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American Cyanamid Company; Pesticide Tolerance Petition Filing
Note: EPA no longer updates this information, but it may be useful as a reference or resource.
[Federal Register: March 26, 1997 (Volume 62, Number 58)]
[Notices]
[Page 14418-14421]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr26mr97_dat-85]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-724; FRL-5594-7]
American Cyanamid Company; Pesticide Tolerance Petition Filing
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
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SUMMARY: This notice announces the filing of a pesticide petition
proposing the establishment of a tolerance for residues of dimethomorph
[(E,Z)4-[3-(4-chlorophenyl)-3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]-
morpholine] in or on the raw agricultural commodity potatoes and grape
commodities. This notice contains a summary of the petition that was
prepared by the petitioner, American Cyanamid Company.
DATES: Comments, identified by the docket control number [PF-724], must
be received on or before April 25, 1997.
ADDRESSES: By mail, submit written comments to: Public Response and
Program Resources Branch, Field Operations Division (7506C), Office of
Pesticide Programs, Environmental Protection Agency, 401 M St., SW.,
Washington, DC 20460. In person, bring comments to Rm. 1132, CM #2,
1921 Jefferson Davis Highway, Arlington, VA 22202.
Comments and data may also be submitted electronically be sending
electronic mail (e-mail) to: 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 in ASCII file
format. All comments and data in electronic form must be identified by
docket control number [PF-724]. Electronic comments on this notice may
be filed online at many Federal Depository Libraries. Additional
information on electronic submissions can be found in Unit II. of this
document.
Information submitted as a comments 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: By mail: Connie B. Welch, Product
Manager (PM) 21, Registration Division (7505W), Office of Pesticide
Programs, Environmental Protection Agency, 401 M St., SW., Washington,
DC 20460. Office location, telephone number, and e-mail address: Rm.
227, CM #2, 1921 Jefferson Davis Highway, Arlington, VA, (703) 305-
6226; e-mail: welch.connie@epamail.epa.gov.
SUPPLEMENTARY INFORMATION: EPA has received a pesticide petition (PP
7F4816) from American Cyanamid Company, Agricultural Products Research
Division, P.O. Box 400 Princeton, NJ 08543-0400 proposing pursuant to
section 408(d) of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C.
section 346a, to amend 40 CFR part 180 by establishing tolerances for
residues of the fungicide, dimethomorph [(E,Z)4-[3-(4-chlorophenyl)-3-
(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]-morpholine] in or on the raw
agricultural commodity potato at 0.05 parts per million (ppm) and a
time-limited tolerance for residues of dimethomorph in or on the raw
agricultural commodity grape at 2.0 ppm. The proposed analytical method
for determining residues is a High Performance Liquid Chromatography
(HPLC) method (FAMS 002-04). A confirmatory method (FAMS 022-03) also
is available which provides for analysis by either Gas Chromatography/
Nitrogen-Phosphorus Detection or by HPLC/UV Detection. EPA has
determined that the petition contains 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.
As required by section 408(d) of the FFDCA, as recently amended by
the Food Quality Protection Act, (Pub. L. 104-170), American Cyanamid
included in the petition a summary of the petition and authorization
for the summary to be published in the Federal Register in a notice of
receipt of the petition. The summary represents the views of American
Cyanamid; EPA is in the process of evaluating the petition. As required
by section 408(d)(3), EPA is including the summary as a part of this
notice of filing. EPA has made minor edits to the summary for the
purpose of clarity.
[[Page 14419]]
I. Petition Summary Prepared by American Cyanamid Company
A. Residue Chemistry
1. Plant metabolism. American Cyanamid believes that the results of
the potato metabolism study show only negligible residues in tubers,
0.01-0.02 ppm total radioactive residues (TRR). This is in contrast to
the aerial portions of the plant which were found to have up to 23.5
parts per million (ppm) TRR, thus demonstrating that translocation of
dimethomorph within the plant was not significant. Almost all of the
radioactive residue (97.8%) was extractable from the plant at harvest.
In the aerial portion of the plant, approximately 70% of the TRR was
identified as dimethomorph. No metabolites were identified that require
regulation. There was no concentration of residue in the peel or tuber.
The latter point indicates that during processing dimethomorph is not
expected to concentrate to a level greater than that of the proposed
tolerance for the raw agricultural commodity, potato tubers.
The results of the grape metabolism study showed that the TRR in/on
grapes harvested 35 days following the last of four applications (0.8
lb active ingredient/application (ai/A) for 4 consecutive weeks) for a
total rate of 3.2 lb ai/A (3x the proposed maximum seasonal rate) was
14.6 ppm. Unmetabolized dimethomorph accounted for 87.3% of the TRR
(12.7 ppm). No metabolites were identified that require regulation.
2. Analytical method. A reliable method for the determination of
dimethomorph residues in potatoes and grapes exists. This method (FAMS
002-04) is appropriate for enforcement purposes. FAMS 002-04 is a HPLC
method. A confirmatory method (FAMS 022-03) also is available which
provides for analysis by either Gas Chromatography with Nitrogen-
Phosphorus Detection or by HPLC with UV Detection.
3. Magnitude of residues. The residue data for potato submitted to
support this tolerance petition were collected from studies conducted
in several European countries; these countries are representative of
potato growing regions of the U.S. Dimethomorph residues observed in
these field residue studies ranged from <0.01 ppm (the Limit of
Quantitation of the method) to 0.04 ppm; however, most residues were
<0.01 ppm. These trials were conducted using multiple applications (5-
12) with a maximum seasonal rate of up to 2.56 lb ai/A. The proposed
U.S. use pattern is five applications at a maximum treatment rate of
0.203 lb ai/A and a maximum seasonal use rate of 1.015 lb ai/A. Residue
levels in domestic potatoes would be expected to be similar or lower (<
0.01 ppm) than that observed in the European trials. Therefore, a
tolerance of 0.05 ppm is appropriate.
The residue data for grape submitted to support this tolerance
petition were collected from studies conducted in various regions of
France; these sites are representative of grape growing regions of
Europe. Dimethomorph residues observed in these field residue studies
ranged from <0.01 ppm (the Limit of Quantitation of the method) to 1.81
ppm. These trials were conducted using multiple applications (3-11)
with a maximum seasonal rate of up to 2.94 lb ai/A. In six studies
conducted on the magnitude of residue in grape processed commodities,
residues of dimethomorph did not concentrate in grape juice or wine.
Therefore, a time-limited tolerance of 2.0 ppm in/on grape commodities
is appropriate.
B. Toxicological Profile
American Cyanamid believes that the toxicity of dimethomorph has
been studied extensively and there is a complete data base to address
the acute and chronic effects, effects on genetic material, the
potential for carcinogenicity or teratogenicity, and effects on
reproductive performance or growth of offspring.
The toxicological data submitted to support the petition for a
tolerance for dimethomorph on potatoes and for a time-limited tolerance
on grape include:
1. Acute toxicity. i. An acute oral toxicity study in the Sprague-
Dawley rat for dimethomorph technical with a LD50 of 4,300
milligrams/kilograms (mg/kg) body weight (bwt) for males and 3,500 mg/
kg bwt for females. Based upon EPA toxicity criteria, the acute oral
toxicity category for dimethomorph technical is Category III or
slightly toxic.
ii. Oral LD50 studies were conducted on the two isomers (E and
Z) alone:
a. An acute oral toxicity study in the Wistar rat for the E-isomer
with a LD50 greater than 5,000 mg/kg bwt for males and
approximately 5,000 mg/kg bwt for females.
b. An acute oral toxicity study in the Wistar rat for the Z-isomer
with a LD50 greater than 5,000 mg/kg bwt for both males and
females.
iii. An acute dermal toxicity study in the Wistar rat for
dimethomorph technical with a dermal LD50 greater than 5,000 mg/kg
bwt for both males and females. Based on the EPA toxicity category
criteria, the acute dermal toxicity category for dimethomorph is
Category IV or relatively non-toxic.
iv. A 4-hour inhalation study in Wistar rats for dimethomorph
technical with a LC50 greater than 4.2 mg/L for both males and
females. Based on the EPA toxicity category criteria, the acute
inhalation toxicity category for dimethomorph technical is Category IV
or relatively non-toxic.
2. Genotoxicity. i. Salmonella reverse gene mutation assays (2
studies) were negative up to a limit dose of 5,000 µg/plate.
Chinese hamster lung cells were negative in V79 cells up to toxic doses
in 2 studies.
ii. Two Chinese hamster lung structural chromosomal studies were
reportedly positive for chromosomal aberrations at the highest dose
tested (HDT) (160 µg/ml/-S9; 170 µg/ml/+S9).
Dimethomorph induced only a weak response in increasing chromosome
aberrations in this test system. These results were not confirmed in
two micronucleus tests under in vivo conditions.
iii. Structural Chromosomal Aberration studies were weakly
positive, in human lymphocyte cultures, but only in S9 activated
cultures treated at the HDT (422 µg/ml) which was strongly
cytotoxic. Dimethomorph was negative in the absence of activation at
all doses. Furthermore, the positive clastogenic response observed
under the in vitro conditions was not confirmed in two in vivo
micronucleus assays.
iv. Micronucleus assay (2 studies) indicated that dimethomorph was
negative for inducing micronuclei in bone marrow cells of mice
following i.p. administration of doses up to 200 mg/kg or oral doses up
to the limit dose of 5,000 mg/kg. Thus, dimethomorph was found to be
negative in these studies for causing cytogenic damage in vivo.
v. Dimethomorph was negative for inducing unscheduled DNA
synthesis, in cultured rat liver cells, at doses up to 250 µg/
ml, a weakly cytotoxic level.
vi. Dimethomorph was negative for transformation in Syrian hamster
embryo cells treated, in the presence and absence of activation, up to
cytotoxic concentrations (265 µg/ml/+S9; 50 µg/ml/-S9).
3. Reproductive and developmental toxicity. i. A rat developmental
toxicity study with a maternal toxicity Lowest-Observed-Effect Level
(LOEL) of 160 mg/kg/day and a maternal toxicity No-Observed-Effect
Level (NOEL) of 60 mg/kg/day. The NOEL for developmental toxicity is 60
mg/kg/day. Dimethomorph is not teratogenic in the Sprague-Dawley rat.
ii. A rabbit development toxicity study with maternal toxicity LOEL
of 650 mg/kg/day and a NOEL of 300 mg/kg/day. The NOEL for developmental
[[Page 14420]]
toxicity is 650 mg/kg/day, the highest dose tested. Dimethomorph is not
teratogenic in the New Zealand white rabbit.
iii. A multi-generational rat reproduction study with parental LOEL
for systemic toxicity of 80 mg/kg/day and a NOEL of 24 mg/kg/day. The
NOEL for fertility and reproductive function was 80 mg/kg/day, the
highest dose tested.
4. Subchronic toxicity. i. A 90-day dietary study in Sprague-Dawley
rats with a NOEL of greater than or equal to 73 mg/kg/day in males and
82 mg/kg/day in females, the highest doses tested.
ii. A 90-day dog dietary study with a NOEL 15 mg/kg/day and a LOEL
43 mg/kg/day.
5. Chronic toxicity. i. A 2-year chronic toxicity study in Sprague-
Dawley rats with a NOEL 9 mg/kg/day for males and 12 mg/kg/day for
females. The LOEL for systemic toxicity is 36 mg/kg/day for males and
58 mg/kg/day for females.
ii. A 1-year chronic toxicity study in dogs with a NOEL of 14.7 mg/
kg/day and a LOEL of 44.6 mg/kg/day.
iii. A 2-year oncogenicity study in Sprague-Dawley rats with a NOEL
for systemic toxicity of 9 mg/kg/day for males and 11 mg/kg/day for
females. The LOEL for systemic toxicity was 34 mg/kg/day for males and
46 mg/kg/day for females. There was no evidence of increased incidence
of neoplastic lesions in treated animals. The NOEL for oncogenicity is
95 mg/kg/day for males and 132 mg/kg/day for females, the highest dose
tested.
iv. A 2-year oncogenicity study in mice with a NOEL for systemic
toxicity of 100 mg/kg/day and a LOEL of 1,000 mg/kg/day. There was no
evidence of increased incidence of neoplastic lesions in treated
animals. The NOEL for oncogenicity is 1,000 mg/kg/day, the highest dose
tested.
6. Animal metabolism. Results from the livestock and rat metabolism
studies show that orally administered dimethomorph was rapidly excreted
by the animals. The principal route of elimination is the feces.
7. Metabolite toxicology. There were no metabolites identified in
potatoes or animal commodities which require regulation.
8. Endocrine effects. There is no evidence of effects of
dimethomorph on the endocrine system. There were no changes noted in
organ weights for the pituitary, thyroid, ovaries or testes. There was
no increased incidence of mammary tumors observed. No effects on
fertility or reproduction were noted and there was no evidence of
related histopathological changes in reproductive or endocrine system
organs.
C. Aggregate Exposure
1. Dietary (food) exposure. Dietary exposure should be based solely
upon the Theoretical Maximum Residue Concentration (TMRC) from the
tolerance of 0.05 ppm dimethomorph in or on potato and the time-limited
tolerance of 2.0 ppm dimethomorph in or on grape. The goat metabolism
study demonstrates that there is no reasonable expectation of transfer
of residues of dimethomorph to meat or milk from potatoes or from
grapes. There are no potato or grape feed commodities fed to poultry.
Therefore, no consumption data associated with meat, milk, poultry or
eggs should be included in the calculation of the TMRC. There are no
other established U.S. tolerances for dimethomorph, and there are no
registered uses for dimethomorph on food or feed crops in the United
States.
2. Dietary (drinking water) exposure. There is no available
information about dimethomorph exposure via drinking water. However,
exposure to dimethomorph from drinking water is not likely to occur as
a result of use on potatoes. Dimethomorph dissipated fairly rapidly
under field conditions with half lives ranging from 14 to 57 days.
Laboratory and field studies demonstrate that dimethomorph is not
mobile in soil. No movement below the top 4 inches was observed in the
field studies. Laboratory leaching studies result in the classification
of dimethomorph as having medium to high adsorption onto soil.
3. Non-dietary exposure. There are no other registered uses of
dimethomorph in the U.S. Thus, there is no potential for non-dietary
exposure.
D. Cumulative Effects
There is no information to indicate that any toxic effects produced
by dimethomorph would be cumulative with those of any other chemical.
The fungicidal mode of action of dimethomorph is unique; dimethomorph
inhibits cell wall formation only in Oomycete fungi. The result is
lysis of the cell wall which kills growing cells and inhibits spore
formation in mature hyphae. This unique mode of action and limited pest
spectrum suggest that there is little or no potential for cumulative
toxic effects in mammals. In addition, the toxicity studies submitted
to support this petition do not indicate that dimethomorph is a
particularly toxic compound. No toxic end-points of potential concern
were identified.
E. Safety Determination
1. U.S. population. The proposed reference dose (RfD) is 0.1 mg/kg
bwt/day, based on a NOEL of 10 mg/kg bwt/day from a 2-year dietary
toxicity study in rats that demonstrated decreased body weight and
liver foci in females. The proposed RfD is also based on an uncertainty
factor of 100. For potatoes, the TMRC from this proposed action is
estimated at 0.000057 mg/kg bwt/day. This represents an aggregate
exposure to the general population of the United States of 0.063
percent of the RfD. The TMRC for the most highly exposed group,
children ages 1 to 6 is estimated at 0.000113 mg/kg bwt/day. This
represents 0.125 percent of the RfD. Establishment of a tolerance for
residues in/on grape commodities is not expected to significantly
change the exposure estimate to the most highly exposed group since the
commodity which is most extensively imported is wine. Since EPA
generally has no concern for exposures below 100 percent of the RfD,
EPA should conclude that there is a reasonable certainty that no harm
will result from aggregate exposure to dimethomorph residues in or on
potato and grape commodities.
2. Infants and children. American Cyanamid believes that the
results of the studies submitted to support this package provide no
evidence that dimethomorph caused reproductive, developmental or
fetotoxic effects. No such effects were noted at dose levels which were
not maternally toxic. The NOELs observed in the developmental and
reproductive studies were 6 to 65 times higher than the NOEL used to
establish the proposed RfD (10 mg/kg bw/day). There is no evidence to
indicate that children or infants would be more sensitive than adults
to toxic effects caused by exposure to dimethomorph.
F. International Issues
No Codex maximum residue levels (MRLs) have been established for
dimethomorph to date.
II. Public Record
A record has been established for this notice under docket control
number [PF-724] (including comments and data submitted electronically
as described below). A public version of the 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 public
record is located in Room 1132 of the
[[Page 14421]]
Public Response and Resources Branch, Field Operations Division
(7506C), Office of Pesticide Programs, Environmental Protection Agency,
Crystal Mall #2, 1921 Jefferson Davis Highway, Arlington, VA.
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.
The official record for this rulemaking, as well as the public
version, as described above will be kept in paper form. Accordingly,
EPA will transfer all comments received electronically into printed,
paper form as they are received and will place the paper copies in the
official rulemaking record which will also include all comments
submitted directly in writing. The official rulemaking record is the
paper record maintained at the address in ``ADDRESSES'' at the
beginning of this document.
List of Subjects
Environmental protection, Administrative practice and procedure,
Agricultural commodities, Pesticides and pests, Reporting and
recordkeeping.
Dated: March 18, 1997.
Stephen L. Johnson,
Director, Registration Division, Office of Pesticide Programs.
[FR Doc. 97-7494 Filed 3-25-97; 8:45 am]
BILLING CODE 6560-50-F