[Federal Register Volume 63, Number 246 (Wednesday, December 23, 1998)]
[Notices]
[Pages 71126-71131]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-33834]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-849; FRL-6047-7]
Notice of Filing of Pesticide Petitions
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
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SUMMARY: This notice announces the initial filing of pesticide
petitions proposing the establishment of regulations for residues of
certain pesticide chemicals in or on various food commodities.
DATES: Comments, identified by the docket control number PF-849, must
be received on or before January 22, 1999.
ADDRESSES: By mail submit written comments to: Public Information and
Records Integrity Branch, Information Resources and Services Division
(7502C), Office of Pesticides Programs, Environmental Protection
Agency, 401 M St., SW., Washington, DC 20460. In person bring comments
to: Rm. 119, CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
Comments and data may also be submitted electronically to: docket@epamail.epa.gov. Follow the instructions under ``SUPPLEMENTARY
INFORMATION.'' No confidential business information should be submitted
through e-mail.
Information submitted as a comment concerning this document may be
claimed confidential by marking any part or all of that information as
``Confidential Business Information'' (CBI). CBI should not be
submitted through e-mail. Information marked as CBI will not be
disclosed except in accordance with procedures set forth in 40 CFR part
2. A copy of the comment that does not contain CBI must be submitted
for inclusion in the public record. Information not marked confidential
may be disclosed publicly by EPA without prior notice. All written
comments will be available for public inspection in Rm. 1132 at the
address given above, from 8:30 a.m. to 4 p.m., Monday through Friday,
excluding legal holidays.
FOR FURTHER INFORMATION CONTACT: The product manager listed in the
table below:
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Office location/
Product Manager telephone number Address
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James Tompkins................ Rm. 239, CM #2, 703- 1921 Jefferson
305-5697, e- Davis Hwy,
mail:tompkins.jimepam Arlington, VA
ail.epa.gov.
Amelia M. Acierto............. Rm. 707A, CM #2, 703- Do.
308-8377, e-
mail:acrieto.ameliaep
amail.epa.gov.
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SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions as
follows proposing the establishment and/or amendment of regulations for
residues of certain pesticide chemicals in or on various food
commodities under section 408 of the Federal Food, Drug, and Comestic
Act (FFDCA), 21 U.S.C. 346a. EPA has determined that these petitions
contain data or information regarding the elements set forth in section
408(d)(2); 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.
The official record for this notice of filing, as well as the
public version, has been established for this notice of filing under
docket control number [PF-849] (including comments and data submitted
electronically as described below). A public version of this record,
including printed, paper versions of electronic comments, which does
not include any information claimed as CBI, is available for inspection
from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal
holidays. The official record is located at the address in
``ADDRESSES'' at the beginning of this document.
Electronic comments can be sent directly to EPA at:
opp-docket@epamail.epa.gov
Electronic comments must be submitted as an ASCII file avoiding the
use of special characters and any form of encryption. Comments and data
will also be accepted on disks in Wordperfect 5.1 file format or ASCII
file format. All comments and data in electronic form must be
identified by the docket number [PF-849] and appropriate petition
number. Electronic comments on notice may be filed online at many
Federal Depository Libraries.
List of Subjects
Environmental protection, Agricultural commodities, Food additives,
Feed additives, Pesticides and pests, Reporting and recordkeeping
requirements.
Dated: December 15, 1998.
James Jones,
Director, Registration Division, Office of Pesticide Programs.
Summaries of Petitions
Petitioner summaries of the pesticide petitions are printed below
as required by section 408(d)(3) of the FFDCA. The summaries of the
petitions were prepared by the petitioners and represent the views of
the petitioners. EPA is publishing the petition summaries verbatim
without editing them in any way. The petition summary announces the
availability of a description of the analytical methods available to
EPA for the detection and measurement of the pesticide chemical
residues or an explanation of why no such method is needed.
1. Monsanto Company
PP 7F4840
EPA has received a pesticide petition (PP 7F4840) from Monsanto
Company, 600 13th Street, N.W., Suite 600, Washington, D.C., 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 by establishing a tolerance
for residues of sulfosulfuron; 1-(4,6-dimethoxypyrimidin-2-yl)-3-(2-
ethanesulfonyl-imidazo 1,2-a pyridine-3-yl)sulfonylurea, and its
metabolites converted to 2-(ethylsulfonyl)-imidaazol 1,2-a pyridine and
calculated as sulfosulfuron in or on the following raw agricultural
commodities and animal products:
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Commodity Part per million (ppm)
------------------------------------------------------------------------
Wheat.....................................
Grain................................... 0.02
Straw................................... 0.1
Hay..................................... 0.3
Forage.................................. 4.0
Animal Products...........................
Milk.................................... 0.006
[[Page 71127]]
Fat (cattle, goats, horses, hogs, sheep) 0.005
Meat (cattle, goats, horses, hogs, 0.005
sheep).
Meat by-products (cattle, goats, horses, 0.05
hogs, sheep).
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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 maybe needed before EPA rules on the
petition.
A. Residue Chemistry
1. Plant metabolism. Metabolism of sulfosulfuron in plants is
negligible. The nature of the major sulfosulfuron residues in wheat
matrices depends primarily on the mode of application with a reliance
upon metabolism in the soil.
Postemergence applications result in residues that are mostly made
up of parent compound, with small amounts of five to six metabolites
that together make up less than 15% of the total radioactive residue
(TRR).
Preemergence application result in soil degradation of the parent
compound followed by uptake primarily of the imidazopyridine ring-
containing metabolites and small amounts of the parent compound. The
pyrimidine ring-containing metabolites under these conditions are
tightly bound to the soil, resulting in negligible uptake of these
residues. Little further metabolism of the imidazopyridine metabolites
takes place in the plant. The predominant residues resulting from
preemergence applications were sulfonamide (22% TRR) and guanidine
(18.3% TRR).
In both cases, translocation of residue to the grain is negligible.
The highest residues are observed following postemergence applications
and the residues are primarily parent compound.
In rotational crops, residues were low, with the TRR's not
exceeding 0.01 ppm in most crops. The most abundant metabolite was
sulfonamide, with low levels of a sulfonamide-sugar conjugate and
parent compound also observed.
2. Analytical method. The primary crop (wheat) residue and the
secondary (animal products) residues are analyzed as total residue by
hydrolyzing sulfosulfuron and its imadazopyrimidine-containing
metabolites under acidic conditions to the common chemophore, ethyl
sulfone. Ethyl sulfone is then separated and quantitated by High
Performance Liquid Chromatography (HPLC) with fluorescence detection.
3. Magnitude of residues. Field residue trials at 25 locations were
made in winter and spring wheat as preplant incorporated (PPI),
preemergent (PRE) and, postemergent (POST) applications at a target
application rate of 0.035 lb a.i./acre. Residues in grain from all
modes of application were < 0.008="" ppm;="" residues="" in="" the="" other="" racs="" in="" pre="" and="" ppi="" applications="" did="" not="" exceed="" 0.016="" ppm.="" residues="" in="" forage="" samples="" from="" post="" applications="" taken="" on="" the="" day="" of="" and="" 2-weeks="" after="" application="" showed="" maximum="" residues="" of="" 3.04="" ppm="" and="" 0.70="" ppm,="" respectively.="" spring="" and="" winter="" wheat="" treated="" with="" an="" exaggerated="" rate="" of="" 10x="" the="" anticipated="" use="" rate="" resulted="" in="" grain="" residues="" below="" the="" analytical="" limit="" of="" quantitation.="" since="" no="" quantifiable="" residue="" were="" detected="" at="" rates="" greater="" than="" the="" maximum="" theoretical="" concentration="" (9x="" for="" wheat),="" processing="" studies="" were="" not="" required.="" b.="" toxicological="" profile="" 1.="" acute="" toxicity.="" a="" rat="" acute="" oral="" study="" with="" an="">50
of >5,000 milligrams/kilogram (mg/kg), EPA Category IV.
i. A rabbit acute dermal study with an LD50 of >5,000
mg/kg, EPA Category IV.
ii. A rat inhalation study with an LC50 of >3.0 mg/l,
the highest concentration generated, EPA Category IV.
iii. A primary eye irritation study in the rabbit showing moderate
eye irritation, EPA Category III.
iv. A primary dermal irritation study in the rabbit showing
essentially no irritation, EPA Category IV.
A dermal sensitization study in the guinea pig showing no potential
for sensitization. Acute and subchronic neurotoxicity studies in rats
demonstrating no neurotoxicity potential. Sulfosulfuron has a low order
of acute toxicity.
2. Genotoxicity--i. An in vitro Ames/Salmonella mutagenicity assay
in five commonly used strains was negative for mutagenic potential. An
in vitro CHO/HGPRT Gene Mutation assay was negativefor mutagenicity up
to the limit of solubility.
ii. An in vitro chromosomal aberration test in cultured mammalian
cells demonstrated the induction of chromosomal aberrations only under
conditions of prolonged incubation at high dose levels that exceeded
the solubility of the test material. The mechanism responsible for this
induction and the biological relevance of the effect is not clear.
Other, more relevant, chromosomal aberration tests were negative.
iii. An in vitro chromosome aberration study in human lymphocytes
was negative for chromosomal aberrations.
iv. An in vivo bone marrow micronucleus assay in the mouse was
negative for chromosomal effects. The weight of evidence demonstrates
that sulfosulfuron does not produce significant genotoxic or mutagenic
effects.
3. Reproductive and developmental toxicity. A developmental study
in the rat demonstrated no signs of maternal or developmental toxicity
up to the maximum dose level of 1,000 mg/kg/day. The no-observed
adverse effect level (NOAEL) was considered to be 1,000 mg/kg/day. A
developmental study in the rabbit demonstrated no signs of maternal or
developmental toxicity up to the maximum dose level of 1,000 milligram/
kilogram/day (mg/kg/day). The NOAEL was considered to be 1,000 mg/kg/
day. A 2-generation reproduction study in the rat demonstrated a
subchronic toxicity NOAEL of 5,000 ppm based on body weight and food
consumption decreases, urinary bladder calculi formation and minor
bladder and kidney pathology. There were no effects on reproduction or
fertility up to 20,000 ppm, the highest dose tested (HDT).
Sulfosulfuron demonstrates no reproductive effects in rats and no
teratogenic or developmental effects in rats, and rabbits.
4. Subchronic toxicity. A 28 day dermal study in the rat with a
NOAEL of at least 1,000 mg/kg/day, HDT. A 90 day feeding study in the
rat resulted in only mild body weight/weight gain effects at 20,000
ppm, the HDT. The NOAEL for both males and females was considered to be
6,000 ppm. A 90 day feeding study in the dog demonstrated subchronic
toxicity, primarily in the urinary bladder, secondary to urinary
crystal formation and, urolithiasis at dose levels of 300 and, 1,000
mg/kg/day in females and, at 1,000 mg/kg/day in males. The NOAEL was
considered to be 100 mg/kg/day in females and, 300 mg/kg/day in males.
Sulfosulfuron has a low order of subchronic toxicity, related only to
the precipitation of test material in the urinary bladder of dogs at
high doses.
5. Chronic toxicity. A 1 year study in the dog demonstrated
toxicity in the urinary bladder secondary to urinary crystal and
calculus formation at 500 mg/kg/day in a single male animal. Urinary
crystal formation was observed in females at 500 mg/kg/day with no
[[Page 71128]]
subsequent pathology. The NOAEL was considered to be 100 mg/kg/day for
male and female dogs.
A combined chronic toxicity/oncogenicity study in the rat
demonstrated chronic toxicity, primarily in the urinary bladder, in
males and females at 5,000 and females at 20,000 mg/kg/day. The NOAEL
for chronic toxicity was considered to be 500 ppm or 24.4 mg/kg/day.
This is the lowest NOAEL and is used in the calculation of the
Reference Dose (RfD).
An 18 month oncogenicity study in the mouse demonstrated chronic
toxicity, primarily in the urinary bladder, of male mice at 3,000 and
7,000 ppm. No chronic toxicity was observed in females. The NOAEL for
chronic toxicity was considered to be 700 ppm for male mice, and 7,000
ppm for female mice.
Sulfosulfuron demonstrates chronic toxicity related only to the
formation of crystals and calculi of the compound in the urinary
bladders of mice, rats, and, dogs.
An 18 month oncogenicity study in the mouse demonstrated a small
increase in the incidence of benign mesenchymal tumors of the urinary
bladder submucosa in male mice with urinary bladder calculi at 7,000
ppm. However, these tumors are reportedly unique to Swiss-derived mice
and were considered to be of biological relevance only to the mouse by
an Independent Working Group on Mouse Mesenchymal Tumors convened by
the International Life Sciences Institute (ILSI).
A combined chronic toxicity/oncogenicity study in the rat (same as
above) demonstrated a urinary bladder transitional cell carcinoma and,
a urinary bladder transitional cell papilloma in two females at 5,000
mg/kg/day, probably secondary to urinary system calculi formation and,
(chronic) irritation.
The low incidences of oncogenicity observed in the oncogenicity
studies conducted with sulfosulfuron are either considered to be
relevant to the mouse only or a secondary threshold effect related to
chronic irritation resulting from bladder stone formation at high
doses. Sulfosulfuron is not considered to be a primary oncogen.
Using the Guidelines for Carcinogenic Risk Assessment published
September 24, 1986, Monsanto believes that the EPA would classify
sulfosulfuron as a Group C carcinogen, without quantitative risk
assessment, i.e., using the margin of exposure (MOE) approach for risk
assessment. Under the proposed guidelines published April 10, 1996,
however, Monsanto believes that sulfosulfuron should be included in the
``Not Likely Human Carcinogen'' category based upon mechanistic
considerations. To quote the 1996 EPA guideline document discussing a
similar effect in a rat study.
A major uncertainty is whether the profound effects of (substance
5) may be unique to the rat. Even if (substance 5) produced stones in
humans, there is only limited evidence that humans with bladder stones
develop cancer. Most often human bladder stones are either passed in
the urine or lead to symptoms resulting in their removal.
In either case, a MOE assessment or RfD approach would be utilized.
Since the chronic NOAEL for male rats is lower than the oncogenic NOAEL
for female rats (24 mg/kg/day vs 30 mg/kg/day), the male rat chronic
NOAEL was used with a 100 fold safety factor for a RfD of 0.24 mg/kg/
day, for the quantitation of human risk.
6. Animal metabolism. An animal metabolism study was conducted in
the rat using sulfosulfuron radio labeled in both the pyrimidine and
iminodazopyridine rings to detect possible cleavage of the sulfonylurea
bond. Following oral dosing of sulfosulfuron, absorption was found to
be greater at low doses (>90%) than at the higher doses (40%).
Sulfosulfuron was readily excreted, mostly unchanged, with urinary
excretion the major route of elimination at low doses and fecal
excretion the major route at high doses. Greater than 90% of the dose
was excreted 3-days after administration. Expiration as carbon dioxide
or volatiles was not a significant route of elimination. Metabolism of
sulfosulfuron in the rat occurred to only a limited extent with
demethylation and pyrimidinering hydroxylation as the major metabolic
routes, yielding desmethyl-sulfosulfuron and 5-hydroxy-sulfosulfuron as
the major metabolites. There was no evidence of bio-retention of
sulfosulfuron or its metabolites; tissue and blood levels were
negligible, with no individual tissue showing levels exceeding 0.2% of
the doses.
7. Metabolite toxicology. Dietary residues are comprised almost
entirely of parent sulfosulfuron and the imidazopyridine-containing
metabolites sulfonamide and guanidine. Specific toxicology data is not
available on these metabolites, but the structures do not suggest any
specific toxicologic concern and the level of dietary exposure is low.
These metabolites are not considered to present a significant
toxicological risk.
8. Endocrine disruption. There was no evidence that exposure to
sulfosulfuron had any effect on reproduction, fertility or mating
indices, development or maturation of embryos, or development, growth
and survival of offspring in the battery of short-term, chronic,
reproductive and, developmental mammalian, avian and aquatic studies
conducted. There were no gross or microscopic pathologic effects in
endocrine organs or endocrine-sensitive tissues, or in any reproductive
organs, tissues or endpoints that were considered related to exposure
to sulfosulfuron. With no evidence of bioaccumulation and low
environmental concentrations, there is negligible risk of endocrine
disruption in humans or wildlife
C. Aggregate Exposure
1. Dietary exposure--i. Food. Estimates of dietary exposure to
residues of sulfosulfuron utilized the proposed tolerance-level
residues for wheat grain (0.01 ppm) and for the following animal
products: milk (0.004 ppm), fat (0.004 ppm), meat (0.004 ppm), and meat
by-products (0.1 ppm, including kidney, and liver). 100% market share
was assumed as well as the assumption that no loss of residue would
occur due to processing and cooking. A RfD of 0.24 mg/kg/day was
assumed based on the low NOAEL from the chronic/oncogenicity study in
rats (24 mg/kg/day) with a safety factor of 100. Since the present
label lists only wheat or fallow as approved rotations, no residues
were entered for rotational crops. Using these conservative
assumptions, dietary residues of sulfosulfuron contribute only 0.000149
mg/kg/day (0.006% of the RfD) for children 1-6 years, the most
sensitive sub-population. For the U.S. population as a whole, the
exposure was only 0.000048 mg/kg/day (0.02% of the RfD).
ii. Drinking water. Given the low use rates, rapid soil
degradation, strong soil binding characteristics and low soil mobility
of sulfosulfuron, the risk of significant ground and surface water
contamination and exposure via drinking water is considered to be
negligible. Assuming that 10% of the RfD is allocated to drinking water
exposure (0.024 mg/kg/day), and the average, 70 kg human consumes 2
liters of water per day, a Maximum Allowable Concentration (MAC) value
for drinking water of 0.84 mg/l is proposed for sulfosulfuron.
iii. Non-dietary exposure. Sulfosulfuron is proposed for a variety
of non-crop uses including roadsides, fence rows,industrial sites,
parks, apartment complexes, schools and, other public areas. Exposure
assessments have been made for mixer/loaders and applicators in these
situations (occupational exposure) and, the cumulative (amortized)
daily
[[Page 71129]]
exposure from both these activities has been estimated to be less than
0.5 mg/kg/day, or approximately 0.2% of the RfD. The non-occupational
exposure in these locations to the casual passer-by would be expected
to be orders of magnitudeless. The exposure in either instance does not
present a significant exposure risk.
D. Cumulative Effects
Sulfosulfuron falls into the common category of sulfonylurea SU
herbicides; however, there is no information to suggest that any of the
SU s have a common mechanism of mammalian toxicity or even produce
similar effects. It is not appropriate to combine exposures in this
case, and Monsanto is considering only the potential risk of
sulfosulfuron in its aggregate exposure assessment.
E. Safety Determination
1. U.S. population. As presented above, the exposure of the U.S.
General population to sulfosulfuron is low, and the risks, based on
comparisons to the reference dose, are negligible. Margins of safety
are expected to be considerable. Monsanto concludes that there is a
reasonable certainty that no harm will result to the U.S. population
from aggregate exposure to sulfosulfuron residues.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of sulfosulfuron,
Monsanto considered data from developmental toxicity studies in the
rat, and rabbit and a 2-generation reproduction study in rats. No
developmental or reproductive effects were observed up to the HDT in
each of the three studies. The NOAELs were 1,000 mg/kg/day, 1,000 mg/
kg/day and 20,000 ppm, respectively. Using the same conservative
assumptions that were made previously for the dietary exposure analysis
for the U.S. general population, the percent of the RfD utilized by
pre-adult sub-populations are: all infants-0.03%;, nursing infants-
0.005%;, and non-nursing infants-0.04%; children, 1-6 years-0.06%;
children, 7-12 years-0.04%. Monsanto concludes that there is a
reasonable certainty that no harm will result to infants and children
from aggregate exposure to sulfosulfuron residues.
F. International Tolerances
There are currently no international (Codex) tolerances established
for sulfosulfuron.
Sulfosulfuron is currently registered on wheat in Ireland,
Switzerland, Poland, the Czech Republic, Slovakia and, South Africa.
There are no harmonized MRL's at the European Union level at present.
Petitions for tolerances for sulfosulfuron in/on wheat have been
submitted in Canada, Australia and, in other countries in the European
Union.
2. 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
----------------------------------------------------------------------------------------------------------------
Analytical method. DBE vapors may be detected by gas
chromatography using a flame ionization detector, for which a detection
limit of 0.7 g/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).
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 no-observed
adverse effect level (NOAEL) of 10,000 ppm (842 milligrams/kilogram/day
(mg/kg-day)). Similarly, body weight gains were significantly reduced
in rats exposed via inhalation to concentrations of 0.4 and 1.0
milligram/liter (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 7-16 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
[[Page 71130]]
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
metaplasiain the olfactory epithelium (Kelly, 1987). Slight changes in
liver weight, body weight, 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 NOAEL.
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. FDA for substances directly added to human food
(21 CFR 184.1009 and 21 CFR 184.1091 respectively). Although glutaric
acidis 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 (21 CFR 172.515). 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 Inter disciplinary 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 milligrams/pound (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
kilogram/body/weight (kg/bwt), 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 kilogram/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. FDA 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 adipateare likely to be less toxic
than succinate, glutarate, and adipate, respectively. In support of
this statement, Trela and Bogdanffy (1991)
[[Page 71131]]
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 (MOEs) of 280 and 380 for dermal, and inhalation exposures,
respectively. Based on these MOEs 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 MOE of 8, and 54 for
dermal and inhalation exposures, respectively. Based on these MOEs,
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 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.
[FR Doc. 98-33834 Filed 12-22-98; 8:45 am]
BILLING CODE 6560-50-F
