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Novartis; 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 14423-14426]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr26mr97_dat-87]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-718; FRL-5590-3]
Novartis; Pesticide Tolerance Petition Filing
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice of filing.
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SUMMARY: This notice is a summary of a pesticide petition (PP) 6F4621
proposing the establishment of a regulation for residues of the
herbicide norflurazon and its desmethyl metabolite in or on
bermudagrass forage and bermudagrass hay. This summary was prepared by
the petitioner, Novartis. The original petitioner, Sandoz Agro, Inc.,
merged with Ciba-Geigy Corp., to form a new corporation, Novartis Crop
Protection, Inc., on January 1, 1997, thus the name of the Petitioner
has been changed.
DATES: Comments, identified by the docket control number [PF-718], must
be received on or before, April 25, 1997.
ADDRESSES: By mail, submit written comments to: Public Response and
[[Page 14424]]
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 by sending electronic mail (e-
mail) to: opp-docket@epamail.epa.gov. Electronic comments on this
notice may be filed online at many Federal Depository Libraries.
Additional information on electronic submissions can be found below in
this document.
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: By mail: Joanne Miller, Product
Manager (PM) 23, Registration Division (7505C), Office of Pesticide
Programs. Environment Protection Agency, 401 M St. SW., Washington, DC
20460. Office location and telephone number: Rm. 237, CM #2, 1921
Jefferson Davis Highway, Arlington, VA 22202. (703) 305-6224, e-mail:
miller.joanne@epamail.epa.gov.
SUPPLEMENTARY INFORMATION: EPA has received a pesticide petition (PP)
6F4621 from Novartis Crop Protection, Inc., P.O. Box 18300, Greensboro,
NC 27419, proposing to amend 40 CFR part 180, pursuant to section
408(d) of the Federal Food, Drug and Cosmetic Act (FFDCA), 21 U.S.C.
346a(d), by establishing tolerances for combined residues of the
herbicide norflurazon, (4-chloro-5-(methylamino)-2-(alpha, alpha,
alpha-trifluoro-m-tolyl)-3-(2H)-pyridazinone) and its desmethyl
metabolite (4-chloro-5-(amino)-2-alpha, alpha alpha-trifluoro-m-tolyl)-
3(2H)-pyridazinone) in or on bermudagrass forage at 3.0 ppm and
bermudagrass hay at 2.0 ppm. The proposed analytical method of
determining residues was gas chromatography. The initial notice of
filing was published previously in the Federal Register of February 1,
1995 (61 FR 3698)(FRL-4994-3). The current notice of filing is required
by EPA to fulfill FQPA requirements. Tolerances requested are the same
as those proposed in the initial filing.
Pursuant to the section 408(d)(2)(A)(i) of the FFDCA, as amended,
Novartis Crop Protection Inc., has submitted the following summary
information, data and arguments in support of their pesticide petition.
This summary was prepared by Novartis and EPA has not fully evaluated
the merits of the petition. EPA edited the summary to clarify the
summary and to remove certain extraneous material and that the
conclusions and arguments are the petitioners and not necessarily the
EPA's.
I. Petition Summary
A. Chemical Uses
Norflurazon, (4-chloro-5-(methylamino)-2-(alpha, alpha, alpha-
trifluoro-m-tolyl)-3-(2H)-pyridazinone), is a selective, pre-emergent
herbicide used to control germinating annual grasses and broadleaf
weeds.
Norflurazon is noncorrosive and is stable under alkaline and acid
conditions, but is sensitive to light. Norflurazon is only slightly
soluble in water (<40 parts per million (ppm)).
B. Norflurazon Safety
Novartis has submitted over 70 separate toxicology studies in
support of tolerances for Norflurazon. EPA has classified norflurazon
as a non-quantifiable Group C, possible human carcinogen. According to
Novartis, norflurazon is not a mutagen and has low oral and dermal
toxicity to mammals. (Updated studies have recently been submitted to
the EPA.) Risk assessment calculations indicate margins of safety for
agricultural workers and the population in general far exceed the EPA
required level of 100.
The following mammalian toxicity studies have been conducted to
support the tolerances of Norflurazon:
Acute Oral, Rat (Male) LD50: 9.3 g/kg (Tox Category IV)
Acute Dermal, Rabbit: LC50 ³20,000 mg/kg (Tox
Category IV)
Acute Inhalation, Rat: LC50 > 2.4 mg/l (Tox Category III)
Primary Eye Irritation, Rabbit: non-irritating (Tox Category IV)
Primary Dermal Irritation, Rabbit: no irritation (Tox Category IV)
Dermal Sensitization, in male Guinea Pig: technical norflurazon at
0.1 percent did not cause sensitization (Tox Category IV)
90-day rat feeding study: The systemic no-observable-effect-level
(NOEL) was considered to be 12.50 mg/kg/day in male rats, and 25.0 mg/
kg/day in female rats.
A 6-month dog feeding study: The systemic NOEL was determined to be
1.53 mg/kg/day for males, and 1.58 mg/kg/day for females. The systemic
LEL was determined to be 5.02 mg/kg/day for males, and 4.77 mg/kg/day
for females.
A 3-week rabbit dermal study: The systemic NOEL was 375 mg/kg/day
for males and females. The dermal NOEL was also 375 mg/kg/day for both
sexes.
A 28-day rat feeding study: NOEL of 50.0 mg/kg/day.
A 28-day mouse feeding study: NOEL of 63.0 mg/kg/day.
A rat dermal absorption study: No more than 0.1 percent of applied
dose was absorbed at doses up to 10 mg/rat.
Gene mutation assays: Negative. There was no evidence of
cytotoxicity in any of the strains at any of the dose concentrations
used. In an in vitro unscheduled DNA synthesis assay, norflurazon
failed to induce unscheduled DNA synthesis in primary rat hepatocytes.
In an in vitro chromosomal aberration assay, norflurazon did not cause
a clastogenic response in the presence of liver S-9 or in the absence
of S-9.
A developmental study in rats: No maternal or developmental effects
at 400 mg/kg/day. Maternal NOEL was <100 mg/kg/day; maternal LEL was
100 mg/kg/day, based on reductions in body weight for the period of
dosing and for the dosing plus post-dosing period.
A developmental study in rabbits: The NOEL for maternal toxicity
was 30 mg/kg/day based on maternal body weight decreases at 60 mg/kg/
day. The NOEL for developmental toxicity was 30 mg/kg/day.
Developmental effects seen at 60 mg/kg/day were decreased fetal weight
and incomplete ossification of the skull, fore and hind limb middle
phalanx, metacarpal, and proximal epiphysis of the tibia.
A three generation reproduction study in rats showed no apparent
effects on reproductive performance at any dose level tested.
A chronic toxicity and carcinogenicity study in Sprague-Dawley
rats: No significant effects of technical norflurazon were evident for
survival, body weight, body weight gain, or food consumption in male or
female rats at any dose level tested. The systemic NOEL was determined
to be 18.75 mg/kg/day for both sexes.
A carcinogenicity study in mice: No significant effects were
observed on body weight, body weight gain, and
[[Page 14425]]
food consumption at any dose. The systemic NOEL was determined to be
12.8 mg/kg/day for male mice, and 58.7 mg/kg/day for female mice.
A rat metabolism study: A rat metabolism study at single oral doses
of 2 or 110 mg/kg, a single i.v. dose of 2.0 mg/kg, or a single oral
dose at 2 mg/kg after animals had ingested 0.1 mg/kg for 14 days showed
that less than 1.0 percent of the administrated dose remained 96 hours
after dosing. Thirteen metabolites were isolated. Norflurazon appears
to be metabolized by N-demethylation, displacement of the chlorine atom
by glutathione, glutatione attack on the aromatic ring, and replacement
of the chlorine atom with hydrogen. Norflurazon appears to be rapidly
absorbed from the gastrointestinal tract and extensively metabolized.
C. Threshold Effects
Chronic effects: Based on the available chronic toxicity data, EPA
has set the Reference Dose (RfD) for norflurazon at 0.02 mg/kg/bwt/day.
The RfD for norflurazon is based on the 6-month dog feeding study with
a threshold NOEL of 1.53 mg/kg/day and an uncertainty factor of 100.
Acute toxicity: Because developmental effects were seen in the
rabbit developmental study, the Agency assessed acute dietary risk from
developmental effects for the subgroup females (13+ years) the only
appropriate group of acute dietary concern. The Margin of Exposure
(MOE), a measure of how closely the high-end exposure comes to the
NOEL, was calculated as the ratio of the NOEL to the exposure and
determined to be 3,000. The Agency is not generally concerned unless
the MOE is below 100 when based upon data generated in animal studies.
D. Non-threshold Effects
Carcinogenicity: The EPA's Health Effects Division Peer Review
Committee classified norflurazon as a Group C, possible human
carcinogen, based on the criteria in the Agency's Guideline for the
Classification of Carcinogens published in the Federal Register of
September 24, 1986, (51 FR 33992-34003), and the statistically
significant increase in comparison to controls in hepatocellular
adenomas and combined hepatocellular adenomas and carcinomas in male
CD-1 mice as well as the statistically significant positive trend for
hepatocellular adenomas and combined adenomas and carcinomas.
That committee also recommended that for the purposes of risk
characterization the RfD approach should be used for the quantification
of human risk. This recommendation was supported by the presence of
only benign tumors in only one sex of one species at one dose level,
and adequate but negative mutagenicity data and no positive analogues.
EPA believes norflurazon poses a negligible cancer risk to humans.
E. Aggregate Exposure:
For the purposes of assessing the potential dietary exposure,
Novartis has estimated the aggregate exposure based on the Theoretical
Maximum Residue Contribution (TMRC) from the tolerances for all crops
on which norflurazon-based products are labeled. The TMRC from the
established and the proposed tolerances is 0.002041 and utilizes 10.2
percent of the RfD for the overall U.S population. The exposure of the
most highly exposed subgroup in the population, non-nursing infants, is
0.009356 mg/kg/bwt/day and utilizes 46.8 percent of the RfD.
No norflurazon-based products are labeled for residential use. Non-
occupational exposure for norflurazon has not been estimated since the
current registrations for norflurazon-based products are limited to
commercial crop production. The potential for non-occupational exposure
to the general population is, therefore, insignificant.
EPA consideration of a common mechanism of toxicity is not
appropriate at this time because Sandoz and EPA do not have information
to indicate that toxic effects produced by norflurazon would be
cumulative with those of any other chemical compounds.
F. Determination of Safety for US population
Reference Dose (RfD): Using a 100-fold safety factor and the NOEL
of 1.53 mg/kg/day determined by the most sensitive species (the 6-month
dog feeding study), the RfD is 0.02 mg/kg/bwt/day. The TMRC from the
established and the proposed tolerances is 0.002041 and utilizes 10.2
percent of the RfD for the overall U.S population. Based on the
completeness and reliability of the toxicity data and the conservative
exposure assessment, Sandoz concludes that there is a reasonable
certainty that no harm will result from the aggregate exposure of
residues of norflurazon including all anticipated dietary exposure.
G. Determination of Safety for Infants and Children
The exposure of the most highly exposed subgroup in the population,
non-nursing infants, is 0.009356 mg/kg/bwt/day and utilizes 46.8
percent of the RfD. Based on the completeness and reliability of the
toxicity data and the conservative exposure assessment, Sandoz
concludes that there is a reasonable certainty that no harm will result
to infants and children from the aggregate exposure of residues of
norflurazon including all anticipated dietary exposure.
H. Estrogenic Effects
No specific tests have been conducted with norflurazon to determine
whether the pesticide may have an effect in humans that is similar or
an effect produced by a naturally occurring estrogen or other endocrine
effects.
I. Chemical Residue
The nature of the residue is adequately understood, and an adequate
analytical method, gas chromatography using electron capture detection,
is available for enforcement purposes.
Tolerances have been established for norflurazon in almonds, hulls
and nutmeat; apples; apricots; asparagus; avocados; blackberries;
blueberries; cattle, fat, meat, and meat-by-products (mbyp); cherries;
citrus fruit; cottonseed; cranberries; filberts; goats, fat, meat and
mbp; grapes; hogs, fat, meat, and mbp; hops, green; horses, fat, meat,
and mbp; milk; nectarines; peaches; peanuts; peanut hay, hulls and
vines; pecans; pears; plums (fresh prunes); poultry, fat, meat and mbp;
raspberries; sheep, fat, meat and mbp; soybeans, forage and hay; and
walnuts. The metabolism of norflurazon in plants is adequately
understood. Metabolism of norflurazon in livestock has been studied and
tolerances for livestock commodities have been established. A ruminant
study adequately identified the metabolites in milk, liver and kidney.
Norflurazon was not detected in ruminant milk or tissue, and total
radioactive residues in fat and muscle were <0.01 ppm.
J. Environmental Fate
The environmental fate of norflurazon is adequately understood.
Norflurazon is persistent and may be mobile. Norflurazons primary route
of dissipation appears to be photodegradation in water and on soil to
desmethyl norflurazon with a half-life of 2-3 days and 12-15 days
respectively. Norflurazon is stable to hydrolysis and degrades slowly
under aerobic soil conditions with a half-life of 130 days. In an
anaerobic aquatic study, norflurazon degrades to desmethyl norflurazon
with a half-life of about 8 months.
Fish accumulation data show that norflurazon has low potential to
bioaccumulate in bluegill sunfish.
[[Page 14426]]
Norflurazon is not currently regulated under the Safe Drinking
Water Act (SWDA). Therefore, no MCL has been established and water
systems are not required to sample and analyze for it. Novartis is
currently performing groundwater monitoring studies to better evaluate
the leaching potential of norflurazon.
Norflurazon is practically non-toxic to avian species on an acute
oral and subacute dietary basis. Norflurazon is also practically
nontoxic to mammals and insects (honeybees).
K. International Tolerances
No international tolerances have been established under CODEX.
Therefore, there is no need to ensure consistency.
II. Public Record
A record has been established for this notice under docket control
number [PF-718] (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 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 notice, 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
record which will also include all comments submitted directly in
writing. The official record is the paper record maintained at the
address in ``ADDRESSES'' at the beginning of this document.
Authority: 21 U.S.C. 346a.
List of Subjects
Environmental protection, Administrative practice and procedure,
Agricultural commodities, Pesticides and pests, Reporting and
recordkeeping requirements.
Dated: March 11, 1997.
Stephen L. Johnson,
Director, Registration Division Office of Pesticide Programs.
[FR Doc. 97-7065 Filed 3-25-97; 8:45 am]
BILLING CODE 6560-50-F