[Federal Register Volume 60, Number 55 (Wednesday, March 22, 1995)]
[Proposed Rules]
[Pages 15113-15115]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-6931]
-----------------------------------------------------------------------
ENVIRONMENTAL PROTECTION AGENCY
40 CFR Parts 180, 185, and 186
[FAP 4H5683/P600; FRL-4935-1]
RIN 2070-AC18
Hexazinone; Pesticide Tolerances and Food/Feed Additive
Regulations
AGENCY: Environmental Protection Agency (EPA).
ACTION: Proposed rule.
-----------------------------------------------------------------------
SUMMARY: This document proposes to amend the current tolerance for
residues of the herbicide hexazinone (3-cyclohexyl-6-(dimethylamino)-1-
methyl-1,3,5-triazine-2,4(1H,3H)-dione and its metabolites (calculated
as hexazinone) in or on sugarcane at 0.2 part per million (ppm) by
revoking the current tolerance and reestablishing the same tolerance
with regional registration and tolerance as described by 40 CFR
180.1(n). EPA also proposes to establish food and feed additive
regulations for residues of hexazinone and its metabolites (calculated
as hexazinone) in sugarcane molasses at 0.5 ppm. E. I. du Pont de
Nemours & Co., Inc., requested these proposed regulations.
DATES: Written comments, identified by the document control number [FAP
4H5683/P600], must be received on or before April 21, 1995.
ADDRESSES: By mail, submit written comments to: Public Response
Section, 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 Hwy., Arlington, VA 22202.
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). Information so marked 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 Virginia address given above, from 8 a.m. to 4 p.m., Monday through
Friday, excluding legal holidays.
FOR FURTHER INFORMATION CONTACT: By mail: Joanne I. Miller, Product
Manager (PM) 23, Registration Division (7505C), Environmental
Protection Agency, 401 M St., SW., Washington, DC 20460. Office
location and telephone number: Rm. 237, CM #2, 1921 Jefferson Davis
Hwy., Arlington, VA 22202, (703-305-7830).
SUPPLEMENTARY INFORMATION: E.I. du Pont de Nemours & Co., Inc., has
requested a regional registration for the use of hexazinone end-use
pesticide products for the use site, sugarcane. The company proposed
that the use-site exclude the State of Florida, because the product is
not efficacious in muck soils at dosages that would be economically
viable to growers. The company has stated that the rate needed for weed
control in the typically high organic soil of Florida used for the
culture of sugarcane would exceed the maximum labelled dosage. In
addition, the company also stated that the high rates would not be
economically viable considering other less expensive, lower application
rate products. Based on the information submitted, the company has
proposed a geographically limited registration for use of hexazinone in
sugarcane. In this case, the company contends that there is little
likelihood for the use of hexazinone in the State of Florida and that
its residue data are representative of all sugarcane-growing areas of
the United States.
Published information on acres of sugarcane grown in the State of
Florida on other than organic soils (Spodosols, Entisols, Mollisols)
was 11.1% of a total of 464,191 acres in 1993 (Sugar Y Azucar 89:(1):
39-44). EPA has no data on potential residues of hexazinone when used
in the culture of sugarcane commodities from studies with sugarcane
cultured in the State of Florida. Residue chemistry data from a Florida
study are required to allow the unrestricted use of hexazinone in the
culture of sugarcane.
EPA issued a notice, published in the Federal Register of July 13,
1994 (59 FR 35179), which announced that E.I. Du Pont de Nemours & Co.,
Inc., had submitted food additive petition (FAP) 4H5683 to EPA
requesting that the Administrator, pursuant to section 409 of the
Federal Food, Drug and Cosmetic Act (FFDCA), 21 U.S.C. 346a(e), amend
40 CFR parts 185 and 186 by establishing tolerances for residues of the
herbicide hexazinone (3-cyclohexyl-6-dimethylamino)-1-methyl-1,3,5-
triazine-2,4-(1H,3H)-dione) in or on sugarcane molasses at 5.0 ppm and
sugarcane bagasse at 0.5 ppm. Sugarcane bagasse is not currently
considered a food or a feed commodity by EPA; therefore, the requested
tolerance is not proposed to be established in this document.
There were no comments received in response to the notice of
filing. The scientific data submitted with the petition and other
relevant material have been evaluated. The toxicological and residue
chemistry data considered in support of the proposed actions include
the following:
1. Plant and animal metabolism studies.
2. Enforcement methodology for determining residues.
3. A 90-day feeding study with rats, with a NOEL of 50 mg/kg/day
and an LEL of 150 mg/kg/day with the effect being decreased body
weights in both sexes.
4. A 90-day feeding study with dogs, with a NOEL of 25 mg/kg/day,
increase alkaline phosphatase, decreased albumin/globulin, and
increased absolute and relative liver weights in both sexes.
5. A 21-day dermal study in rabbits, with a NOEL of 1,000 mg/kg/
day, the highest dose tested (HDT).
6. A 12-month chronic feeding study with dogs, with a NOEL of 5.0
mg/kg/day and a lowest effect level (LEL) of 37.5 mg/kg/day with
thinness in one male dog, increased alkaline phosphatase in males,
decrease albumin and increased golbulin in males, pale kidneys in one
female, and increased incidence of hepatocellular vacuolation in males,
and cytoplasmic inclusions and pigmented Kupffer cells in the livers of
females.
7. A 24-month carcinogenicity study in mice that was equivocal for
adenomas/carcinomas, with no statistical significance in pair-wise
comparison between control and dosed animals; systemic NOEL of 30 mg/
kg/day and systemic LEL of 375 mg/kg/day.
8. A developmental toxicity study with rats, with a maternal NOEL
of 100 mg/kg/day and maternal LEL of 400 mg/kg/day; a developmental
NOEL of 100 mg/kg/day and developmental LEL of 400 mg/kg/day (decreased
fetal body weight, increased incidence of fetuses with no kidney
papilla, and increased incidence of fetus with unossified sternebrae).
9. A developmental toxicity study in rabbits, with a maternal NOEL
of 50 mg/kg/day and a maternal LEL of 125 mg/kg/day (decreased body
weight gains, increased resorptions and increased clinical signs); and
with a developmental NOEL of 50 mg/kg/day and a developmental LEL of
125 mg/kg/day (decreased body weight and delayed ossifications of
extremities). [[Page 15114]]
10. A two-generation reproductive study with rats with a
reproductive NOEL of 10 mg/kg/day and an LEL of 100 mg/kg/day and an
LEL of 100 mg/kg/day (decreased pup weight in F1, F2a, and
F2b litters) and decreased pup survival at 250 mg/kg/day in
F2b litters; systemic NOEL of 10 mg/kg/day and LEL of 100 mg/kg/
day (decreased body weight and body weight gains).
11. A chronic feeding/carcinogenicity study in rats with a negative
carcinogenic potential and a systemic NOEL of 10 mg/kg/day and an LEL
of 50 mg/kg/day (decreased food efficiency and weight gains in
females).
12. A gene mutation assay with Salmonella strains TA1535, TA1537,
TA1538, TA100, and TA98 with and without S-9 activation, negative.
13. A gene mutation (in vitro) CHO/HGPRT assay at cytotoxic doses
(13.9 mM, without S-9 and 9.9 mM with S-9 activation), negative.
14. A structural chromosome aberration (mammalian cells in culture)
cytogenetic assay in Chinese hamster ovary cells with CHO chromosomal
aberrations with and without S-9 metabolic activation, positive.
15. A structural chromosome aberration (mammalian cells in culture)
cytogenetic assay in rat bone marrow, negative.
16. An unscheduled DNA synthesis study with rats at doses of 1 x
105 to 30 mM, negative.
17. A rat metabolism study with a single dose, resulted in 97% of
radioactivity excreted within 7 days (20 percent in feces and 77
percent in urine); the major metabolites were demethylated hydroxylated
compounds.
As part of EPA's evaluation of potential human health risks,
hexazinone has been the subject of two Peer Reviews by the Office of
Pesticides' Carcinogenicity Peer Review Committee. The first Peer
Review, dated October 10, 1991, indicated that based on the weight of
evidence, hexazinone was classified as a Group C carcinogen, possible
human carcinogen. The committee recommended that for the purposes of
risk characterization, the EPA reference dose (RfD) approach should be
used for quantification of human risk.
E. I. du Pont de Nemours & Co. questioned the finding of the first
Peer Review and presented a reevaluation of the mouse carcinogenic
study based on contemporary diagnostic nomenclature of the pathology of
the neoplasium found. The pathologist classified the hepatocellular
carcinomas and hyperplastic nodules as either hepatocellular carcinoma,
hepatocellular adenoma, or a focus of cellular alteration
(nonneoplastic). The Peer Review findings were based on a pathological
diagnosis that classified all hyperplastic nodules as tumors/adenomas.
A second Peer Review dated May 11, 1994, was conducted based on the
reclassification of the pathology. Based on another weight-of-evidence
evaluation the Carcinogenicity Peer Review Committee determined that
hexazinone should be recategorized as a Group D, not classifiable as to
human carcinogenicity. That is, the evidence is inadequate and cannot
be interpreted as showing either the presence or absence of a
carcinogenic effect. Based on this conclusion, EPA determines that
hexazinone does not induce cancer within the meaning of the Delaney
Clause.
The Peer Review Committee considered the following facts regarding
the toxicology data on hexazinone in a weight-of-evidence determination
of carcinogenic potential:
1. Based on the registrant's submission of reevaluated liver
sections, hexazinone feed in the diet of CD-1 male and female mice was
not associated with any pairwise statistically significant increases in
adenomas, carcinomas, or combined adenomas/carcinomas, when the
controls were compared to the treated groups. Female mice had a
statistically significant dose-related trend (P = 0.014) for combined
hepatocellular adenoma/carcinoma, but the pairwise comparison of the
high-dose group to control was not statistically significant. The
incidence of combined hepatocellular adenomas/carcinomas (9%) in
females at the highest dose exceeded the range of these tumors in
historical controls (0-5%).
Male mice had a statistically significant increasing dose-related
trend in foci of cellular alteration in the liver and also a
significant increase (p = 0.004) in these nonneoplastic lesions in the
pairwise comparison of the highest dose and the controls. The HDT,
although very high, was not considered by the Committee to have been
excessive for assessing the carcinogenic potential of hexazinone in
mice.
2. Hexazinone fed in the diet to male and female Spragus-Dawley
rats at doses up to 125 mg/kg/day was not associated with statistically
significant increases of any neoplasms in either sex.
The dosing in this study was considered to be marginally adequate
based on the lack of significant toxicity and enhanced survival.
3. Hexazinone was mutagenic both with and without S-9 activation in
an in vivo assay for chromosomal aberrations in Chinese hamster ovary
cells (almost at the level of a positive control without activation).
The response in a Chinese hamster ovary (CHO) gene mutation assay with
activation was equivocal. Hexazinone was negative in the Salmonella
assay, in an in vivo cytogenetic assay, and in a UDS assay.
4. Hexazinone is structurally, but not chemically (lacks
aromaticity), related to the 2-triazines, which are usually associated
with mammary gland tumors in Sprague-Dawley rats (the same strain used
in the hexazinone study). Phenobarbital was considered to be a closer
analog, both structurally and chemically, but unlike hexazinone,
phenobarbital has no known genotoxicity. Hexazinone may also be viewed
as a pyrimidine analog, a property which is thought to be predictive of
carcinogenicity.
The Reference Dose (RfD) is established at 0.05 mg/kg/day, based on
a NOEL of 5.0 mg/kg/day in the 12-month dog-feeding study and an
uncertainty factor of 100. The Anticipated Residue Contribution (ARC)
from the current actions is estimated at 7.4 x 10-5 mg/kg of
body weight/day for the general population and utilizes less than 15%
of the RfD for the U.S. population. The ARC for the most exposed
subgroups is 2.0 x 10-2 mg/kg/body weight/day for nonnursing
infants (less than 1 year old) and 1.0 x 10-2 mg/kg/body weight/
day for children (1 to 6 years old), or 40.0 and 20.0 percent of the
RfD, respectively. No appreciable risk is expected from chronic dietary
intake because the RfD is not exceeded for either the general
population or any subgroup.
The nature of the residue is adequately understood for establishing
these tolerances.
An adequate analytical method, gas chromatography with a nitrogen-
phosphorus detector, is available for enforcement purposes.
The pesticide is considered useful for the purpose for which these
tolerances are sought, and these tolerances will limit dietary exposure
to this pesticidal chemical. There are currently no actions pending
against the registration of this chemical.
Based on the information and data considered, the Agency has
determined that the tolerances and food/feed additive regulations
established by amending 40 CFR parts 180, 185, and 186 would protect
the public health. Therefore, it is proposed that the tolerances and
food/feed additive regulations be established as set forth below.
Any person who has registered or submitted an application for
registration [[Page 15115]] of a pesticide, under the Federal
Insecticide, Fungicide, and Rodenticide Act (FIFRA) as amended, which
contains any of the ingredients listed herein, may request within 30
days after publication of this document in the Federal Register that
this rulemaking proposal be referred to an Advisory Committee in
accordance with section 408(e) of the FFDCA.
Interested persons are invited to submit written comments on the
proposed regulation. Comments must bear a notation indicating the
document control number, [FAP 4H5683/P600]. All written comments filed
in response to this petition will be available in the Public Response
and Program Resources Branch, at the address given above from 8 a.m. to
4 p.m., Monday through Friday, except legal holidays.
Under Executive Order 12866 (58 FR 51735, Oct. 4, 1993), the Agency
must determine whether the regulatory action is ``significant'' and
therefore subject to all the requirements of the Executive Order (i.e.,
Regulatory Impact Analysis, review by the Office of Management and
Budget (OMB)). Under section 3(f), the order defines ``significant'' as
those actions likely to lead to a rule (1) having an annual effect on
the economy of $100 million or more, or adversely and materially
affecting a sector of the economy, productivity, competition, jobs, the
environment, public health or safety, or State, local or tribal
governments or communities (also known as ``economically
significant''); (2) creating serious inconsistency or otherwise
interfering with an action taken or planned by another agency; (3)
materially altering the budgetary impacts of entitlement, grants, user
fees, or loan programs; or (4) raising novel legal or policy issues
arising out of legal mandates, the President's priorities, or the
principles set forth in this Executive Order.
Pursuant to the terms of this Executive Order, EPA has determined
that this rule is not ``significant'' and is therefore not subject to
OMB review.
Pursuant to the requirements of the Regulatory Flexibility Act
(Pub. L. 96-354, 94 Stat. 1164, 5 U.S.C. 601-612), the Administrator
has determined that regulations establishing new tolerances or raising
tolerance levels or establishing exemptions from tolerance requirements
do not have a significant economic impact on a substantial number of
small entities. A certification statement to this effect was published
in the Federal Register of May 4, 1981 (46 FR 24950).
List of Subjects in 40 CFR Parts 180, 185, 186
Administrative practice and procedure, Agricultural commodities,
Food additives, Feed additives, Pesticides and pests, Processed foods,
Reporting and recordkeeping requirements.
Dated: March 9, 1995.
Daniel M. Barolo,
Director, Office of Pesticide Programs.
Therefore, it is proposed that 40 CFR parts 180, 185, and 186 be
amended as follows:
PART 180--[AMENDED]-
1. In part 180:
a. The authority citation for part 180 continues to read as
follows:
Authority: 21 U.S.C. 346a and 371.
b. In Sec. 180.396, the existing text is designated as paragraph
(a), and the table therein is amended by removing the entry for
sugarcane, and new paragraph (b) is added, to read as follows:
Sec. 180.396 Hexazinone; tolerances for residues.
(a) * * *
(b) A tolerance with regional registration, as defined in
Sec. 180.1(n) and which excludes use of hexazinone on sugarcane in
Florida, is established for combined residues of the herbicide
hexazinone (3-cyclohexyl-6-(dimethylamino)-1-methyl-1,3,5-triazine-
2,4(1H,3H)-dione) and its metabolites (calculated as hexazinone) in or
on the following raw agricultural commodity:
------------------------------------------------------------------------
Parts per
Commodity million
------------------------------------------------------------------------
Sugarcane.................................................. 0.2
------------------------------------------------------------------------
PART 185--[AMENDED]
2. In part 185:
a. The authority citation for part 185 continues to read as
follows:
Authority: 21 U.S.C. 346a and 348.
b. By adding new Sec. 185.3575, to read as follows:
Sec. 185.3575 Hexazinone; tolerances for residues.
A food additive tolerance with regional registration, as defined
in Sec. 180.1(n) and which excludes use of hexazinone on sugarcane in
Florida, is established for combined residues of the herbicide
hexazinone (3-cyclohexyl-6-(dimethylamino)-1-methyl-1,3,5-triazine-
2,4(1H,3H)-dione) and its metabolites (calculated as hexazinone) in or
on the following commodity:
------------------------------------------------------------------------
Parts per
Commodity million
------------------------------------------------------------------------
Sugarcane, molasses........................................ 0.5
------------------------------------------------------------------------
PART 186--[AMENDED]
3. In part 186:
a. The authority citation for part 186 continues to read as
follows:
Authority: 21 U.S.C. 348.
b. By adding new Sec. 186.3575, to read as follows:
Sec. 186.3575 Hexazinone; tolerances for residues.
A feed additive tolerance with regional registration, as defined
in Sec. 180.1(n) and which excludes use of hexazinone on sugarcane in
Florida, is established for combined residues of the herbicide
hexazinone (3-cyclohexyl-6-(dimethylamino)-1-methyl-1,3,5-triazine-
2,4(1H,3H)-dione and its metabolites (calculated hexazinone) in or on
the following feed commodity:
------------------------------------------------------------------------
Parts per
Commodity million
------------------------------------------------------------------------
Sugarcane, molasses........................................ 0.5
------------------------------------------------------------------------
[FR Doc. 95-6931 Filed 3-21-95; 8:45 am]
BILLING CODE 6560-50-F