pyridate (Lentagran, Tough) Pesticide Petition Filing 7/98
[Federal Register: August 5, 1998 (Volume 63, Number 150)]
>From the Federal Register Online via GPO Access [wais.access.gpo.gov]
ENVIRONMENTAL PROTECTION AGENCY
Notice of Filing of Pesticide Petitions
AGENCY: Environmental Protection Agency (EPA).
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-818, must
be received on or before September 4, 1998.
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-
firstname.lastname@example.org. Follow the instructions under ``SUPPLEMENTARY
INFORMATION.'' No confidential business information should be submitted
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. 119 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
Product Manager telephone number Address
Sidney Jackson................ Rm. 268, CM #2, 703- 1921 Jefferson
305-7610, e- Davis Hwy,
mail:jackson.sidney@e Arlington, VA
Beth Edwards.................. Rm. 206, CM #2, 703- Do.
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
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-818] (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:
Electronic comments must be submitted as an ASCII file avoiding the
use of special characters and any form of encryption. Comment 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 (insert docket number) 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
Dated: July 23, 1998.
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. Interregional Research Project 4 (IR-4)
EPA has received a pesticide petition (PP 6E4667) from the
Interregional Research Project 4(IR4), 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
pyridate, 0-(6-chloro-3-phenyl-4-pyridazinyl)-S-octyl carbonothioate
and its metabolite 6-chloro-3-phenyl-pyridazine-4-ol (known as SAN
1367), and conjugates of SAN 1367 in or on the raw agricultural
commodity garbanzo beans (also known as chick peas) at 0.1 ppm.
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 support granting of the petition.
Additional data may be needed before EPA rules on the petition. This
notice contains a summary of the petitions prepared by Novartis Crop
Protection, Inc. (formerly Sandoz Agro Inc.), the registrant.
2. Novartis Crop Protection, Inc.
EPA has received a pesticide petition (PP 6F4754) from Novartis
Crop Protection, Inc, 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 pyridate, 0-(6-
chloro-3-phenyl-4-pyridazinyl)-S-octyl carbonothioate and its
metabolite 6-chloro-3-phenyl-pyridazine-4-ol (known as SAN 1367), and
conjugates of SAN 1367 in or on the raw agricultural commodities head
and stem Brassica Subgroup 5A at 0.3 parts per million (ppm). (Sidney
A. Residue Chemistry
1. Plant metabolism. The metabolism of pyridate in plants is well
understood based on studies with broccoli, corn, and peanut. Pyridate
is rapidly broken down by hydrolysis to its major degradation product,
SAN 1367. The SAN 1367 metabolite is further conjugated to glucoside
2. Analytical method. The proposed analytical method is ``Method of
analysis of determination of residues of pyridate and its metabolites
and conjugated CL 9673 in plant materials'', Report No. 758e, March
1992, Agrolinz Agrarchemikalien Ges.m.b.H. (V/6).
3. Magnitude of residues. Residue trials have been conducted with
pyridate on the additional crops requested in the pending petitions.
The proposed tolerances are recommended at the limit of determination
for the method, which is the maximum expected residue from the
geographically representative field trial data.
Pyridate strongly adsorbs to soil and was shown to be immobile in
soil column leaching studies. Pyridate has a short half-life, low water
solubility, and low volatility. Due to its solubility and hydrolysis
characteristics, pyridate will not persist in the environment.
San 1367 is further degraded and mineralized to volatile CO2 and
bound metabolites. It is susceptible to photolysis. Column leaching
studies and field dissipation studies indicated that SAN 1367 tends to
degrade faster than it is translocated below the 0-15 cm layer.
Therefore under typical agricultural conditions and labeled uses,
leaching of SAN 1367 is not an issue of concern.
B. Toxicological Profile
Data are summarized below concerning the mammalian toxicity of
pyridate. According to Novartis' interpretation of these data, pyridate
is not a carcinogen or a mutagen, has low oral and dermal toxicity to
mammals, and causes no reproductive or developmental effects.
1. Acute toxicity. Results of a rat acute oral study showed a
lethal dose LD<INF>50</INF> of 4,690 milligram/kilogram (mg/kg) body
weight/day (bwt/day) (5,993 mg/kg in males and 3,544 mg/kg in females).
In a rat acute dermal study, the LD<INF>50</INF> was shown to be >2,000
mg/kg. A rat acute inhalation study yielded a LD<INF>50</INF> >4.37 mg/
Results of a primary eye irritation study in the rabbit indicated
that pyridate is a mild irritant. A primary dermal irritation study
showed pyridate to be a moderate skin irritant, whereas, a dermal
sensitization study indicated it is a sensitizer.
2. Genotoxicity. Pyridate was tested in the Ames test, mouse
micronucleus assay, chromosome aberration assay with Chinese hamster
ovary cells, the REC assay, and rat hepatocyte unscheduled DNA
synthesis assay. Results were negative for mutagenicity and chromosome
3. Reproductive and developmental toxicity. A developmental
toxicity study in the rat dosed at 0, 55, 165, 400, and 495 milligram/
kilograms/day (mg/kg/day) showed maternal toxicant no-observed effect
level (NOEL) of 165 mg/kg/day, and developmental NOEL >495 mg/kg/day.
A developmental toxicity study in the rabbit with doses of 0, 150,
300, and 600 mg/kg/day showed a maternal toxicant NOEL of 300 mg/kg/day
and developmental NOEL >600 mg/kg/day.
Results of a multi-generational reproduction study with rats dosed
at 0, 2.2, 10.8, and 67.5 mg/kg/day showed a NOEL of 10.8 mg/kg/day for
maternal and developmental toxicity.
4. Subchronic toxicity. Results of a 21-day dermal study showed a
NOEL >1,000 mg/kg. A 90-day feeding study in rat dosed at 0, 62.5, 177,
and 500 mg/kg/day showed a NOEL of 62.5 mg/kg/day. No neuropathological
effects were found. A 90-day feeding study in dogs with doses of 0, 20,
60 and 200 mg/kg/day showed a NOEL of 20 mg/kg/day. Slight degenerative
myelopathy in the peripheral nerves was observed at the highest dose
level (HDL), which is much higher than the NOEL and the expected
exposure from field use.
5. Chronic toxicity. A 1-year feeding study in dogs was conducted
with doses of 0, 5, 20 and 60 mg/kg/day for 34-weeks. After week 34,
the doses were increased to 30, 100, and 150 mg/kg/day because no toxic
effects were evident at the lower doses. The final results showed a
systemic NOEL of 20 mg/kg/day.
A lifespan (121 week) chronic/carcinogenicity study in rats treated
with analytical levels of 0, 2.2, 10.8, and 67.5 mg/kg/day (equivalent
to 0, 48, 240, and 1,500 ppm) showed a systemic NOEL of 10.8 mg/kg/day
(240 ppm) based on body weight depression. No carcinogenic potential
In an 18- month carcinogenicity study, mice were fed doses of 0,
400, 800, 1,600 and 7,000 ppm of pyridate. In males, dose levels were
approximately 0, 47.7; 97.1; 169.5, and 882.6 mg/kg bwt/day; in
females, dose levels were approximately 0, 54.5, 114.6, 204.3, and
1,044.6 mg/kg bwt/day. NOEL was 800 ppm (97.1 mg/kg in males and 114.6
mg/kg in females). Results showed no evidence of carcinogenicity.
i. Chronic effects. The Reference Dose (RfD) has been established
based on the chronic toxicity database. The RfD = 0.11 mg/kg bwt/day
based on the NOEL of 10.8 mg/kg bwt/day from the lifespan rat
oncogenicity study due to body weight depression in males, and assuming
a safety factor of 100.
ii. Acute effects. Acute dietary analysis compared the daily
dietary exposure to the lowest NOEL for subchronic studies. EPA's
current policy for Tier I analysis uses the conservation assumption
that all residues are at a high end estimate or maximum, typically
taken as the tolerance value. Acute dietary assessment for pyridate was
generated by comparing the ratio of exposure and the NOEL from the 90-
day feeding study in dogs of 20 mg/kg bwt/day to determine a margin of
exposure (MOE). The exposure estimate includes all current and pending
tolerances from Novartis Agro, Inc. and IR-4. MOE of 100 or more are
considered acceptable. For all subgroups evaluated, the MOE is greater
iii. Carcinogenicity. Existing data demonstrate that there is no
evidence of carcinogenicity in rats at 1,500 ppm (67.5 mg/kg/day) or
mice at 7,000 ppm (883 mg/kg bwt/day in males, and 1,044.6 mg/kg bwt/
day in females). These data have been obtained at dosing in excess of
any dietary exposure.
6. Animal metabolism. Pyridate has been tested in rats, dogs,
cattle,goats, and hens. In every study, pyridate was hydrolyzed to SAN
1367 and rapidly excreted, primarily through the urine as SAN 1367 or
its glucoside or glucuronide conjugates.
Data from bovine metabolism and feeding studies established that
the uses proposed do not yield secondary residues in meat and milk
above the limit of detection. Novartis believes that data from
metabolism and feeding studies in poultry established that at the
maximum expected dietary burden from crops treated with pyridate will
not result in quantifiable residues above the limits of the analytical
method. Pyridate and its metabolites are not persistent and do not
accumulate in animal systems.
7. Metabolite toxicology. Pyridate has been tested in rats, dogs,
cattle, goats, and hens. In every study, pyridate was hydrolyzed to SAN
1367 and rapidly excreted, primarily through the urine as SAN 1367 or
its glucoside or glucuronide conjugates. Pyridate and its metabolites
are not persistent and do not accumulate in animal systems.
C. Aggregate Exposure
Based on environmental fate data, pyridate is not expected to be
found in drinking water. There are no non-crop uses for pyridate, and
no non-occupational exposure for residential use. Exposure would be
limited to dietary exposure described below. Novartis Agro has no
information that would indicate that pyridate would have a mechanism of
toxicity common to any other registered pesticide.
1. Dietary exposure--food. Pyridate is registered for use in corn,
peanut, and cabbage. The pending petitions add the use in grain
sorghum, collards, and the stem and head Brassica subgroup. The
potential dietary exposure of the population to residues of pyridate or
its metabolites is calculated based on Theoretical Maximum Residue
Contribution (TMRC) for all crops with pyridate use. The TMRC is a
worst case estimate of dietary exposure since it assumes that 100% of
all crops for which tolerances are established are treated with
pyridate, and that pesticide residues are present at the tolerance
levels. Novartis maintains that this method of calculation result in an
overestimation of the exposure and is considered conservative. Dietary
exposure is not expected in meat, milk, poultry, or eggs, based on cow
and hen feeding studies, animal metabolism studies, and the fact the
residue studies indicate that residues are not present in crops fed to
animals above the limit of detection.
2. Drinking water. Drinking water is not expected to be a means of
exposure to pyridate. Environmental studies indicate that pyridate
binds to the soil and is rapidly hydrolyzed into its metabolites. The
metabolites are then photolyzed and further degraded and finally
mineralized to CO<INF>2</INF>. Leaching studies and lysimeter studies
indicate that under typical agricultural conditions, neither pyridate
nor its metabolites were detected below 30 cm. Groundwater monitoring
studies conducted in Europe have not confirmed any detection of
pyridate or metabolites. Therefore significant movement of pyridate is
not likely and is not a considerable factor in assessing human health
3. Non-dietary exposure. There are no registered uses for pyridate
on residential or recreational turf. Therefore, non-dietary exposure of
pyridate is not likely and not a factor in assessing human health risk.
D. Cumulative Effects
Pyridate belongs to the pyridazine group of herbicidal compounds
and has a unique mode of action in plants. Novartis does not have data
to indicate a common mechanism of toxicity to other compounds in
humans. Therefore, Novartis concludes that cumulative effects from
common mechanisms of action are unlikely.
E. Safety Determination
1. U.S. population. The RfD is calculated to be 0.11 mg/kg bwt/day.
The estimates of exposure are based on conservative assumptions that
all crops with a tolerance for pyridate are treated and that all
residues found are at the maximum or tolerance level. The dietary
exposure to the U.S. population for the current uses plus the garbanzo
beans and Brassica uses is estimated at most to be 0.000019 mg/kg/day,
which is 0.017% of the RfD. Therefore Novartis concludes that there is
reasonable certainty of no harm from aggregate exposure of residues of
pyridate or its metabolites including all dietary and other non-
2. Infants and children. Pyridate is not a reproductive or
developmental toxicant. Therefore no specific effects on infants and
children are expected. Based on the weight of evidence of the toxicity
studies, Novartis concludes that an additional safety factor is not
Using the same assumptions as above, the exposure to infants and
children is presented as a percent of RfD. The dietary exposure for the
current uses plus the garbanzo beans and Brassica uses for non-nursing
infants is estimated at 0.000045 mg/kg/day, which is 0.041% of the RfD.
For children age 1-6, the estimated exposure is 0.000057 mg/kg/day,
0.052% of the RfD, and exposure to children age 7-12 is estimated to be
0.000044 mg/kg/day, which is 0.040% of the RfD. Therefore, Novartis
concludes that there is reasonable certainty of no harm from aggregate
exposure of residues of pyridate or its metabolites including all
dietary and other non-occupational exposures.
F. International Tolerances
No international tolerances have been established by CODEX
Alimentarius Commission (Sidney Jackson).
[FR Doc. 98-20769 Filed 8-4-98; 8:45 am]
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