) 1 5 00

1 The LOC is based on a 1 0 00X safety factor for inter

- and intra

- species extrapolatio n and 10 FQPA SF

2 MOE food = [(short

- or intermediate

- term oral NOAEL)/(chronic dietary exposure)]. Chronic dietary exposure values from Table 8

3 MOE re sidential from Table 9

4 Aggregat e MOE (food and residential) = NOAEL/(mg/kg/day (food and water) + mg/kg/day (residential) )

6.0 Cumulative Risk

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 a29 particular pesticide's residues and “other substances that have a common mechanism of toxicity.” EPA

has not found DME GSA to share a common mechanism of toxicit y with any other substances, and

DME GSA s 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 DME GSA 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

.

7 .0 Environm ental Fate

In determining the environmental fate of DMEGSA t he Agency considered data submitted by the petitioner as well as information available from the Hazar dous Substances Data Bank (HSDB) , the

EPA ’s HPV Document for Dibasic Esters, the Decision Doc ument for Petition #5E4442 and the robust summaries of DBE, DMA, DMG, and DMS sponsored by SOCMA (2002) as part of the EPA HPV Challenge Program. See Tables 1

- 3 for the physical/chemical properties for these chemicals.

DMA, DMG, and DMS have similar phy sical

- chemical properties and are components of the mixture DBE. As with its component chemicals, DBE is expected to photodegrade when rel eased to air, with a

half

- life of ranging from 3

- 24 days

. If released to soil, DBE is expected to have high mobility through soil, based on its Log K

ow . In a microbial biodegradation test using the shake

- flask method, DBE had a

half

- life of 2.5 to 3.2 days. DMG degraded 98% after 28 days and DMS degraded >95% after 10 days in aerobic tests with activated sludge.

If rel eased to water, DBE is not expected to volatilize from surface waters or adsorb to suspended solids

and sediments in water column , but will biodegrade in the presence of bacteria in a matter of days and hydrolyze in a matter of months to years depending on pH

. Based on the moderate vapor pressure it is believed that these chemicals will be moderately volatile and that when released to the atmosphere they will exist primarily in the vapor phase.

The estimated Log BCF indicates that the potential for bioaccu mulation is low. They are not persistent (B1) and are not bioaccumulative (P1).

8. 0 Ecological Effects

8 .1 A c ute F ish T o x i c i t y

Bra c hy da n io r erio

Bra c hy da n io r erio were ex p o sed t o D M S. L i m i ted st u d y i n f o r m ation was available. The 9 6

- h our L C 50

= 5 0

- 1 0 0 mg/L. (EPA , 2008 b )

L e p o mis m a cro c hiru s Bl u e g il l su n f is h ( L e p o mis m a cro c hiru s) ; 10 / per c o nc e n trati o n w e re ex po s ed to D M G at no m i n al

c o nc e n trati o ns of 2 0

- 5 0 m g /L for 9 6 ho u rs un d er static c o n d itio n s. The 9 6

- h our L C 50 = 30.9 m g /L. (EPA , 2008 b )

Pim e p hal e s prom e las30 Fa th e a d minnows ( Pim e p hal e s prom e las ) w e r e e x pos e d to D B E with the t e st m e dium in a non

- G L P

t e st with a p r oto c ol c omp ara ble to E P A ’ s t e st g ui d e line O PP TS 850.1075 (F ish Ac ute To x i c i t y T e s t )

. The t e st a nim a ls w e r e e x pos e d to nomin a l c on ce n t ra tions of 0, 10, 13, 18, 24, 32, 42, 56, 75, a nd 100

ppm ( v/v) u n d e r st a tic c onditions.

The t e mp e r a tu re , pH, a n d o x y g e n in the m e dium w er e m a int a i n e d. D B E e x hib i t e d mod era te a c ute

to x i c i t y to fa th ea d minnows und e r st a ti c , un ae r a t e d t e st c o n ditions du r ing a 9 6

- hour e x posu re . T h e 96

- hour L C 5 0 rang e d b e t w ee n t h e No O b s er v e d E ffect C on ce nt ra tion ( NOE C ) o f 18 ppm ( v/v) a nd the

Low e st Obs er v e d E f f

ec t C on ce nt ra tion ( L OE C ) of 24 ppm ( v/v )

. Th eref o re , the 9 6

- hour L C 5 0 o f D B E

to f ish wa s e stim a t e d to be g r ea t e r th a n 18 ppm ( v/v) but l e ss th a n 24 ppm ( v/v) in l a bo ra to r y

supp l y w a t e r

. (EPA , 2008 b )

8 ,2 A cu t e I nv e r t eb r a te T o x i c i t y

Daphnia m a gna D. m a gn a (2 0 / conc e n trati on ) were e xp o sed to DMA at m ean m easured c o ncen t rations of 6

. 9, 1 4

, 2 9

, 5 8

o r 1 2 0 m g /L f o r 48 ho u rs un d er static c o nd i tions. The 4 8

- h our E C 50 = 72 m g /L . (EPA , 2008 b )

Daphnia m a gna Two studies on DBE exposed D. m agna at concentrations of 100 to 30 0 m g /L and 112 and 150 mg/L for

4 8 h o urs un d er static c o n d iti o ns. The 4 8

- h our E C 50 were 1 3 6 m g /L and >1 1 2 and < 150 m g /L, respectively. (EPA , 2008 b )

Daphnia m a gna In another study (OSCPP 850.1010)

, DME w a s t e st e d f o r acu t e t o x i c i t y to Daphnia m a gn a. Tw e n t y d a phnids w e r e e x pos e d to DME f or 24 hou r s a t c on ce nt r a tions of 39, 90, 120, 140, 200, 290, 440, a nd

68 0 m g / L . No immobil i z a tion w a s obs er v e d up to 120 m g / L a nd 100% mo r t a li t y w a s obs er v e d a t 290

m g / L . The N OEC w a s 120 m g / L a nd t h e L O EC w a s 140 m g / L . T h e r e fo r e
, t he 24

- hou r E C 5 0 fo r DME

w a s calculated to be 180 m g / L b y g r aph i ca l m e an s

. ( MRID 48968812 )

8 .3 A cu t e A l g al T o x i c i t y

P se u dokir c hn e riella s u b c apit a t a Gre e n a l gae ( P se u dokir c hn e riella s u b c apit a t a ) w e re e x p o s e d to D M A f o r 72 ho u rs at m e asur e d

co ncen t rations o f 6

. 2 5

, 1 2 .5, 2 5

, 5 0 , a n d 100 m g /L, u nd e r static co nd itio n s. The E C 50 (bio m a s s ) >1 00 mg/L a nd E C 50 ( g r o w t h ) > 10 0 m g /L

. (EPA , 2008 b )

P se u dokir c hn e riella s u b c apit a t a A 72

- hour Algal Growth Inhibition Test (OSCPP 850.4500) for DME was performed on Pseudokirchneriella subcapitata . The measured concentrations of the test item in the test media of th e test concentrations of 4.6, 10, 22, 46, a nd 100 m g / L were 99 and 100% of the nominal values, respectively, at the start of the test. At the end of the test, 62 to 72% of the nominal values were found.

The mean measured test concentrations were between 78 and 85% of the nominal values.31 DME h a d a st a tisti ca l l y si g ni f i ca nt inhibito r y e f f

e c t on the g r o w th of the a l g a e (a v e r a g e g r o wth ra te

a nd y i e ld) a f t e r the t e st p er iod o f 72 h ou r s a t the m ea n m e a su r e d c on ce nt r a tion of 85 m g / L . Thus, this

c on ce nt ra tion w a s d e t er min e d to be the 72

- h o ur L OE C . The 72

- ho u r N OEC w a s d e t er min e d to be

36 m g / L , sin c e up to a nd in c lud i ng this m ea n m e a su re d t e st con c en t r a ti o n , the g r ow t h ra te a nd y i e ld

o f the a l g a e af t e r 72 hou r s w er e n o t st a tisti ca l l y si g ni f i ca nt l y low e r th a n i n the c ont r ol ( MRID

48968824 ).

9 .0 Risk Characterization

D BE has been previously approved by the agency under 40 CFR 180.1277 for use as a solvent and/or

anti

- freeze at 10% w/w or less in microencapsulated pesticide formulations with the active ingredi ent cyfluthrin. In addition, DMEGSA are used as solvents, plasticizers, polymer intermediates, and as components in paint strippers, polishes, an d lacquer thinners. DMS and the metabolites adipic acid and

succinic acid are considered GRAS chemicals and ar e directly added to food. Methanol, a metabolite of DMEGSA, is an approved food use inert ingredient in pesticide formulations under 40 CFR Part

180.910 and 180.920 as a solvent and 180.930 as a solvent/co

- solvent.

Various inhalation and in vitro studies have shown that DMEGSA is hydrolyzed to its corresponding monomethyl esters and subsequent dicarboxylic acid metabolites (i.e., adipic, glutaric, and succinic acid) by car bo x y l e st e ra s e s lo c a t e d in the n a s a l/ol fac to r y e pith e lium. Carboxylesterases are also found in many other mammalian tissues including the liver, kidney, brain, testis, and gastrointestinal tract. Following oral exposure, dimethyl esters are expected to be metabolized in the body similar to what was seen in rodent nasal mucosa; however, diff erent areas of the body may be more or less efficient at metabolizing DBEs. For instance, olfactory mucosal homogenates hydrolyze DBE to their corresponding metabolites more efficiently (7 to 10 fold higher) than respiratory mucosal homogenates

.

A c ute to x i c i t y studi e s c ondu c t e d with DME d e monst ra t e low acute oral and dermal toxicity. DME

showed minimal eye irritation and no dermal irritation

. A d er m a l p e n e t ra tion stu d y c ond u c t e d with D B E

d e m on s t ra t ed th a t the d er m a l a bso rpti o n ra te is hi g h e r in r a t skin c o mp are d to hum a n skin ( 2.12 x 10 - 3 to
4.18 x 10 - 3 c m/h v er sus 6.81 x 10 - 5 to 1.69 x 10 - 4 c m/ h

, r e s p e c ti v e l y )

. R e s u l ts o f a d e r m al s e nsiti z a tion

c ondu c t e d with DME w er e n e g a ti v e

.

The repeat dose database for DMEGSA contains oral, dermal, and inhalation stud ies. Due to their prevalence in commercial paint strippers, polishes, and lacquer thinners t he majority of the studies were conducted via inhalation

, the most expected route of exposure from non

- pesticidal uses

. The relevance

of these studies to humans is discussed later in this section.

Two oral rat studies have been conducted on DBE, a 14

- day and a one month study. Animals in the 14

- day study showed reduced weight gain and food consumption at 1,684 mg/kg/day but showed no adverse effects at 842 mg/kg/da y. Animals in the one month study showed no adverse effect s at the limit dose of 1,000 mg/kg/day. A 14

- day dermal study was also conducted with DBE and DMEGSA. Although mild skin irritation was noted in rats at doses equal to and greater than 100 mg/kg/day , the effects were reversible and no systemic effects were observed at any dose tested up to the limit dose of 1,000 mg/kg/day.32 Based on t he limited oral data for DMEGSA oral studies on the metabolites were also used to support a safety finding for DMEGS A. Available repeat dose oral studies on the metabolites include a 13

- week study on succinic acid, two 90

- day studies on glutaric acid and a two year study on adipic acid. Succinic acid was shown to cause decreased body weight gain in rats at and above 2,5 00 mg/kg/day. Glutaric acid also caused a decrease in body weight gain in both rats and dogs at 1,000 and 750 mg/kg/day, respectively. Similarly, adipic acid was seen to cause decreased body weight gain and food consumption in rats at 2,250 mg/kg/day. The results of these studies indicate that the metabolites of DMEGSA are of low toxicity via the oral route of exposure.

The majority of the repeat dose and reproductive/developmental studies conducted on DBE and/or

DMEGSA are via the inhalation route of ex posure . The available database includes three 90

- day inhalation studies in rats, one co nducted with DMEGSA and two with DBE. In the first study rats were exposed to DMS and DMA at doses of 0 or 0.4 mg/L and DMG at doses of 0, 0.01, 0.05, or 0.4 mg/L.

D egen eration of the olfactory epithelium was observed for all chemicals at and above 0.05 mg/L with the severity of the effect being dose dependent. Exposed animals also showed microscopic alterations in the liver (males) and lung (females).The hormonal changes observed in these studies with DMS, DMA, and DMG were: an increase in sperm counts (2/3 studies), a decrease in testosterone levels (1/3 studies), and a decrease in leutenizing hormone levels (1/3 studies) in males and a decrease in estradiol levels in

fe males (1/3 studies). The significance of these findings is unclear because the decrease in male hormone levels should result in a decrease in sperm counts, yet the opposite effect was observed. The single study showing changes in estradiol was not observed in the other two studies. Furthermore, there were no functional parameters such as estrous cycle and sperm motility or morphology affected. In addition, a reproductive study was conducted with DBE and there were no effects on fertility, viability of pups at birth, and the ability of the mothers to lactate.

The two other 90

- day rat studies tested DBE and again, degeneration of the olfactory epithelium was noted at all doses tested (0.02

- 1.0 mg/L). In both studies decreases in liver weight were observed but no histopathological findings were evident. Similarly, when rats were exposed to 1 mg/L DBE slight increases in relative heart and testes weights in males and a slight decrease in absolute spleen weight in females were observed. These slight organ weight changes were not accompanied by any histopathological changes and are therefore considered of minimal biological significance. No other significant effects were observed.

Repeat dose inhalation studies have demonstrated the chemicals potential to a ffect the olfactory mucosa

in the nasal passage of rats

. T h ese local e f f

e c ts ar e believed to b e re l a t ed to the h y d r o l y sis of DMEGSA

b y car bo x y l e st e ra s e s lo c a t e d in the n a s a l/ol fac to r y e pith e lium to the di c a r bo x y l i c a c id m e t a bolit e s.
T h e se e f f

e c ts on the ol f ac to r y e pith e lium ar e e x p ec t e d t o be of mu c h low e r imp a c t in hum a ns due to

m a jor p h y si o l o g i ca l d i f f

ere n ce s b etw ee n r a ts an d hu m a n s. R a ts h a v e a l a r g er s u r f ac e o f n a s al e pith e lium

a nd di ffe r e nt a ir f low a nd b rea thi n g p a tt er n c omp a r e d to hum a n s. The a i r f low is no t di rec t e d to th e

o l fac t o r y e pith e lium to the s a me e x t en t in t h e hu m a n n a s a l cav i t y so t h e l o c al e x posu r e will th eref o r e b e si g ni f i c a nt l y lo w e r in h um a ns. In addition, rodents are obligate nasal breathers while man breathes through both the mouth and nose. R a ts a lso h a v e g r ea t er carbo x y l e st e ra se ac ti v i t y in n a s a l/ o l fac t o r y

ep i t h el i u m th a n do hum a ns

. “Preliminary in vitro experiments with human nasal tissue homogenates suggest that DBE metabolism in human nasal tissue is 100 to 1000 times less active that ra t nasal tissue.” (US CPSC, 1994 ) T h e ref o re, hu m an s a r e e x p e c t e d t o b e l e ss much s e nsitiv e

.33 In addition to much of the repeat dose testing

, inhalation was also the route of exposure used in much of the reproductive and developmental studies. Depressed pup weights were observed in a on e

- g e n era tion

r e p r o d u c tion inh a l a tion toxi c i t y stu d y with D B E at 1.0 mg/L but were only seen in the presence of maternal toxicity. Two d e v e lopm e nt a l inh a l a tion to x i c i t y stu d ies were c ondu c t e d

, one testing DBE on

rats and with DM G on rabbits. In both studies no developmental effects were observed at doses up to and including 1.0 mg/L. Similarly, no adverse developmental effects were observed in oral studies on the metabolites glutaric acid (rat and rabbit) and adipic acid (rat and mice) at doses up to and including 1,300 mg/kg/day.

An Am e s t e st c ondu c t e d with D B E w a s n e g a tiv e ; how e v er
, a c h r omosome a b er r a tion stu d y c ond u c t e d

with D B E w a s positive a t hi g h c o n ce nt ra tions ( 3.3 a nd 4.4 m g / m L ) in the p re s e n c e of S 9 m e t a b olic

ac tiv a tion ( n e g a tive without S 9 ac tiv a tion) in l y mpho c y t e s fro m fe m a le don o r s. This re sult is not

c onsist e nt with wh a t is known a bout the h y d r o l y sis p r odu c ts of the m e t h y l e s t er s. M e th a nol is not

c l a s to g e nic o r g e noto x i c . Gl u t ar ic ac i d, s u c c i n i c ac id, a nd a dipic ac i d a r e a ll e nd o g e nous a nd not

c onsid ere d to be c l a sto g e nic o r g e noto x i c ; a c h r omoso m e a b e r ra tion stu d y c ond u c t e d with a dipic a c id

w a s n e g a tiv e . As s u ch, it is po s sible t h at, i n t h e p r e s e n c e o f S 9 m e t abo l ic ac ti v ati on
, t h e e st e r s w e r e h y d r o l y z e d a nd the ac id s re l ea s e d, a f fec ti n g the p H, m a king it mo r e ac idi c

. This is known to c au s e f

a lse po s iti v e ef f

ec ts in c y t o g e n i c i t y a ss a y s. T h e ref o re
, an in v i v o g e noto x i c i t y a ss a y on s o m a tic ce lls

w a s p e rf o r m ed

. A bon e m a rro w mi cron u c l eu s a ss a y w as p erf o r m e d in mi c e f oll o wing a si n g le

inh a l a to r y nos e

- on l y e x posu r e to D B E fo r six hou r s. Th er e w e r e no st a t isti ca l l y si g ni f i ca nt di f f

e r e n ce s in the p r op o r tion of mi cr onu c l ea t e d po l y c h r o m a tic e r y th r o c y t e s b e tw e e n mi c e of a ll g r oups in c l uding

c ont r ols a t a n y s a mpling time up t o 72 hou r s f ollowing e x posu r e up to a v e r y hi g h c on ce nt ra tion of 19

m g / L , illust ra ting t he a bs e n c e of c l a stog e ni c i t y of the t e st subst a n c e i n vi v o

. In a ddition, a ra t
mi cr onu c l e us stu d y c ond u c t e d with DMG w a s n e g a tiv e

.

No n e u r op a tholo g i ca l c h a n g e s o r e f fe c ts on t he f un c tion a l obs er v a tion b a tt e r y p ara m e t er s w er e re p o r t e d in any of the studies. The agency does not believe DMEGSA will be neurotoxic

. C h r oni c / carc in o g e ni c i t y studi e s c ould not be id e nti f i e d f or DMEGSA ; however, a DE R EK e v a lu a tion

f

or DMG a nd D M S w a s c ondu c t e d a nd did not show a n y s p ec i a l a l er ts. I n a dd i ti on
, carcinogenicity

stu d ies were c ondu c t e d with a dipic a c id and monosodium succinate in ra ts and no carc in o g e n i c e f f

e c ts

w er e obs er v e d. Therefore, the agency does not expect DMEGSA to be carcinogenic in humans.

Repeated exposures to DMEGSA via inhalation show local effects (likely a result of irritation at the point of contact in the nasal region) as well as some changes in hormone levels that, although consistently observed, are not considered to b e toxicologically significant. The point of departure for the risk assessment for chronic oral routes of exposure was from the 14

- day oral toxicity study in rats. The NOAEL was 842 mg/kg/day and the LOAEL was 1684 mg/kg/day based on reduced weight gain and food consumption. A 1000 fold uncertainty factor was used for the chronic exposure (10X interspecies extrapolation, 10X for intraspecies variability and 10X FQPA factor (See Section 3.4 for more information on the FQPA safety factor)).

Exposure to DMEGS A will be primarily through the oral route of exposure when eating food treated with pesticides containing the chemical. In order to estimate the dietary exposure to DMEGSA the EPA’s highly conservative I

- DEEM model, which incorporates a default drinking w ater concentr ation of 100 ppb, was used. I

- DEEM showed the exposure from the use of this inert ingredient in pesticide formulations (including exposure through drinking water) would result in acceptable risk to all34 subpopulations. The most highly exposed s ubpopulation wa s children 1

- 2 years old at 83.9 % of the

cPAD.

Residential exposure to outdoor pesticide products were evaluated using Agency approved models to estimate the risk to residential post

- application oral exposures to treated lawns. The dermal s tudy did not result in an endpoint of concern therefore dermal exposure was not assessed. . The residential and aggregate level of concern (LOC) is for margins of exposure (MOE) that are less than 1000 and is based

on 10X for interspecies extrapolation, 10 X for intraspecies variability, and a 10X F QPA safety factor.

All exposure scenarios resulted in acceptable levels of risk (i.e., MOEs >1000) to all subpopulations evaluated. Exposure to DMEGSA inert ingredients via paint, residential antimicrobials, and pet products were not evaluated in this risk assessment. When residential and dietary exposures were combined exposure did not exceed the acceptable level of risk.

Occupational exposure would be expected via the dermal an d inhalation routes of exposure; however,

b ecause endpoint s of concern were not identified for these routes of exposure in animal studies a qualitative occupational assessment was conducted.

Based on ecological (i.e., fish, invertebrates, and algae) and fate studies t he a gency concluded that

DMEGSA does not pose an ecological risk to terrestrial or aquatic species. DBE is expected to photodegrade when released to air, with a half

- life of ranging from 3

- 24 days. If released to soil, DBE is expected to have high mobility through soil and d egrade rapidly. If released to water, DBE is not expected to volatilize from surface waters or adsorb to suspended solids and sediments in water column, but will biodegrade in the presence of bacteria in a matter of days and hydrolyze in a matter of months to years depending on pH. Based on the moderate vapor pressure it is believed that these chemicals will be moderately volatile and that when released to the atmosphere they will exist primarily in the vapor phase. DMEGSA is not expected to persist in the environment and the potential for bioaccumulation is

low.

Many of the studies for DMEGSA and DBE showed olfactory effects in rats following inhalation exposure. While these effects were observed in rats, it is unlikely that the same effects will be seen in humans due to physiological and chemical differences between the species. In addition, some studies showed hormonal changes; however, these effects were not seen in other studies and were not accompanied by histological changes.

Based on the evaluate d toxicity studies coupled with the expected exposure from the use of these chemicals as inert ingredients in pesticide products, EPA concludes that there is a reasonable certainty that no harm will result to the general population, including infants and c hildren, from aggregate

exposure to residues of DMEGSA when used as an inert ingredients in pesticide formulations under 40

CFR 180. 910

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US EPA Ver. 3.16, 03

- 08

- d

DEEM

- FCID Chronic analysis for INERTS

- APG NHANES 2003

- 2008 2

- day

Residue file name: C: \ Documents and Settings \ dsunderl \ My Documents \ I

DEEM \ INERTS_57ACTIVE_100PPBH2OREV.R08 Adjustment factor #2 NOT used. Analysis Date 10

- 29

- 2013/14:36:37 Residue file dated: 09

- 26

- 2013/10:32:39 Reference dose (RfD, Chronic) = .842 mg/kg bw/day NOEL (Chronic) = 842 mg/kg bw/day COMMENT 1: Inert 57 active ingredients + drinking wat er (100ppb)

=============================================================================== Total exposure by population subgroup

-------------------------------------------------------------------------------

Total Exposure

----------------------------------- Population mg/kg Margin of Percent

Subgroup body wt/day Ex posure of RfD

-------------------------------------- ------------- ---------- ---------- Total US Population 0.189343 4,447 22.5% Hispanic 0.206762 4,072 24.6%

Non

- Hisp

- White 0.185800 4,532 22.1%

Non

- Hisp

- Black 0.175951 4,785 20.9%

Non

- Hisp

- Other 0.223356 3,770 26.5% Nursing Infants 0.248204 3,392 29.5%

Non

- Nursing Infants 0.459734 1,831 54.6%

Female 13+ PREG 0.165239 5,096 19.6%

Children 1

- 6 0.5 46673 1,540 64.9%

Children 7

- 12 0.227410 3,703 27.0%

Male 13

- 19 0.133762 6,295 15.9%

Female 13

- 19/NP 0.135932 6,194 16.1%
Male 20+ 0.140996 5,972 16.7%
Female 20+/NP 0.153162 5,497 18.2%
Seniors 55+ 0.152687 5,515 18.1%

All Infants 0.394428 2,135 46.8%

Female 13

- 50 0.146403 5,751 17.4%

Children 1

- 2 0.706242 1,192 83.9%

Children 3

- 5 0.485634 1,734 57.7%

Children 6

- 12 0.250554 3,361 29.8%

Youth 13

- 19 0.134797 6,246 16.0%

Adults 20

- 49 0.144740 5,817 17.2%

Adults 50

- 99 0.151788 5,547 18.0%

Female 13

- 49 0.146333 5,754 17.4%

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