diuron (Karmex) Pesticide Tolerance Petition 1/97
ENVIRONMENTAL PROTECTION AGENCY
Drexel Chemical Company; Pesticide Tolerance Petition Filing
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice of filing.
SUMMARY: This notice is a summary of a pesticide petition proposing the
establishment of a tolerance for residues of diuron in or on the edible
portions of catfish. The summary was prepared by the petitioner, Drexel
DATES: Comments, identified by the docket number [PF-693], must be received on
or before, February 24, 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.
Comments and data may also be submitted electronically by sending electronic
mail (e-mail) to: firstname.lastname@example.org. Electronic comments should 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
in 5.1 file format or ASCII file format. All comments and data in electronic
form must be identified by docket number [PF-693]. Electronic comments on this
proposed rule may be filed online at many Federal Depositary Libraries.
Additional information on electronic submissions may be found below in this
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: Phillip V. Errico, Product Manager (PM) 25,
Registration Division (7505C), Office of Pesticide Programs, Environmental
Protection Agency, 401 M St., SW., Washington, DC 20460. Office location,
telephone number, and e-mail address: Rm. 245, CM#2, 1921 Jefferson Davis
Highway, Arlington, VA, (703) 305-6027; e-mail:
SUPPLEMENTARY INFORMATION: EPA has received pesticide petition (PP) 6F4680
from Drexel Chemical Company, POB 13327, Memphis, TN 38133-0237, proposing to
amend 40 CFR 180.106 by establishing a tolerance for residues of the herbicide
diuron [3-(3,4-dichlorophenyl)-1,1- dimethylurea] in or on the raw
agricultural commodity catfish at 1 part per million (ppm). The proposed
analytical method is gas chromatography (GC) with a nitrogen-phosphorous
Pursuant to section 408(d)(A)(i) of the Federal Food, Drug, and Cosmetic Act
(FFDCA), 21 U.S.C. 346a(e), as amended, Drexel Chemical Company has submitted
the following summary of information, data and arguments in support of their
pesticide petition. The summary was prepared by Drexel Chemical Company and
EPA has not fully evaluated the merits of the petition. EPA edited the summary
to clarify that the conclusions and arguments were the petitioner's and not
necessarily EPA's and to remove certain extraneous material.
I. Petition Summary
A. Residue Chemistry
1. Analytical method. An analytical method is available, a modified form of
DuPont Agricultural Products method #5470. The principle of the determination
is the hydrolysis of diuron and its metabolites by alkaline reflux to 3,4-
dichloroanaline (3,4-DCA), followed by a distillation of the aniline into an
acid solution. The acid distillate is made alkaline with concentrated base and
subsequently extracted into an organic solvent (hexane) and analyzed by gas
chromatography. With the modified method, recoveries exceeded 70% and the
limit of quantitation (LOQ) is 0.01 <greek-m>g/g.
2. Magnitude of the residues. Residue trials were conducted in contained
catfish ponds on a 30, 60 and 90-day treatment schedule. In the 30-day
treatment schedule pond, diuron residues in catfish fillet were between 0.8
and 0.9 ppm after the first week post treatment, and declined to 0.2 ppm after
8 weeks post treatment. Due to mortality from Proliferative Gill Disease
(PGD), no catfish were available after the last treatment day for residue
determination from the 60-day treatment schedule pond. Diuron residues in
catfish fillet from the 90-day treatment schedule pond were 1.2 ppm on the
last treatment day, rose slightly to 1.4 ppm by day 7 post treatment, and
declined to 1.1 ppm by day 28 post treatment.
Using data from the magnitude of the residue study, a pharmacokinetic model
was developed that allowed the prediction of diuron residues in catfish fillet
using a treatment schedule of applying 0.01 ppm diuron to the pond every 7
days for 56 days. Based on the model, the maximum mean fillet residue from
this treatment schedule is predicted to be 0.75 ppm.
The pharmacokinetic model was validated using data from an efficacy study.
Catfish were grown in ponds treated with 0.01 ppm diuron every 7 days. Diuron
residues in catfish fillet were determined after 113 days of treatment. The
analysis found mean fillet residues of 0.92 ppm. The pharmacokinetic model
predicted day 113 diuron residues in catfish fillet of 0.89 ppm. This
excellent agreement between prediction and found values demonstrates the
utility of the model.
B. Toxicological Profile
1. Acute toxicity. The rat acute oral single dose LD50 is 3.5 g/kg. The rabbit
acute dermal single dose LD50 is greater than 2 g/kg of bodyweight. The rat
acute inhalation LD50 is less than 2.5 mg per liter. A primary eye irritation
study in the rabbit shows that diuron is moderately irritating to the unwashed
eye when instilled undiluted. A primary dermal irritation showed that diuron
is not a skin irritant when applied undiluted. A skin sensitization study
(Buehler) in the guinea pig shows that diuron is not a skin sensitizer when
2. Genotoxicity. In the CHO/HGBRT assay the results for diuron are negative up
to cytotoxic levels in the presence of S9 activation (0.75 mm) and in the
absence of S9 metabolic activation (1.25 mm).
For the in vivo cytogenic study in rats, diuron is clastogenic at 5,000 mg/kg,
the highest dose level tested.
For the in vitro unscheduled DNA synthesis assay in primary rat hepatocytes,
diuron is negative up to 20 mm, the highest concentration tested.
Diuron was not considered to be mutagenic to TA97, TA98, TA100 and TA1535
strains of Salmonella typhimurium (Ames Salmonella plate assay) either with or
without metabolic activation at the concentrations tested (-S9, 0.5, 1, 2.5, 5
and 10 <greek-m>g/plate; S9, 10, 25, 100 and 250 <greek-m>g/plate).
3. Developmental and reproductive toxicity. In a reproductive toxicity study
in the rat, the no-observed effect level/lowest observed effect level
(NOEL/LOEL) for parental/offspring systemic toxicity and developmental
toxicity were determined to be 250 and 1,750 ppm (16.9 and 120 mg/kg/day for
males and 20.3 and 144 mg/kg/day for females), respectively, based on
decreased body weight gain and food consumption in both sexes and generations.
There was no evidence that diuron affected reproductive performance in the
In a developmental toxicity study in the rat, the maternal toxicity NOEL/LOEL
were considered to be 16 and 80 mg/kg/day, respectively, based on reduction in
body weight and food consumption. The developmental toxicity NOEL/LOEL were
considered to be 80 and 400 mg/ kg/day, respectively, based on statistically
significant increases in delayed ossification of the vertebrae and sternebrae
and decreased fetal weights.
In a developmental toxicity study in rabbits, the NOEL/LOEL maternal toxicity
were considered to be 10 and 50 mg/kg/day, respectively, based on decreased
body weight and food consumption. There was no evidence of developmental
effects in the study.
4. Subchronic toxicity. In a non-guideline subchronic (6-month) oral toxicity
study in rats, the systemic NOEL of technical diuron was sought. The scope of
the study was primarily restricted to parameters affecting the erythrocytes.
Based on the study findings, the systemic NOEL of diuron could not be
determined, since some findings were judged to be equivocal.
5. Chronic toxicity/oncogenicity. The chronic rat oral toxicity study was
acceptable as supplementary data. However, deficiencies exist in the study
because several organs were not examined, such as the mammary glands. No NOEL
was determined. The LOEL was considered to be 25 ppm (1.02 and 1.69 mg/kg/day
for males and females, respectively), the lowest dose level tested in this
study based on increased erythrocyte count in females, increased hemosiderin
in the spleen, increased spleen weight, bone marrow activation, increased
hematopoietic marrow, decreased fat marrow, and thickened urinary bladder wall
The chronic oral toxicity study in dogs was acceptable. The NOEL/ LOEL in the
study were considered to be 25 and 125 ppm (1.88 and 9.33 mg/kg/day,
respectively, for both males and females) based on abnormal blood pigments in
The oncogenicity phase of the combined chronic toxicity/ oncogenicity study in
rats was considered to be supplementary. However, deficiencies exist in the
study because several organs were not examined, such as the mammary glands.
The oncogenicity study in mice was considered to be acceptable. The NOEL/LOEL
for systemic toxicity were considered to be 250 ppm (50.8 and 77.5 mg/kg/day
for males and females, respectively) based on decreased body weight gain, and
increased spleen and liver weight in males, elevated leucocyte and
reticulocyte counts, mean corpuscular volume and mean corpuscular hemoglobin,
and bilirubin values in both sexes; increased incidence of intracellular
pigments in renal tubules in females and in the spleen of males and females;
increased incidence of hemosiderin deposits in liver cells in males; increased
incidence of liver single cell necrosis and cell mitosis in both sexes;
increased incidence of enlarged degenerative cells in females and of
hepatopathy and Kupffer cells in males; increased incidence of urinary bladder
edema and epithelial hyperplasia, thickened mucosa and enlarged uterine horn
in females. In the study, a statistically significant increase (14%, <ls-thn-
eq> 0.01) of ovarian luteoma was noted in mice of the 2,500 ppm group as
compared to the concurrent controls (6%). This value was higher than the
historical control incidence of 1.7% for ovarian luteoma tumor. Combined
ovarian sex cord tumors were also increased. Mammary gland tumors
(adenocarcinoma type A and B) in the 2,500 ppm group were statistically
significantly higher than the concurrent control (12%, p <ls-thn-eq> 0.05 vs.
4% in the concurrent control) and higher than the historical control of 3.3%.
C. Aggregate Exposure
1. Dietary exposure.--a. Food. A Registration Eligibility Document (RED) for
diuron is not scheduled for completion until outstanding data requirements
requested by the EPA's Office of Pesticide Programs Environmental Fate and
Effects Division are completed. Therefore, a dietary exposure assessment using
anticipated residues is not available. In the absence of a dietary exposure
assessment, the petitioners conducted a very conservative exposure assessment
with proposed tolerance level residues (maximum residues permitted) for all
crops for which the technical registrants intend to provide supporting data.
The food, "freshwater finfish" was included with an anticipated residue level
of 0.75 ppm, to represent catfish consumption.
Since freshwater finfish can come from a number of sources, including sport
fishing, commercial catch, and aquaculture, and could be other popular finfish
species, such as trout or tilapia, the consumption estimate is extremely
conservative. In addition, diuron is applied to contained ponds used in
commercial catfish production during a 2 to 4-month period in the summer and
fall. However, the fish are harvested from the ponds the year round. Residue
estimates for other foods were adjusted to reflect the percent of crop
treated, based on USDA data.
Exposure estimates were compared to a Reference Dose (RfD) of 0.003 mg/kg
bwt/day (mkd), which was recommended by the RfD Review Committee at their
September 26, 1996, meeting.
The maximum total exposure to the U. S. population for all uses of diuron,
including the use in catfish ponds, is 0.000593 mkd, which represents 19.8% of
the RfD. The most highly exposed subgroup of the U. S. population was non-
hispanic other than black or white (e.g., asians), which had a total exposure
of 0.000787 mkd, representing 26.6% of the RfD.
Exposure to all infants was 0.001537 mkd (51.2% of the RfD), and exposure to
non-nursing infants less than a year old was 0.000675 mkd (63.3% of the RfD).
Exposure to children from 1 to 6 years old was 0.001386 (46.2% of the RfD),
and exposure to children 7 to 12 years old was 0.000795 mkd (26.5% of the
RfD). Exposure to females of childbearing age (13 to 50 years of age) was
0.000435 mkd (14.5% of the RfD).
b. Drinking water. Data concerning potential exposure through drinking water
is not available. The proposed use in catfish ponds is not expected to add
potential exposure to drinking water. Contained catfish ponds are drained for
levee repair every 5 to 10 years. The water is returned to the pond to the
greatest extent possible after the repair. In some cases, the water may be
released to a ditch or a stream. Because market catfish are harvested from the
ponds year round as the catfish in a pond reach marketable size, the repair
work is not seasonal, but completed on a staggered basis, and does not
necessarily occur during the time of year when diuron may be applied to the
pond waters. Diuron is moderately toxic, there have been detections in
groundwater, and it has low to intermediate mobility in fine to coarse
textured soils and freshwater sediment (according to the Diuron Environmental
Fate Profile completed for the U.S. EPA by Dynamac, dated June 10, 1982, pp
37-49). Based on these three factors, a conservative 10% of exposure has been
reserved for drinking water.
2. Non-dietary exposure. Diuron is not expected to be used in residential
settings. However, some registered product labels include uses, while not
intended for residential use, could conceivably result in residential
exposure. These uses include application to ornamentals, use as a wood
preservative (algicide in boat paints), or application to turf. A conservative
5% of the total exposure has been reserved to account for the uses which could
potentially result in residential or lawn use.
D. Cumulative Effects
Linuron is the only chemical, registered in the United States as a pesticide,
which is chemically similar to diuron. Despite the structural similarity,
based on publicly available information, some of their toxicological
activities differ significantly. In the carcinogenicity studies, mice treated
with 2,500 ppm diuron developed mammary adenocarcinomas and ovarian luteomas.
Rats treated with 2,500 ppm diuron developed urinary bladder carcinomas.
Mammary glands were not evaluated in this study. For linuron, mice in the
carcinogenicity study developed hepatocellular adenomas. Rats developed
testicular carcinomas which were not hormone dependant. The carcinogen
classification of diuron is currently under review. Linuron is considered a
Group C carcinogen (without Q*) Non-tumor lesions in rats administered diuron
included anemia and an increased reticulocyte count. In the chronic linuron
study, there was a decrease in the reticulocyte count.
Based on these considerations, there is insufficient evidence to determine if
cumulative toxicity will occur.
E. Safety Determination
1. U. S. population. Maximum exposure to the U. S. population resulting from
the use of diuron, including the use in catfish ponds, is not expected to
exceed 0.000593 mkd, representing 19.8% of the RfD. After adding 10% for
potential drinking water and 5% for potential residential/lawn exposure, the
total exposure represents only 34.8% of the RfD. Therefore, there is a
reasonable certainty of no harm resulting from aggregate exposure of diuron to
the general population.
2. Infants and children. Maximum exposure to the most highly exposed infants
and children subgroup, non-nursing infants less than a year old, is not
expected to exceed 0.001900 mkd, which represents 63.3% of the RfD. After
adding 10% for potential drinking water exposure, and 5% for potential
residential/lawn exposure, the total exposure to this subgroup represents only
78.3% of the RfD. Therefore, there is a reasonable certainty of no harm
resulting from aggregate exposure of diuron to infants and children.
These results represent very conservative consumption and residue levels. An
exposure estimate based on anticipated residues for all foods, and consumption
of farm-raised catfish only, would result in a greatly diminished risk.
F. International Tolerances
A maximum residue level has not been established for diuron by the Codex
II. Public Record
Interested persons are invited to submit comments on this notice of filing.
Comments must bear a notation indicating the docket control number, [PF-693].
A record has been established for this notice of filing under docket control
number [PF-693] (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 public record is located in Rm.
1132 of the Public Response and Program Resources Branch, Field Operations
Division (7506C), Office of Pesticide Programs, Environmental Protection
Agency, Crystal Mall #2, 1921 Jefferson Davis Highway, Arlington, VA.
Electronic comments may be sent directly to EPA at: opp-
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 notice, as well as the public version, as
described above, will be kept in paper form. Accordingly, EPA will transfer
all comments received electronically to printed, paper form as they are
received and will place the paper copies in the official notice 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 requirements.
Dated: January 16, 1997.
Stephen L. Johnson, Director
Office of Pesticide Programs
[FR Doc. 97-1751 Filed 1-23-97; 8:45 am]