Document ID: EPA-HQ-OPP-2007-0182-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-08-29T04:00Z

July 27, 2007

MEMORANDUM

SUBJECT:	Decision Document for Petition # 5E4442: Dibasic Esters (DBE;
CAS Reg. No. 95481-62-2)

		

FROM:	R. Tracy Ward, Biologist  

		Inert Ingredient Assessment Branch (IIAB)

		Registration Division (7505P)

TO:		Pauline Wagner, Chief

		Inert Ingredient Assessment Branch (IIAB)

		Registration Division (7505P)

  SEQ CHAPTER \h \r 1 

OVERVIEW	

	This document is the science assessment for dibasic esters (DBE; CAS
Reg. No. 95481-62-2), a mixture of dimethyl adipate (CAS Reg. No.
627-93-0), dimethyl glutarate (CAS Reg. No. 1119-40-0), and dimethyl
succinate (CAS Reg. No. 106-65-0).  Whitmire Micro-Gen Research Labs,
Inc petitioned the Agency requesting a tolerance exemption for the inert
ingredient mixture DBE.  The company requested the use of DBE as a
solvent material/anti-freeze limited to 10% or less of microencapsulated
pesticide formulations with the active ingredient cyfluthrin.  The
Agency published a Notice of Filing containing the petitioner’s
request on December 23, 1998 in the Federal Register (63 FR 71126).  No
comments were received on this Notice.

	This assessment summarizes available information on the use,
physical/chemical properties, toxicological effects, exposure profile,
environmental fate, and ecotoxicity of DBE.  The purpose of this
document is to assess the risk to human health and the environment of
the inert ingredient DBE as required under the Food Quality Protection
Act (FQPA).  

EXECUTIVE SUMMARY

This document evaluates the petition submitted by Whitmire Micro-Gen
Research Labs, Inc for the use of DBE (published on December 23, 1998,
in the Federal Register, 63 FR 71126) as an inert ingredient solvent
material/anti-freeze limited to 10 % or less of microencapsulated
pesticide formulations with the active ingredient cyfluthrin.

DBE has low acute oral and inhalation toxicity and low subchronic oral
toxicity with a no observed effect level (NOEL) of 842 mg/kg/day).  In
acute eye toxicity studies on the rabbit, DBE had mild to moderate eye
irritation.  In subchronic inhalation studies, DBE had a systemic
inhalation NOEL ≥ 0.40 mg/L (400 mg/m3), but a nasal irritation NOEL <
0.02 mg/L (20 mg/m3).  DBE did not induce neurotoxicity or
carcinogenicity in the studies reviewed, and it was negative for
mutagenicity in most tests, but positive for chromosomal aberrations
under activated conditions.  In a repeat-dose inhalation reproduction
toxicity study, DBE had a NOEL of 0.40 mg/L (400 mg/m3) and a lowest
effect level (LEL) of 1.0 mg/L (1000 mg/m3) based on decreased pup
weights at weaning.  In repeat-dose inhalation exposure studies,
developmental toxicity was observed at higher doses (1.0 mg/L or 1000
mg/m3) than maternal toxicity (0.16 mg/L or 160 mg/m3).  

In studies, DBE did not cause dermal irritation in animals exposed for
four hours, but caused severe irritation (severe erythema and mild
edema) in one animal and reversible mild to moderate irritation in
animals exposed to DBE for 24 hours.  DBE was not considered to be a
skin-sensitizer in guinea pigs.  In repeat-dermal exposure studies
conducted on the rat, DBE had a systemic dermal NOEL of 1000 mg/kg/day,
and dermal irritation lowest observed adverse effect level (LOAEL) of
100 mg/kg/day based on the slight, but reversible, erythema and edema. 

	The use of DBE in pesticide products is being limited to 10% or less of
microencap-sulated pesticide formulations with the insecticide active
ingredient cyfluthrin.  Uses of cyfluthrin are currently limited to
food-use applications such as spot and crack and crevice treatments in
food processing plants and food storage areas, and it is typically
applied by commercial applicators.  Dietary exposures of concern from
residues in food and drinking water are not anticipated.  The
microencapsulated formulation and its restriction to use with one active
ingredient will reduce the potential for residential exposures
(inhalation and dermal) to a minimal level.  DBE is also used in
non-pesticide consumer products such as paint solvents.  The use of DBE
as an inert ingredient in pesticide formulations, with the above
limitations, is not expected to contribute significantly to exposures
from its use in non-pesticide consumer products.

	

	Taking into consideration all available information on DBE, it has been
determined that there is a reasonable certainty that no harm to any
population subgroup (including infants and children) will result from
aggregate exposure to DBE when considering exposure through food
commodities and all other non-occupational sources for which there is
reliable information.  Therefore, it is recommended that the exemption
from the requirement of a tolerance established for residues of DBE when
used as an inert ingredient in pesticide products can be considered safe
under section 408(q) of the FFDCA.  

Background

	

The petitioner, Whitmire Micro-Gen Research Laboratories, Inc.,
submitted petition #5E4442 to the Agency requesting an exemption from
the requirement of a tolerance for the dibasic esters (DBE), when used
as a solvent material/anti-freeze at 10% or less in microencapsulated
pesticides utilizing the active ingredient cyfluthrin.

II.  Physical and Chemical Properties

	Some of the physical and chemical characteristics of DBE, provided in a
Du Pont Chemicals Material Safety Data Sheet (MSDS 1994) submitted by
Whitmire, are in Table 1. 

Table 1.  Physical and Chemical Properties of DBE mixture as Submitted
by the Petitioner

Parameter	Value	Reference

Percentage of Mixture	Dimethyl adipate 10-25 %	DuPont MSDS 1994

	Dimethyl glutarate 55-75 %	DuPont MSDS 1994

	Dimethyl succinate 19-26 %	DuPont MSDS 1994

CAS #	95481-62-2	SOCMA 2002

Molecular Weight	~ 159	DuPont MSDS 1994

Common Names	Aliphatic Dibasic Esters, Dibasic Ester Mixture 	DuPont
MSDS 1994

Physical State	Colorless liquid	DuPont MSDS 1994

Melting Point 	~ - 20°C	DuPont MSDS 1994

Boiling Point  	196-225°C	DuPont MSDS 1994

Density	1.092 g/cm3	SOCMA 2002

Vapor Pressure 	0.2 mm Hg @ 20ºC 	DuPont MSDS 1994

Log Kow	0.19	SOCMA 2002

Water Solubility	5.3 wt% @ 20ºC; 121-131 g/L @ 25 ºC	DuPont MSDS 1994;
SOCMA 2002

The Agency summarized some of the available information on the physical
and chemical properties of dimethyl adipate (DMA), dimethyl glutarate
(DMG), and dimethyl succinate (DMS), along with their structures and
nomenclature, in Tables 2 - 4.  The Synthetic Organic Chemical
Manufacturers Association Dibasic Esters Group (SOCMA DBE Group)
submitted data on DBE and its components as part of the TSCA Section 4
Enforceable Consent Agreement with the EPA in August 8, 1999.  

Table 2.  Physical and Chemical Properties of Dimethyl Adipate

 	ChemIDPlus 2004

CAS #	627-93-0

	Molecular Weight	174

	Common Names	Hexanedioc acid, dimethyl ester, dimethyl hexanedioate,
dibasic acid ester (dimethyl adipate), 1,4 butanedicarboxylic acid,
dibasic dimethyl ester of adipic acid, DMAD, and DBE-6	SOCMA 2002

Melting Point	8.5°C	SOCMA 2002

Boiling Point  	230.9°C	SOCMA 2002

Density 	1.062 g/cm3 	SOCMA 2002

Vapor Pressure 	0.17 hPa @ 20ºC; 0.06 mm Hg @ 25ºC (estimated)	SOCMA
2002; HSDB 2006

Log Kow 	1.03 (estimated)	SOCMA 2002; HSDB 2006

Water Solubility	29.9 g/L @ 20ºC	SOCMA 2002

Henry's Law Constant	2.31 x 10-6 atm-m3/mole @ 25ºC (estimated); 9.77 x
10-7 atm-m3/mole (estimated)	ChemIDPlus 2004; HSDB 2006

Table 3.  Physical and Chemical Properties of Dimethyl Glutarate

 	ChemIDPlus 2004

CAS #	1119-40-0	SOCMA 2002

Molecular Weight	160	SOCMA 2002

Common Names	Dibasic acid ester (dimethyl gluterate), DBE-5, dimethyl
pentanedioate, and dibasic dimethyl esters of glutaric acid	SOCMA 2002

Melting Point 	-37 °C	SOCMA 2002

Boiling Point  	213.5-214°C	SOCMA 2002

Density 	1.0876 g/cm3 @ 20ºC	SOCMA 2002

Vapor Pressure 	0.7 mm Hg @ 20ºC	SOCMA 2002

Log Kow	0.62 (calculated)	SOCMA 2002

Water Solubility	4.3 wt% @ 20ºC	SOCMA 2002

Henry's Law Constant	6.43 x 10-7 atm-m3/mole @ 25ºC	ChemIDPlus 2004

Table 4.  Physical and Chemical Properties of Dimethyl Succinate

 	ChemIDPlus 2004

CAS #	106-65-0	SOCMA 2002

Molecular Weight	146	SOCMA 2002

Common Names	Dimethyl butanedioate, dibasic acid ester (dimethyl
succinate), dimethyl ester, mixture with dimethyl butanedioate, dibasic
dimethyl esters of succinic acid, and DMS	SOCMA 2002

Melting Point 	19°C	SOCMA 2002

Boiling Point  	196°C	SOCMA 2002

Density 	1.11 g/cm3 @ 25°C	SOCMA 2002

Vapor Pressure 	0.03 hPa @ 20°C; 0.46 mm Hg @ 25ºC	SOCMA 2002; HSDB
2006

Log Kow	0.19 @ 25°C	SOCMA 2002

Water Solubility	131 g/L @ 25°C	SOCMA 2002

Henry's Law Constant	6.4 x 10-8 atm-m3/mole @ 25°C	ChemIDPlus 2004;
HSDB 2006

III.	Human Health Assessement

Petitioner’s Toxicological Data

The following are brief summaries of acute, subchronic, chronic,
mutagenic, neurotoxic, developmental and reproductive toxicity data
submitted by Whitmire Micro-Gen Research Labs, Inc.  Please note that
Whitmire submitted a Du Pont MSDS (1994) and studies sponsored by E.I.
du Pont de Nemours and Co., Inc. (MRID# 45740501-45740509). 

Acute Toxicity 

	The acute toxicity information provided by Whitmire Micro-Gen suggests
that DBE has low acute oral and inhalation toxicity, moderate acute
dermal toxicity and primary eye irritation, and mild to severe primary
skin irritation, but is not a dermal sensitizer (Table 5).  

Table 5. Summary of Acute Toxicity Data for DBE Submitted by Whitemire
Micro-Gen Research Labs, Inc.	

Endpoint	Species	Result	Reference*

Oral LD50	Rat	8,191 mg/kg	Du Pont MSDS 1994

Dermal LD50	Rabbit	> 2,250 mg/kg	Du Pont MSDS 1994

Inhalation LC50 (1 hour)	Rat	> 10.7 mg/L (10700 mg/m3)	Du Pont MSDS 1994

Inhalation LC50 (4 hour)	Rat 	> 11.0 mg/L (11000 mg/m3	Du Pont MSDS 1994

Primary Eye Irritation	Unknown	Moderate Eye Irritant	Du Pont MSDS 1994

Primary Skin Irritation	Unknown	Mild to Severe Skin Irritant	Du Pont
MSDS 1994

Primary Skin Irritation	Rabbit	Severe Skin Irritant	Sarver 1989

Skin Sensitization	Unknown	Not a Sensitizer	Du Pont MSDS 1994

In a primary dermal irritation study using the Draize method, 0.5 mL of
the undiluted DBE was applied to the intact clipped back skin of six
rabbits and occluded (Sarver 1989).  One animal had no observed effects
throughout the study.  Mild erythema was observed in four animals and
moderate erythema was observed in one animal 24 hours post-treatment. 
At 48 hours, there was moderate erythema in two animals and slight edema
in one of these.  At 72 hours one animal exhibited severe erythema with
fissuring and slight edema.  These findings indicate that DBE is a
severe skin irritant (Toxicity Category I).

From the Du Pont MSDS (1994):

“A single application of 10 (L to the eye caused corneal opacity.  The
administration of 10 - 100 (L of a similar mixture caused corneal
opacity, transient increases in corneal thickness, and transient corneal
anesthesia.  A single application of approximately 60 mg/kg to the skin
cause transient increases in the distance from the cornea to the
anterior surface of the lens of the eye.”  

And,

 “The mixture is a mild to severe skin irritant and a moderate eye
irritant, but is not a skin sensitizer in animals.  Toxic effects
described in animals from exposure by inhalation include upper
respiratory tract irritation.  A single 4-hour exposure to 60 ppm caused
transient corneal opacity and transient increases in the distance from
the cornea to the anterior surface of the lens of the eye.” 

Subchronic Toxicity 

	Whitmire submitted subchronic repeat dose toxicity studies by E. I. du
Pont de Nemours and Co., Inc. (Henry et al 1981 summary, MRID#457405-06;
Kelly 1987a, MRID#457405-03; and Kelly 1987b, MRID#457405-04).  

	Subchronic Oral.  

In a 14-day oral toxicity study, rats were fed DBE at doses of 10,000,
20,000, or 50,000 ppm (~842, 1684, or 4210 mg/kg/day; Henry et al 1981
summary).  There were no mortalities and no gross or microscopic
pathologic effects observed that could be attributed to exposure to DBE.
 Initial and sporadic weight loss occurred, but no other clinical signs
were detected.  Body weight gain was reduced in rats fed 20,000 or
50,000 ppm, but this reflects, in part, lower food intake.  Test rats
returned to the control diet (ground lab chow) gained slightly more
weight than control rats, however, the 50,000 ppm (~4210 mg/kg/day)
group weighed approximately 7% less than the controls at the end of the
recovery period.  

Subchronic Inhalation.   

Rats were exposed whole-body for six hours a day, five days a week, for
90 days to DBE vapor concentrations of 160 or 400 mg/m3, or to a 1000
mg/ m3 (0.16, 0.40, or 1.0 mg/L) concentration of a DBE aerosol-vapor
mixture (Kelly 1987a).  Mild microscopic lesions of the nasal olfactory
region were observed in all groups exposed to atmospheric DBE in this
study.  No other harmful effects were found upon histopathological
examination.  There were dose-dependent decreases in absolute and
relative liver weights in female rats in all groups exposed to DBE, and
for males exposed to 1.0 mg/L of the DBE aerosol-vapor mixture. 
However, a histopathologic examination revealed no toxic effects in the
liver.  The biological significance of the reduced liver weights is
unknown.  There were slight decreases in blood sodium concentrations in
both male and female 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 considered to be of minimal biological significance.  

	In a second repeat-dose inhalation study, rats were exposed whole-body
to DBE vapor concentrations of 20, 76, or 390 mg/m3 (0.020, 0.076, or
0.390 mg/L; Kelly 1987b).  Nasal lesions were observed in exposed rats
at all DBE exposure concentrations and were still visible after six
weeks.  Absolute liver weights in female rats exposed to 0.390 mg/L 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 effects observed histopathologically. 
The biological significance of the reduced liver weights is unknown. 
Blood sodium concentrations were decreased in all DBE-exposed male rats
and in female rats exposed to 0.076 or 0.390 mg/L of DBE.  Blood sodium
levels were still slightly low in rats exposed to 0.390 mg/L after six
weeks recovery, but this was considered to be of minimal biological
significance.  A no-effect exposure concentration was not established
based on the nasal lesions observed in rats exposed to DBE.

Mutagenicity

The petitioner submitted unpublished mutagenicity studies from E.I. du
Pont de Nemours and Co. (MRID#457405-05; MRID#457405-07 – 457405-09). 
DBE tested negative for 

mutagenicity in the majority of tests, but positive for clastogenic
activity in human lymphocytes. 

In the Salmonella/Microsome Assay (Koops 1977): 

DBE “was tested in Salmonella typhimurium strains TA 1535, TA 1537, TA
1538, TA 98 and TA 100 in concentrations up to 5000 (g per petri plate. 
The compound was not mutagenic in the microbial assays either in the
presence or absence of a liver microsomal system, i.e., it did not
induce a significant increase over the spontaneous mutation
frequency.”

For the Salmonella typhimurium Suspension and Microforward Assays (Arce
1988):

“A sample of dibasic esters (DBE) was tested for mutagenic activity in
Salmonella typhimurium strains TA98 and TA100 in the presence and
absence of a rat liver activation system using a suspension assay, and
in a microforward mutation assay in strain TM677 in the presence of
female rat olfactory activation.  Under the conditions of these assays,
DBE is negative.”

In a Mouse Bone Marrow Micronucleus Assay (Rickard 1987):

“DBE was tested for its ability to induce micronuclei in bone marrow
polychromatic erythrocytes of male and female mice.  The animals were
exposed nose-only to atmospheres of 5.5, 11 or 19 mg/L of DBE aerosol in
air for 6 hrs.  Bone marrow smears were prepared approximately 24, 48,
and 72 hrs after the beginning of exposure and 1000 polychromatic
erythrocytes per animal were scored for the presence of micronuclei.

Significant depression in the ratio of young, polychromatic erythrocytes
to mature, normochromatic erythrocytes was detected in the 11 mg/L- and
19 mg/L-treated females at the 24-hr sampling as compared to their
concurrent negative controls.  No statistically significant increases in
the frequency of micronucleated cells were seen in DBE-treated animals
at any sampling time.  Under the conditions of this assay, DBE does not
induce micronuclei.”

In an in vitro Chromosome Aberration Test (Vlachos 1987):

“A sample of dibasic esters (DBE) was evaluated for in vitro
clastogenic (chromosome-damaging) activity in human lymphocytes with and
without metabolic (S-9) activation.  As demonstrated by cell cycle delay
and/or reduced mitotic index, cytotoxicity was observed at DBE
concentrations greater than or equal to 0.3%, v/v (3.3 mg/mL, based on
approximate average molecular weight of components).  

Chromosome aberration analyses following nonactivated treatments showed
no statistically significant increase in the percent abnormal cells in
cultures treated with DBE.  Under activated conditions, however,
statistically significant increases in structural chromosome aberrations
were reproducibly observed at DBE concentrations greater than or equal
to 0.3%, v/v.  These aberrations were predominant in cells from female
(but not male) donors.  Under the conditions of this assay, DBE is
clastogenic; the test material is positive.”

Reproductive and Developmental Toxicity

Whitmire submitted an inhalation reproduction toxicity study and an
inhalation teratogenicity study produced by E. I. du Pont de Nemours and
Co., Inc. (Kelly 1988, MRID #457405-02; and Alvares 1988,
MRID#457405-01).  DBE caused nasal lesions, liver and lung weight
changes, reduced feed consumption and reduced body weights, but no other
reproductive or teratogenic effects.  

Reproduction Toxicity.

In an inhalation reproduction toxicity study, rats were exposed
whole-body to 0.16 or 0.40 mg/L (160 or 400 mg/m3) of DBE vapor
concentrations, or to 1.0 mg/L (1000 mg/m3) of DBE aerosol-vapor mixture
for six hours per day, five days a week for 14 weeks (Kelly 1988).  DBE
exposure continued while the rats were bred (15 days) and during
gestation (21 days) and lactation (21 days).  Dam exposure to DBE
stopped after the 19th day of gestation and started again on the 4th day
post-partum.  Offspring were not exposed to DBE.  There was minimal
squamous metaplasia in the olfactory epithelium of rats exposed to 0.16
mg/L of DBE, and mild to moderate squamous metaplasia in rats exposed to
0.40 or 1.0 mg/L of DBE.  In addition, there was a dose-dependent
decrease in liver-to-body weight ratios in rats exposed to 0.40 and 1.0
mg/L of DBE, and slightly increased lung-to-body weight ratios and
slightly depressed body weights in rats exposed to 1.0 mg/L of DBE.  The
biological significance of the liver-to-body weight ratios is not known
due to the absence of deleterious pathological effects.  A no-effect
exposure concentration was not established for DBE due to the squamous
metaplasia of the olfactory epithelium in rats exposed to DBE.  Pup
weights were depressed at the 1.0 mg/L (1000 mg/m3) exposed group from
day 1 to day 21 postpartum, but there were no other treatment-related
reproductive effects.  

Developmental Toxicity.

For an inhalation developmental toxicity study, female rats were exposed
whole-body to 0, 0.16, 0.40, or 1.0 mg/L (0, 160, 400, or 1000 mg/m3) of
DBE on GD 7 through 16 (Alvarez 1988).  Maternal body weights were
significantly reduced during the exposure period for rats exposed to 0.4
or 1.0 mg/L of DBE.  Maternal feed consumption was also significantly
reduced for the first six days of the exposure period at these levels. 
There were no observed effects on fetal survival, fetal weight, litter
size or nidations, and no incidences of treatment-related fetal
malformations and variations.  A maternal no-observable-effect level
(NOEL) of 0.16 (160 mg/m3) was determined based on reduced body weight
gains, while a fetal NOEL of 1.0 mg/L (1000 mg/m3) based on the absence
of fetal toxicity at this dose. 

Agency Toxicological Discussion

The Agency has reviewed the data and information submitted by Whitmire
Micro-Gen Research Laboratories, Inc. described in the section above. 
In this section, the Agency provides its review and conclusions
concerning the toxicity data set for DBE submitted by Whitmire, and
additional information from the SOCMA DBE Group submitted as part of the
TSCA Section 4 Enforceable Consent Agreement (ECA) of August 5, 1999 (64
FR 42692).  The reader is referred to this Federal Register Notice for
the full evaluation of these studies.

Acute Toxicity

The Agency reviewed the information submitted by Whitmire for DBE, and
additional information on DBE, DMA, DMG and DMS in studies and robust
summaries provided by the SOCMA DBE Group.  Based on the acute toxicity
study results for DMA, DMG and DMS, the Agency agrees with Whitmire that
DBE has low acute oral toxicity and moderate eye irritation (Table 6).  

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

Table 6. Summary of Acute Toxicity Data for DBE From SOCMA (2002)

Endpoint	Species	DMA	DMG	DMS

Oral LD50	Rat	>5000 to 7500 mg/kg	>5000 mg/kg	>500 and <5000 mg/kg

Dermal LD50	Rabbit	>5000 mg/kg	>5000 mg/kg	>5000 mg/kg

Primary Eye Irritation	Rabbit	Mild to moderate, transient ocular
irritation	Mild to moderate, transient ocular irritation	Mild to
moderate, transient ocular irritation

Primary Skin Irritation	Rabbit	Non-irritating to skin	Non-irritating to
skin	Non-irritating to skin

Subchronic Toxicity

Subchronic Oral.

In the summary of a 14-day subchronic repeat dose oral toxicity study
submitted by Whitmire, DBE exhibited low subchronic oral toxicity.  The
Agency agrees that DBE has low subchronic oral toxicity.  The Agency
determined that DBE has a NOEL of 10,000 ppm (842 mg/kg/day) and a
lowest observed effect level (LOEL) of 20,000 ppm (1,624 mg/kg/day)
based on decreased body weight gain and decreased food consumption in
this study (Henry et al 1981 summary).

Subchronic Dermal.

Whitmire did not submit a repeat dose dermal toxicity study.  The Agency
reviewed 14-day dermal toxicity studies for DBE, dimethyl adipate (DMA),
dimethyl glutarate (DMG) and dimethyl succinate (DMS) that were
submitted to the Agency as part of the ECA (Kirkpatrick 2000). 
Undiluted DBE, DMA, DMG, or DMS was applied to the shaved intact dorsal
skin of rats at doses of 100, 300 or 1000 mg/kg/day for seven days a
week for two weeks.  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.  Based on these results, none of
the chemicals tested was considered very irritating dermally, and all
observed effects were completely reversible.  For DBE, DMA, DMG and DMS,
the Agency determined a no observed adverse effect level (NOAEL) of 1000
mg/kg/day for systemic effects, because there were no mortalities or
clinical effects observed.  The Agency also established a dermal
irritation lowest observed adverse effect level (LOAEL) of 100 mg/kg/day
for these chemicals based on the erythema and edema observed at this
dose.

Subchronic Inhalation.

In the two 90-day inhalation dose studies submitted by Whitmire,
exposure to DBE produced mild microscopic lesions in the nasal region of
rats at all dose levels tested.  The Agency determined a nasal
irritation NOEL < 0.02 mg/L (20 mg/m3) for DBE and a systemic NOEL ≥
0.40 mg/L (390 mg/m3) for DBE based on a lack of other significant
systemic effects.  In the following 90-day inhalation toxicity study,
the Agency determined a NOAEL of 0.01 mg/L (10 mg/m3), and a LOAEL of
0.05 mg/L (50 mg/m3) for DMG 

The Agency reviewed a 90-day inhalation toxicity study in rats
(Bamberger 2000).  Rats were exposed whole-body to 0, 0.01, 0.05, or
0.40 mg/L (0, 10, 50, or 400 mg/m3) DMG, or 0.40 mg/L (400 mg/m3) of DMA
or DMS over a 90-day period.  Decreased body weights and body weight
gain was observed in male rats exposed to 0.40 mg/L (400 mg/m3) of DMA
or DMG.  Male rats exposed to 0.40 mg/L of DMA had lower food
efficiency.  Both male and female rats exposed to 0.40 mg/L of DMA, DMG
or DMS had dose-related minimal to mild degeneration/atrophy of
olfactory mucosa in nasal tissue.  Male rats exposed to 0.05 and 0.40
mg/L DMG had decreased serum testosterone and LH concentrations, but
increased epididymal sperm counts.  The biological significance of these
changes is unknown.  Male rats exposed to 0.40 mg/L of DMS had
significantly increased (141-153% of control) epididymal sperm counts. 
Female rats exposed to 0.40 mg/L of DMS had decreased serum estradiol
concentrations, but it was not determined whether the decrease was a
dose-dependant response to DMS.  NOAELs were not established for DMA and
DMS because effects were observed at the only exposure concentration
tested.  The Agency determined a LOAEL for DMA and DMS of 0.40 mg/L (400
mg/m3) based on increases in epididymal sperm counts, increases in
relative epididymal weight and decreases in serum estradiol
concentrations.  The Agency determined a NOAEL of 0.01 mg/L (10 mg/m3)
and a LOAEL of 0.05 mg/L (50 mg/m3) for DMG based on decreased serum
testosterone and LH concentrations and increased epididymal sperm count.
 

Neurotoxicity

Whitmire did not submit neurotoxicity studies.  In the Agency-reviewed
90-day inhalation study described above, DMA, DMG, and DMS did not
induce neurotoxicity in rats.  There were no microscopic
neuropathological changes that could be attributed to exposure to these
chemicals.  The incidence of axonal/myelin degeneration occurred in rats
exposed to DMA, DMG or DMS at levels comparable to control rats.  There
were no test substance-related effects on functional observational
battery parameters in male and female rats at any dose level of DMA,
DMG, or DMS.

Mutagenicity

Whitmire submitted studies indicating that DBE was non-mutagenic in most
assays (Salmonella/microsome, Salmonella/suspension and microforward,
and mouse bone marrow micronucleus assays), 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.  

The Agency reviewed additional mutagenicity studies sponsored by SOCMA. 
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/m3, 1000 mg/m3, or 2000 mg/m3; Mason et al 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).   

Reproductive and Developmental Toxicity

In the inhalation reproductive toxicity study in rats submitted by the
petitioner, exposure to DBE resulted in reduced body weights in both
pups and adults, and, in adults only, there were nasal lesions, liver
and lung weight changes, and reduced feed consumption.  The Agency
determined a reproductive NOEL of 0.40 mg/L (400 mg/m3) for DBE, and a
lowest effect level (LEL) of 1.0 mg/L (1000 mg/m3) based on decreased
pup weights at weaning.  The Agency also established a systemic NOEL <
0.16 mg/L (160 mg/m3) for DBE and a LEL of 0.16 mg/L (160 mg/m3) based
on squamous metaplasia of the olfactory epithelium.   

In the inhalation teratogenicity study in rats submitted by Whitmire,
there were no developmental or teratogenic effects in pups exposed to
DBE at dose levels that caused maternal effects.  The Agency determined
that the maternal NOEL for DBE is 0.16 mg/L (160 mg/m3) for 6 hours/day,
and determined a maternal LOEL of 0.40 mg/L (400 mg/m3).  The Agency
determined that, in pups, both the NOEL and LOEL are > 1.0 mg/L (1000
mg/m3) based on the absence of any developmental effects.  

The Agency also reviewed an inhalation developmental toxicity study in
rabbits sponsored by the SOCMA DBE Group.  Time-mated rabbits were
administered whole-body inhalation exposures to 0, 0.03, 0.10, 0.30 or
1.0 mg/L (0, 30, 100, 300, or 1000 mg/m3) of DMG for six hours each day
on gestation days (GD) seven to 28 (Munley 2003).  There were two
mortalities in does exposed to 1.0 mg/L (1000 mg/m3) DMG.  One litter at
this dose consisted entirely of late resorptions, but there were no
resorptions of live fetuses observed at this dose.  A statistically
significant decrease in the number of implantation sites and a lower
mean corpora lutea count was observed in does administered 1.0 mg/L DMG.
 Wet fur and reductions in food consumption were also observed in does
at this dose level.  Maternal body weight significantly decreased and
clear ocular discharge was observed in rabbits treated with 0.30 and 1.0
mg/L of DMG.  There were no effects on pup viability, sex ratio, or pup
body weight at any dose level.  However, the Agency determined that an
increase in sternebral ossification at the 1.0 mg/L (1000 mg/m3) of DMG
was treatment-related.  The Agency established a maternal NOAEL of 0.1
mg/L (100 mg/m3) and a LOAEL of 0.30 mg/L (300 mg/m3) of DMG based on
maternal body weight reductions and clear ocular discharge.  The NOAEL
for developmental toxicity was 0.3 mg/L DMG and the developmental LOAEL
was the highest concentration tested, 1.0 mg/L (1000 mg/m3) based on
increased sternebral ossification. 

	Based on the absence of developmental toxicity for DBE 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 formulations.  For
the same reason, a safety factor analysis has not been used to assess
risk and, therefore, the additional tenfold safety factor for the
protection of infants and children is also unnecessary.  

	Carcinogenicity

	

	Whitmire did not submit carcinogenicity data on DBE, however, based on
the results of the mutagenicity studies reviewed above, the Agency does
not consider DBE to be a cancer concern.

Metabolism and Pharmacokinetics

Whitmire stated in their Notice of Filing that:

“The compounds that comprise DBE are derivatives of three naturally
occurring dicarboxylic acids (adipic, glutaric and succinic acids). 
Specifically, DBE consists of dimethyl esters of these three acids.  Due
to the presence of carboxylesterases and other diesterases in mammalian
tissues, these dimethyl esters are rapidly cleaved in the body to form
their corresponding dicarboxylic acids: adipic, glutaric and succinic
acids.”  

And,

“By the oral route, the toxicity of DBE metabolites is low.  The
principle metabolites of DBE are naturally occurring dicarboxylic acids:
succinic, glutaric, and adipic acids.  Adipic and succinic acids are
classified as Generally Recognized As Safe (GRAS) by the U.S. Food and
Drug Administration for substances directly added to human food (CFR
184.1).  Although glutaric acid is not classified as GRAS, its relative
safety can be inferred since its carbon chain length (5) is intermediate
of adipic (6) and succinic (4) acids.  The dicarboxylic acids are
substrates for glycolytic and gluconeogenic reactions in the cell, and
as such, the components of DBE possess nutritional value (Ladriere et al
1996).

By the inhalation route, the metabolites of DBE are irritants to the
nasal mucosa, and are likely responsible for the metaplasia of the
olfactory epithelia observed in exposed rats.  In vitro studies indicate
that inhibition of nasal carboxylase activity reduces the toxicity in
rat nasal explants (Trela and Bogdanffy 1991).  In the rat,
carboxylesterases appear to be preferentially localized in cells of the
Bowman’s gland and sustentacular epithelial cells which are
immediately adjacent to olfactory nerve cells (Olson et al. 1993).”

	Agency Discussion of Metabolism:  

The Agency reviewed the robust summaries submitted by the SOCMA DBE
Group (2002) as part of the EPA High Production Volume (HPV) Challenge
Program for information on the metabolism of DBE and the abstract for
the Ladriere et al (1996) study described in the Whitmire Notice of
Filing.  

	In the metabolism study of DBE components, 80 (M/g of DMS displayed
significant nutritional value when infused in starved rats, and may
prevent imbalances in ATP generation and select metabolic situations
(Ladriere et al 1996).  However, mitochondrial ATP synthesis was
inhibited 11 to 27% in rat hepatic mitochondria at 100 (M/g of the
dibasic esters, with an order of potency of DMA> DMG > DMS (Bodgdanffy
and Londergan 1989 as cited in SOCMA 2002).  DBE-induced cytotoxicity
appears to result from esterase-mediated hydrolysis to acid metabolites
and interference with intermediary metabolism.  

In studies by Bodgdanffy et al, and Trela and Bogdanffy (1991 and 1991b;
both as cited in SOCMA 2002), DMA, DMG and DMS induced increases in rat
nasal explant acid phosphatase release.  Both the monomethyl ester (MME)
and diacid metabolites of DBE are cytotoxic, but the level of
contribution of each to cytotoxicity in vivo may depend on their rate of
formation during exposure.  Bodganffy et al (1991b as cited in SOCMA
2002) found further support showing that organic acid accumulation in
the olfactory mucosa plays a significant role in the pathogenesis of
DBE-induced nasal lesions.   

Trela and Bogdanffy (1990 and 1991a, both as cited in SOCMA 2002)
conducted an 

in vitro study to determine whether DBE toxicity is dependent on
metabolic activation by carboxylesterase.  DBE caused a dose-related
increase in rat nasal explant acid phosphatase release and a parallel
increase in carboxylesterase-mediated MME formation.  MME concentrations
and acid phosphatase release were higher in olfactory tissues than in
respiratory tissues.  Rat nasal tissue treated with a carboxylesterase
inhibitor, bisnitrophenyl phosphate, had markedly reduced MME formation
and DBE-induced cytoxicity.

	From a study using rat nasal tissues (Olson et al 1993, as cited in
SOCMA 2002): 

“The enzymatic esterase activity of carboxylesterases is integral to
the nasal toxicity of many esters, including DMG, DMS, and DMA. 
Inhalation of these esters specifically damages the olfactory mucosa of
rodents….Within the olfactory mucosa, anti-carboxylesterase did not
bind to sensory neurons, the target cell for ester-initiated toxicity;
these cells apparently lack carboxylesterase.”  

The carboxylesterases were instead bound by cells of Bowman’s glands
and sustentacular epithelial cells adjacent to the olfactory sensory
neurons.

IV.	Environmental Fate Characterization and Drinking Water
Considerations

	Whitmire did not submit environmental fate data for DBE.  	The Agency
reviewed information available on the Hazardous Substances Data Bank
(2006) and the robust summaries of DBE, DMA, DMG, and DMS sponsored by
SOCMA (2002) as part of the EPA HPV Challenge Program. 

 

	DMA and DMS are expected to photodegrade if released to the air via
reaction with photochemically-produced hydroxyl radicals and have
estimated half-lives of four and 14 days based on vapor pressures of
0.06 and 0.46 mm Hg (HSDB 2006).  DMG is also expected to photodegrade
in the atmosphere based on a vapor pressure of 0.70 mm Hg.  DMA and DMS
are expected to have high mobility in soil based on Kocs of 11 and 37
(estimated from Log Kows of 1.03 and 0.19).  DMG has a Log Kow (0.62)
and is also expected to leach from soils.  DMA, DMG and DMS are expected
to partition primarily to water and soil (SOCMA 2002).  

DMA and DMS have estimated hydrolysis half-lives of ≥ 2 years at pH 7
and 60 to 85 days at pH 8 due to the presence of hydrolysable functional
groups (SOCMA 2002 and HSDB 2006).  DMA and DMS are not expected to
adsorb to suspended solids and sediments in water, and are not expected
to volatilize from surface waters based on their Henry’s Law constants
(9.77 x 10-7 atm-m3/mole and 6.4 x 10-8 atm-m3/mole) (HSDB 2006).  DMG
has a Henry’s Law constant of 6.4 x 10-7 and is also not expected to
adsorb to soil and sediments in water or to volatilize from surface
waters. 

	DMA, DMG, and DMS have similar physical-chemical properties and are
components of the mixture DBE.  As with its component chemicals, DBE is
expected to photodegrade when released to air, with a calculated
half-life of 24.8 days (SOCMA 2002).  If released to soil, DBE is
expected to have high mobility through soil, based on its Log Kow of
0.19.  In a microbial biodegradation test using the shake-flask method,
DBE had a half-life of 2.5 to 3.2 days.  If released to water, DBE is
not expected to volatilize from surface waters or adsorb to suspended
solids and sediments in water, but will biodegrade in the presence of
bacteria in a matter of days and hydrolyze in a matter of months to
years.  

V.	Aggregate Exposure Assessment 

A.	Petitioner’s Exposure Assessment

Whitmire stated in their Notice of Filing:

“Dietary exposure due to use of DBE as an antifreeze agent is believed
to be minimal…DBE is not intended to be directly applied to foods. 
Rather, the use of DBE in pesticide formulations for food handling areas
will be limited to sprays and aerosols for crack/crevice applications. 
Any incidental dietary exposure to DBE from such uses will be minimal in
comparison to the currently permitted use of DBE component, dimethyl
succinate, as a food additive in beverages, ice cream, candy, and baked
goods (CFR 21.3.170-199).  Furthermore, the levels of dimethyl esters
present in food as a result of DBE application in food areas are likely
to be far less, on a molar equivalent basis, than the levels of
naturally occurring dicarboxylic acids present in foods.”

And,

“Because DBE-containing pesticide formulations are not applied to
agricultural crops, its migration to groundwater aquifers or to surface
water bodies that may serve as suitable sources of drinking water is not
anticipated.”

And, finally,

“Furthermore, because the components of DBE are readily metabolized to
polar, water-soluble metabolites, DBE is not expected to be persistent
in biological tissues.  Because DBE is irritating to the skin and nasal
passages, any exposures are expected to be self-limiting.”

Agency Exposure Discussion

	In examining aggregate exposure, the FFDCA section 408 directs EPA to
consider available information concerning exposures from the pesticide
residue in food and all other nonoccupational exposures, including
drinking water (ground water or surface water) and exposure through
pesticide use in gardens, lawns, or buildings (residential and other
indoor uses).  For DBE, a qualitative assessment for all pathways of
human exposure (food, drinking water, and residential) is appropriate
given the lack of human health concerns associated with exposure to DBE
as an inert ingredient in pesticide formulations.

	The use of DBE in pesticide products is being limited to 10% or less of
microencap-sulated pesticide formulations with the insecticide active
ingredient cyfluthrin.  Uses of cyfluthrin are currently limited to
food-use applications such as spot and crack and crevice treatments in
food processing plants and food storage areas, and it is typically
applied by commercial applicators.  Dietary exposures of concern from
residues in food and drinking water are not anticipated.  The
microencapsulated formulation will reduce the potential for residential
exposures (inhalation and dermal) to a minimal level.  DBE is also used
in non-pesticide consumer products such as paint solvents.  The use of
DBE as an inert ingredient in pesticide formulations, with the above
limitations, is not expected to contribute significantly to exposures
from its use in non-pesticide consumer products.

	The Agency concludes that dietary and residential exposures will be
minimal and exposures of concern are not anticipated from the inert
ingredient use of DBE considering the limitations imposed by its
proposed use as a solvent material/anti-freeze limited to 10% or less of
microencapsulated pesticide formulations with the active ingredient
cyfluthrin. 

VI.	Cumulative Exposure

	Section 408(b)(2)(D)(v) of FFDCA requires that, when considering
whether to establish, modify, or revoke a tolerance, the Agency consider
"available information" concerning the cumulative effects of a
particular pesticide's residues and "other substances that have a common
mechanism of toxicity." 

	Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mechanism of toxicity, EPA has not made a
common mechanism of toxicity finding as to DBE and any other substances
and, this material does not appear to produce a toxic metabolite
produced by other substances.  For the purposes of this tolerance
action, therefore, EPA has not assumed that DBE has a common mechanism
of toxicity with other substances.  For information regarding EPA's
efforts to determine which chemicals have a common mechanism of toxicity
and to evaluate the cumulative effects of such chemicals, see the policy
statements released by EPA's Office of Pesticide Programs concerning
common mechanism determinations and procedures for cumulating effects
from substances found to have a common mechanism on EPA's website at  
HYPERLINK "http://www.epa.gov/pesticides/cumulative/" 
http://www.epa.gov/pesticides/cumulative/ .

VII.	Ecotoxicity and Ecological Risk Characterization

A.	Petitioner’s Ecological Data

	According to the Du Pont MSDS (1994) submitted by Whitmire, DBE has an
LC50 (96-hour) of 18-24 mg/L in fathead minnows, and an LC50 (48-hour)
of 112-150 mg/L in the invertebrate Daphnia magna.  

Agency Ecological Risk Discussion 

	The Agency concludes that DBE does not pose an ecological risk to
terrestrial or aquatic species based on its use pattern as a
microencapsulated solvent/antifreeze in pesticide formulations, high
volatility and photolytic properties, and low acute oral and inhalation
toxicity in terrestrial animals and low to moderate toxicity in marine
invertebrates and fish.  DBE is expected to have low potential to
bioconcentrate in aquatic organism because its components DMA, DMG and
DMS have low bioconcentration factors (1.1, 3.2, and 1.2, respectively)
(SOCMA 2002).  

VIII.	Risk Characterization  

A.	Human Health	

DBE has low acute oral and inhalation toxicity and low subchronic oral
toxicity (NOEL = 842 mg/kg/day).  In acute eye toxicity studies on the
rabbit, DBE had mild to moderate eye

irritation.  In subchronic inhalation studies, DBE had a systemic
inhalation NOEL ≥ 0.40 mg/L (400 mg/m3), but a nasal irritation NOEL <
0.02 mg/L (20 mg/m3).  DBE did not induce neurotoxicity or
carcinogenicity in the studies reviewed, and it was negative for
mutagenicity in most tests, but positive for chromosomal aberrations
under activated conditions.  In a repeat-dose inhalation reproduction
toxicity study, DBE had a NOEL of 0.40 mg/L (400 mg/m3) and a LEL of 1.0
mg/L (1000 mg/m3) based on decreased pup weights at weaning.  In
repeat-dose inhalation exposure studies, developmental toxicity was
observed at higher doses (1.0 mg/L or 1000 mg/m3) than maternal toxicity
(0.16 mg/L or 160 mg/m3).  

Dermal irritation was not observed in animals exposed to DBE for four
hours, but 24 hours of exposure to DBE caused mild to moderate
irritation observed at 24 and 48 hours post-exposure.  At 72 hours, one
rabbit had slight edema and severe erythema, but no edema and no mild to
moderate erythema were observed in the remaining rabbits.  DBE was also
found to be non-irritating to the skin of guinea pigs, however the
duration of exposure was not provided.  DBE was also not considered to
be a skin-sensitizer in guinea pigs.  In repeat-dermal exposure studies
conducted on the rat, DBE had a systemic dermal NOEL of 1000 mg/kg/day,
and dermal irritation LOAEL of 100 mg/kg/day based on the slight, but
reversible, erythema and edema. 

	The use of DBE in pesticide products is being limited to 10% or less of
microencap-sulated pesticide formulations with the insecticide active
ingredient cyfluthrin.  Uses of cyfluthrin are currently limited to
food-use applications such as spot and crack and crevice treatments in
food processing plants and food storage areas, and it is typically
applied by commercial applicators.  Dietary exposures of concern from
residues in food and drinking water are not anticipated.  The
microencapsulated formulation and its restriction to use with one active
ingredient will reduce the potential for residential exposures
(inhalation and dermal) to a minimal level.  DBE is also used in
non-pesticide consumer products such as paint solvents.  The use of DBE
as an inert ingredient in pesticide formulations, with the above
limitations, is not expected to contribute significantly to exposures
from its use in non-pesticide consumer products.

	The toxicity database is sufficient for DBE and potential exposure is
adequately characterized based on the significant limitations of its
use.  In terms of hazard, there are low concerns and no residual
uncertainties regarding prenatal and/or postnatal toxicity.  Considering
the low to moderate acute and subchronic toxicity and that developmental
effects were observed at or above the level of maternal toxicity,
effects of concern are not anticipated from the application of DBE when
limited to 10% or less of microencapsulated pesticide formulations with
the active ingredient cyfluthrin,

	Taking into consideration all available information on DBE, it has been
determined that there is a reasonable certainty that no harm to any
population subgroup (including infants and children) will result from
aggregate exposure to DBE when considering exposure through food
commodities and all other non-occupational sources for which there is
reliable information.  Therefore, it is recommended that the exemption
from the requirement of a tolerance established for residues of DBE when
used as an inert ingredient in pesticide products can be considered safe
under section 408(q) of the FFDCA.  

Ecological Assessment

	The Agency concludes that DBE does not pose an ecological risk of
concern to terrestrial or aquatic species based on its use pattern as a
microencapsulated solvent/antifreeze in pesticide formulations, high
volatility and photolytic properties, low toxicity in terrestrial
animals and low to moderate toxicity in marine invertebrates and fish,
and low potential to bioconcentrate in aquatic organisms.

REFERENCES

Alvarez, L.  1988.  Teratogenicity Study of Dibasic Esters in Rats. 
Unpublished study by E.I. du Pont de Nemours and Co., Inc. February 11,
1988. MRID#457405-01. 

Arce, G.T.  1988.  Mutagenicity Testing of Dibasic Esters in The
Salmonella typhimurium Reverse and Microforward Suspension Assays. 
Unpublished study by E.I. du Pont de Nemours and Co., Inc. February 15,
1988.  MRID#457405-09.

Bamberger, J.R.  2000.  Dimethyl Glutarate, Dimethyl Succinate, and
Dimethyl Adipate:  90-Day Inhalation Toxicity Study in Rats. 
Unpublished study E.I. du Pont de Nemours and Co., Inc.  December 8,
2000.  

ChemIDPlus. 2004.  U.S. National Library of Medicine. National
Institutes of Health, Department of Health & Human Services.  Last
modified: September 9, 2004.  <http://chem.sis.nlm.nih.gov/chemidplus/>.

Clare, M.G. et al.  2002.  Dimethyl Glutarate: Mammalian Cell Mutation
Assay.  Unpublished study by Huntingdon Life Sciences Ltd., England. 
February 11, 2002.  

	Du Pont Chemicals. 1994. Material Safety Data Sheet for DBE. January
19, 1994.

HSDB. Hazardous Substance Data Bank. 2006. U.S. National Library of
Medicine,

National Institutes of Health.  Updated: April 8, 2006 
<http://toxnet.nlm.nih.gov>. 

 Henry, J. et al. 1981.  Summary of a 14-Day Oral Subacute Feeding Study
in Rats (Summary Only). Unpublished study by E.I. du Pont de Nemours and
Co., Inc. December 15, 1981. MRID#457405-06. 

Kelly, D.P.  1987a. 90-Day Inhalation Toxicity Study in Rats with
Dibasic Esters (DBE).  Unpublished study by E.I. du Pont de Nemours and
Co., Inc. February 24, 1987.  MRID# 457405-03.

Kelly, D.P.  1987b.  90-Day Inhalation Toxicity Study in Rats with
Dibasic Esters (DBE).  Unpublished study by E.I. du Pont de Nemours and
Co., Inc. November 12, 1987. MRID#457405-04.

Kelly, D.P.  1988.  Inhalation Reproduction Study in Rats Exposed to
Dibasic Esters (DBE).  Unpublished study by E.I. du Pont de Nemours and
Co., Inc. April 5, 1988.  

MRID#457405-02.

	Kirkpatrick, J.B.  2000.  A 14-Day Dermal Toxicity Study with Dimethyl
Adipate (DMA), Dimethyl Succinate (DMS), Dimethyl Glutarate (DMG) and
the Mixture (DBE) in Rats.  Unpublished study sponsored by SOCMA DBE
Group as part of the ECA of 1999.  February 24, 2000.

Koops, A.  1977.  Mutagenic Activity of Dibasic Acid Esters in the
Salmonella/Microsome Assay.  Unpublished study by E.I. du Pont de
Nemours and Co., Inc. May 27, 1977.  MRID#457405-05.

Mason, C.E. et al.  2001.  Dimethyl Adipate: Rat Micronucleus Test. 
Unpublished study by Huntingdon Life Sciences Ltd., England.  May 16,
2001.

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Sarver, J.W.  1989.  Skin Irritation Test in Rabbits of DBE. Unpublished
study by E.I. du Pont de Nemours and Co., Inc. June 20, 1989.  

Synthetic Organic Chemical Manufacturers Association (SOCMA) Dibasic
Esters (DBE) Group. 2002.  EPA/OPPT/High Production Volume Challenge
Program.  Robust Summaries and Test Plans for Dibasic Esters Category. 
Posted January 30, 2002. <  HYPERLINK "http://www.epa.gov/chemrtk/" 
http://www.epa.gov/chemrtk />

	Vlachos, D.A.  1987. In Vitro Evaluation of Dibasic Esters (DBE) For
Chromosome Aberrations in Human Lymphocytes.  Unpublished study by E.I.
du Pont de Nemours and Co., Inc. October 9, 1987.  MRID#457405-08  

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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

    OFFICE OF  

            PREVENTION, PESTICIDES, AND 

        TOXIC SUBSTANCES