Document ID: EPA-HQ-OPP-2007-0182-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-08-29T04:00Z

SEQ CHAPTER \h \r 1 Company Notice of Filings for DIBASIC ESTERS

 (Dated: 8/1/98)

EPA Registration Division contact: [Amelia M. Acierto, 703-308-8377]	

		

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1. [Whitmire Micro-Gen Research Laboratories, Inc.] 

 

PP [#5E4442]

	EPA has received a pesticide petition (PP [#5E4442])from [Whitmire
Micro-Gen Research Laboratories, Inc.], [3568 Tree Court Industrial
Bvd., St. Louis MO 63122-6682].   proposing pursuant to section 408(d)
of the Federal Food, Drug and Cosmetic Act, 21 U.S.C. 346a(d), to amend
40 CFR Part 180 to establish an exemption from the requirement of a
tolerance for [Dibasic esters (DBE)].  EPA has determined that the
petition contains data or information regarding the elements set forth
in section 408(d)(2) of the FFDCA; however, EPA has not fully evaluated
the sufficiency of the submitted data at this time or whether the data
supports granting of the petition.  Additional data may be needed before
EPA rules on the petition.

A. Residue Chemistry                                        

DBE is a colorless liquid that consists of a mixture of dimethyl
glutarate (55-75%), dimethyl adipate (10-25%), and dimethyl succinate
(19-26%).  The identity and properties of each component of DBE is
summarized in the table below.

DBE Component	CAS #	Formula	MW	Density

Dimethyl succinate	106-65-0	CH3OOC(CH2)2COOCH3	146.14	1.12

Dimethyl glutarate	1119-40-0	CH3OOC(CH2)3COOCH3	160.17	1.09

Dimethyl adipate	627-93-0	CH3OOC(CH2)4COOCH3	174.20	1.06

1. Plant metabolism. [NA-REMOVE].

2. Analytical method. [DBE vapors may be detected by gas chromatography
using a flame ionization detector, for which a detection limit of 0.7
ug/L has been reported (Morris et al. 1991).  In aqueous media, DBE may
be detected by high pressure liquid chromatography using a diode ray
detector, for which no detection limit was reported (Bogdanffy et al.
1991)].

3. Magnitude of residues. [NA-REMOVE].

B. Toxicological Profile 

1. Acute toxicity. [Acute (24 hours) dermal contact with DBE produced
mild to severe erythema and mild edema in rabbits exposed to undiluted
DBE (Sarver, 1989).  Fourteen-day dietary exposure to large
concentrations of DBE in feed (10,000, 20,000, or 50,000 ppm) did not
produce any gross or microscopic pathological changes in rats (Henry,
1981).  Body weight gain was slightly reduced in a dose-dependent manner
at the end of the exposure period.  This study identified a NOEL of
10,000 ppm (842 mg/kg-day).  Similarly, body weight gains were
significantly reduced in rats exposed via inhalation to concentrations
of 0.4 and 1.0 mg/L DBE for 6 hours/day, 5 days/week for 2 weeks
(Alvarez, 1988).  In both studies, however, decreases in body weight
gain appear to be attributable to a dose-dependent decreases in feed
consumption, rather than a pathological change caused by treatment].

2. Genotoxicity. [DBE was not mutagenic in a Salmonella typhimurium
assay in the presence or absence of a rat liver activation system
(Koops, 1977; Arce, 1988).  A significant increase in chromosomal
aberrations was observed in vitro in human lymphocytes when
metabolically activated  (using a rat liver S-9 fraction), but not in
the absence of metabolic activation (Vlachos, 1987).  However, in an in
vivo mouse bone marrow micronucleus assay, no significant increase in
micronucleated cells were observed (Rickard, 1987)].

3. Reproductive and developmental toxicity. [No effects on fetal
survival, fetal weight, litter size,  implantation, or the incidence of
terata were observed in rats exposed via inhalation to concentrations
0.16, 0.4, or 1.0 mg/L DBE on days 7 through 16 of gestation (Alvarez,
1988).  In addition, no treatment-related effects were observed for
various reproduction indices (male fertility, female fertility, born
alive, viability, gestation, and lactation) in rats exposed via
inhalation to 0.16, 0.4, or 1.0 mg/l DBE for 14-weeks prior to mating,
and continuing through breeding (15 days), gestation (21 days), and
lactation (21 days).   Pup weights were significantly reduced at
concentrations of 1.0 mg/L DBE, however,  this appears to be
attributable to decreased food intake and body weight gain in maternal
animals, which were significantly depressed at concentrations of 0.4
mg/L and higher (Kelly, 1988)].

4. Subchronic toxicity. [In rats exposed via inhalation to 0.02, 0.08,
or 0.40 mg/L DBE for 6 hours/day, 5 days/week, for 14 weeks, the only
histopathological change of significance included mild squamous
metaplasia in the olfactory epithelium (Kelly, 1987).  Slight changes in
liver weight, body weight, and blood calcium and sodium levels were also
reported, however, these were considered to be of minimal biologic
significance.  A no effect concentration was not identified for nasal
effects.  However, for systemic effects, the highest concentration
tested (0.4 mg/L) was considered to be a NOEL].

5. Chronic toxicity. [In rats exposed via inhalation to 0.16, 0.4, or
1.0 mg/L DBE for 22 weeks, the only histopathological change of
significance included squamous metaplasia in the olfactory epithelium
(Kelly, 1988).  The incidence and severity of the nasal lesions was
greater in this study in comparison to the 14-week study discussed
above.  A no effect concentration was not identified for nasal effects].

6. Animal metabolism. [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].

7. Metabolite toxicology. [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)].

8. Endocrine disruption. [Mono- and dimethyl esters of succinic acid are
capable of stimulating insulin release in rats (Vicent et al. 1994;
Ladriere et al. 1996).  However, rather than evidence of endocrine
disruption, this observation is likely attributable to the nutritional
value of DBE].

C. Aggregate Exposure

1. Dietary exposure. [Dietary exposure due to use of DBE as an
antifreeze agent is believed to be minimal, as is discussed for food and
drinking water below].

2. Food. [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].

3. Drinking water. [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.].

4. Non-dietary exposure. [The greatest potential for exposure to DBE is
to pesticide applicators, who may be exposed via inhalation or dermal
routes.  USEPA’s Pilot Interdisciplinary Risk Assessment Team (PIRAT,
1997) evaluated potential exposures to workers using a handwand
applicator or a backpack applicator.   

For the handwand applicator scenario, assuming a unit exposure of 29.178
mg/lb handled for the dermal pathway and a unit exposure of 1.063 mg/lb
handled for the inhalation pathway, average daily doses of 0.03 and
0.001 mg/kg-day were calculated for dermal and inhalation exposures,
respectively.  In their calculations, USEPA conservatively assumed 100%
absorption via both routes, a 70 kg body weight, an application rate of
0.08 lbs DBE/day for product containing 4.2% (w/w) DBE yielding a finish
spray containing 0.065% DBE. 

For the backpack applicator scenario, assuming a unit exposure of
482.581 mg/lb handled for the dermal pathway and a unit exposure of
0.329 mg/lb handled for the inhalation pathway, average daily doses of
1.0 and 0.007 mg/kg-day were calculated for dermal and inhalation
exposures, respectively.  In their calculations, USEPA conservatively
assumed 100% absorption via both routes, a 70 kg body weight, an
application rate of 0.14 lbs DBE/day for product containing 4.2% (w/w)
DBE yielding a finish spray containing no more than 1% DBE].

D. Cumulative Effects

[Since exposures to DBE from food and drinking water are believed to be
minimal, the potential for cumulative exposures (i.e., summed across
multiple routes of exposure) exceeding those estimated for pesticide
applicators is very small.  Furthermore, because the components of DBE
are readily metabolized to polar, water-soluble metabolite, 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.  For these reasons, the potential for cumulative
effects from exposure to DBE is low].

E. Safety Determination

1. U.S. population.[Potential dietary exposures to DBE are not likely to
pose a significant risk to the general U.S. population. The components
of DBE are dimethyl esters of three naturally occurring dicarboxylic
acids (adipate, succinate, and glutarate), two of which are currently
classified as GRAS by the U.S. Food and Drug Administration for direct
addition to human foods.  It should be noted that the presence of methyl
groups does not increase the toxicity of DBE.  To the contrary,
methylation is one of the metabolic pathways by which the body attempts
to detoxify xenobiotics (Hodgson and Levi, 1987).  As such, dimethyl
succinate, dimethyl glutarate, and dimethyl adipate are likely to be
less toxic than succinate, glutarate, and adipate, respectively.  In
support of this statement, Trela and Bogdanffy (1991) reported that
succinate, glutarate, and adipate produced concentration-dependent
increases in cytotoxicity in a rat nasal explant system.  The
cytotoxicity of DBE in the same system, however, was greatly diminished
by a carboxylesterase inhibitor which effectively blocks the conversion
of DBE to the dicarboxylic acids.

The potential hazards posed by DBE  to pesticide applicators exposed via
 inhalation and dermal routes are low.  For the handwand applicator, the
average daily dermal and inhalation doses of 0.03 mg/kg-day and 0.001
mg/kg-day, respectively, are well below exposures which are believed to
be without risk of deleterious effects (8.42 mg/kg-day for dermal
exposures, and 0.38 mg/kg-day for inhalation exposures).  Specifically,
USEPA conservative assumptions for a worker applying a DBE-containing
(4.2% w/w) product with a handwand maintain margin-of-exposures of 280
and 380 for dermal and inhalation exposures, respectively.  Based on
these margin-of-exposures, workers applying a hypothetical formulation
containing 100% DBE would still be adequately protected.  For the
backpack applicator, the average dermal and inhalation doses of 1 and
0.007 mg/kg-day, are also below exposures which are believed to be
without risk of deleterious effects.  USEPA’s conservative assumptions
for a backpack applicator maintain a margin-of-exposure of 8 and 54 for
dermal and inhalation exposures, respectively.  Based on these
margin-of-exposures, workers applying a hypothetical formulation
containing 33% DBE would still be adequately protected.  As this
percentage far exceeds the levels anticipated for DBE-containing
products, no concentration limit need  be specified for DBE.].

2. Infants and children. [There is no information available which
suggests that infants and children are more highly exposed or are more
susceptible to the effects of DBE.  The lack of any significant toxicity
in reproductive/developmental studies on DBE suggests the that growing
organisms are not at increased risk.  Since potential dietary exposures
to infants and children are minimal based on anticipated use patterns,
and since the toxicity of DBE by the oral route is very low, it is
unlikely that these types exposures will result in any deleterious
effects.  Direct exposures to infants and children via the inhalation
and dermal routes are not anticipated for the intended use of DBE].

F. International Tolerances

[Whitmire is not aware of any tolerances for DBE outside of the United
States].