[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: opp-
[email protected]. 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:

------------------------------------------------------------------------
                                   Office location/
        Product Manager            telephone number          Address
------------------------------------------------------------------------
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.
------------------------------------------------------------------------

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:
    [email protected]


    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:

 
------------------------------------------------------------------------
                 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).
------------------------------------------------------------------------

    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 LD50 
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