[Federal Register Volume 61, Number 227 (Friday, November 22, 1996)]
[Notices]
[Pages 59440-59443]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-29930]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-673; FRL-5573-8]
Pesticide Tolerance Petition; Notice of Filing
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice of filing.
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SUMMARY: This notice is a summary of a pesticide petition proposing the
establishment of a regulation for residues of thiazopyr in or on orange
and grapefruit. This summary was prepared by the petitioner.
DATES: Comments, identified by the docket number [PF-673], must be
received on or before, December 23, 1996.
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 by sending
electronic mail (e-mail) to: opp-docket@epamail.epa.gov. Electronic
comments on this notice may be filed on-line at many Federal Depository
Libraries. Additional information on electronic submissions can be
found below in 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 a.m. to 4:30 p.m., Monday through Friday,
excluding legal holidays.
FOR FURTHER INFORMATION CONTACT: Joanne Miller (PM-23) Rm. 237, CM #2,
1921 Jefferson Davis Highway, Arlington, VA (703) 305-6224. e-mail:
miller.joanne@epamail.epa.gov.
SUPPLEMENTARY INFORMATION: EPA has received a pesticide petition (PP)
3F4187 from Rohm and Haas Company, Philadelphia, PA, 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 the herbicide thiazopyr in or on the raw agricultural
commodity orange (whole fruit) and grapefruit (whole fruit) at 0.05
ppm. The proposed analytical method is gas chromatography using mass
selective detection.
Pursuant to section 408(d)(2)(A)(i) of the FFDCA, as amended, Rohm
and Haas Company has submitted the following summary of information,
data and arguments in support of their pesticide petition. This summary
was prepared by Rohm and Haas 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 petitioners and not necessarily EPAs
and to remove certain extraneous material.
I. Rohm & Haas Petition Summary
A. Residue Chemistry
1. Plant metabolism. Metabolism studies were conducted on peanuts,
cotton and lemon. The metabolism of thiazopyr in all crops was
extensive. Little thiazopyr was observed in crop tissues. About 10
metabolites were identified and quantified in each study. In peanuts,
cotton, and lemon, any individual metabolite represented less than 13-,
9-, and 10-percent of the total dosage, respectively. The metabolic
pathway for all three crops is the same.
2. Analytical method. A gas-liquid chromatographic analytical
method using mass selective detection has been validated in citrus for
enforcement purposes. This method converts thiazopyr and its
metabolites to a common moiety which is quantified. The limit of
quantitation of the method is 0.025 ppm for citrus whole fruit and
processed fractions.
3. Magnitude of residues. The maximum application rate of 2 pounds
of the active ingredient per acre was applied 3 months prior to harvest
in 20 field trials. No detectable thiazopyr residue was found above the
limit of quantitation of the residue method in whole fruit. After a
single application of thiazopyr at 10 pounds per acre 3 months prior to
harvest, processed commodities of citrus were produced and analyzed. No
residue was found above the limit of quantitation of the method in the
processed fractions.
B. Toxicological Profile
1. Acute toxicity. Thiazopyr technical was practically non-toxic by
ingestion of a single dose (LD50 > 5.0 g/kg) in rats and was
practically non-toxic by dermal application (LD50 > 5.0 g/kg in
rats). Thiazopyr technical was not significantly toxic to rats after a
4-hr inhalation exposure, with an LC50 value of > 1.2 mg/L
(highest concentration attainable) for both sexes. Thiazopyr technical
was classified as slightly irritating to the eye and no more than
slightly irritating to the skin. Thiazopyr technical was not a dermal
sensitizer.
2. Genotoxicity. Thiazopyr technical was negative (non-mutagenic)
in the Ames microbial mutation assay with and without hepatic enzyme
activation. Thiazopyr technical was negative in a hypoxanthine guanine
phosphoribosyl
[[Page 59441]]
transferase (HGPRT) gene mutation assay using Chinese hamster ovary
(CHO) cells in culture when tested with and without hepatic enzyme
activation. In isolated rat hepatocytes, thiazopyr technical did not
induce unscheduled DNA synthesis (UDS) or repair when tested up the
maximum soluble concentration in culture medium. In an in vivo bone
marrow cytogenetic (micronucleus) assay no significant increases in
micronuclei were seen in bone marrow cells. Thiazopyr did not produce
chromosome effects in vivo. On the basis of the results of this battery
of tests, it is concluded that thiazopyr is not mutagenic or genotoxic.
3. Reproductive and developmental toxicity. No observed effect
levels (NOELs) for developmental toxicity were established at 100 mg/
kg/day in the rat and 175 mg/kg/day in the rabbit. In a 2-generation
reproduction study in rats there were no treatment-related effects on
any reproductive parameter in the adults or their offspring. The NOEL
was considered to be 1,000 ppm for reproductive effects (73 - 91 mg/kg/
day for males and females, respectively) and 10 ppm for adult toxicity
(0.72 - 0.94 mg/kg/day for males and females, respectively). Overall,
thiazopyr was not associated with significant developmental or
reproductive effects below maternally toxic doses.
4. Subchronic toxicity. The NOEL in a 90-day rat feeding study was
100 ppm (6.6 - 8.0 mg/kg/day in males and females, respectively), and
the LOEL was 1,000 ppm (68 - 79 mg/kg/day in males and females,
respectively) based on increases in absolute and relative liver
weights, hepatic enlargement and discoloration, hepatocellular
hypertrophy, and effects on parameters associated with altered liver
function.
In a 90-day dog feeding study the NOEL was 10 ppm (0.2 mg/kg/day
for males; 0.3 mg/kg/day for females) and the lowest observed effect
level (LOEL) 100 ppm based on hepatocellular hypertrophy/hyperplasia.
In a 21-day dermal toxicity study in the rat, the NOEL was 100 mg/
kg/day. The LOEL was 500 mg/kg/day based on minimal hepatocellular
vacuolation in females.
5. Chronic toxicity. In a 2-year combined chronic toxicity/
oncogenicity study in the rat the NOEL was 100 ppm (4.4 - 5.6 mg/kg/day
for males and females, respectively), and the LOEL was 1,000 ppm (44.4
- 56.0 mg/kg/day) based on hematologic and clinical chemistry changes,
increased organ weights and incidences of hepatocellular hypertrophy
and vacuolation, nephropathy, and thyroid follicular hypertrophy and/or
hyperplasia. An increased incidence of thyroid follicular tumors was
observed in males at the two highest doses of 1,000 and 3,000 ppm. The
thyroid tumors were determined in three special thyroid function
studies to be secondary to a disturbance of thyroid/pituitary
homeostasis and were attributed to a hormonally-mediated mechanism for
thyroid tumor induction. The effects were dose-responsive and with the
exception of thyroid weight, all effects were completely reversible
when thiazopyr was removed from the diet.
In an 18 month combined chronic toxicity/oncogenicity study in the
mouse the NOEL was 10 ppm in males (1.6 mg/kg bw/day) and 100 ppm in
females (26.8 mg/kg bw/day) and the LOEL 100 ppm in males (16.9 mg/kg
bw/day) and 400 ppm in females (108.1 mg/kg bw /day) based on increased
absolute and relative liver weights, serum chemistry changes, enlarged
and/or discolored livers, hepatocellular hypertrophy, increased
eosinophilia and vacuolization in livers of both sexes. No evidence of
oncogenicity was observed at any dose level.
In a 1-year dog feeding study the NOEL was 20 ppm (0.8 mg a.i./kg
bw/day) and the LOEL 200 ppm (8.0 mg/kg/day) based on liver hypertrophy
and changes in clinical chemistry parameters associated with liver
function.
6. Animal metabolism. Thiazopyr technical administered by the oral
or intravenous route in the rat was extensively absorbed and
extensively degraded via oxidation of the thiazoline ring, oxidation of
the isobutyl side chain of the pyridine ring and cleavage of the methyl
ester. Thiazopyr was rapidly and extensively eliminated, with very low
residues in the tissue and carcass. Glycine thioamide ester and
unsaturated nitrile acid were the major metabolites in rat excreta.
Thiazopyr was also rapidly eliminated from goats and chickens, and
oxidation of the thiazoline ring and the isobutyl side chain were also
the major route for metabolic degradation of thiazopyr in goat and
chicken.
7. Metabolite toxicity. Common metabolic pathways for thiazopyr
have been identified in animals (rat, hen, goat, bluegill sunfish) and
crop plants (cotton, peanut, citrus). Pathways common to both types of
metabolism include oxidative opening of the thiazoline ring, oxidation
of the isobutyl side chain and methyl ester cleavage. Overall, the
metabolism of thiazopyr is similar in plants and animals. Thiazopyr
undergoes extensive degradation and elimination to polar metabolites
that are unlikely to accumulate in humans or animals exposed to these
residues in the diet.
A 4-week dietary study was conducted to assess the subchronic
toxicity of thiazopyr monoacid. The results of this study suggest that
thiazopyr monoacid also perturbs thyroid/liver homeostasis by the same
mechanism elucidated for the parent compound, thiazopyr. The NOEL for
this study was 1,000 ppm (1,591 mg/kg/day for males, 1,740 mg/kg/day
for females). In comparison to the NOEL of 100 ppm in the rat
subchronic and chronic dietary studies, the NOEL of 1,000 ppm in this
study suggests that thiazopyr monoacid is approximately 10-fold less
toxic than the parent, thiazopyr.
8. Conclusions. Using its Guidelines for Carcinogen Risk Assessment
published September 24, 1986 (51 FR 33992), the EPA's Health Effects
Division Carcinogenicity Peer Review Committee concluded that there was
limited evidence for carcinogenicity and therefore classified thiazopyr
as a Group C--possible human carcinogen. A Margin of Exposure (MOE)
approach was recommended to evaluate potential consequences of human
exposure. A NOEL of 4.4 mg/kg/day and a LOEL of 44.2 mg/kg/day were
selected as the critical dose levels to be used in the MOE
carcinogenicity risk assessment.
The database for chronic toxicity assessment is complete. Based on
chronic toxicity testing, the dog was the most sensitive species. The
RfD Committee of the USEPA Health Effects Division established an
Reference Dose (RfD) for thiazopyr of 0.008 mg/kg/day based on the NOEL
of 0.8 mg a.i./kg/day and application of a 100-fold safety factor.
C. Aggregate Exposure
1. Dietary exposure--(i) food. For purposes of assessing the
potential dietary exposure under this tolerance, EPA estimates
aggregate exposure using the tolerance on citrus whole fruit at 0.05
ppm. The potential exposure is obtained by multiplying the tolerance
level residues by the consumption data which estimates the amount of
citrus or citrus products eaten by various population subgroups. Citrus
pulp is fed to animals, thus exposure of humans to residues in citrus
pulp might result if such residues are transferred to meat, milk,
poultry, or eggs. However, based on the results of animal metabolism
studies and the amount of thiazopyr residues expected in animal feeds,
EPA has concluded that there is no reasonable expectation that
measurable residue of thiazopyr will occur in meat and milk. Citrus
pulp is not a poultry
[[Page 59442]]
feed item, thus no residues are expected in poultry or eggs. There are
no other established U.S. tolerances for thiazopyr, and there are no
registered uses for thiazopyr on food or feed crops in the United
States.
Using a Dietary Risk Evaluation System analysis, Rohm and Haas
calculates that the potential exposure to thiazopyr from consumption of
orange and grapefruit products represents 1.47 percent of the thiazopyr
RfD for the general population. The percentage of the RfD for the most
highly exposed sub-group, non-nursing infants, is 3.14 percent. In
conducting this exposure assessment, Rohm & Haas has made very
conservative assumptions--that 100 percent of the oranges and
grapefruit contain thiazopyr residues and that those residues would all
be at the level of the tolerance. This clearly is an overestimation of
the potential human exposure.
(ii) Drinking water. Other potential dietary sources of exposure of
the general population to residues of pesticides are residues in
drinking water. A prospective ground water study conducted in a citrus
grove, in an area considered vulnerable to leaching of pesticide
residue to groundwater, demonstrated that thiazopyr does not leach. A
degradate of thiazopyr, thiazopyr monoacid, was observed. Using
consumption of 2 liters per day of drinking water (consistent with the
National Primary Drinking Water Regulations--Synthetic Organic and
Inorganic Chemicals, (56 FR 3526, January 30, 1991)), and the most
conservative estimate of potential monoacid concentration, Rohm and
Haas calculates that the monoacid uses 2.9 percent of the thiazopyr
RfD. This value is substantially below the 20 percent of the RfD
typically allocated for drinking water in 56 FR 3526. In conducting
this exposure assessment, Rohm and Haas has made the very conservative
assumption that all drinking water contains the maximum level of
monoacid residues observed in a study designed to evaluate the worst
case situation. In addition, the thiazopyr monoacid was considered for
purposes of this assessment to be toxicologically equivalent to the
parent compound, even though the monoacid metabolite is expected to be
of lower overall toxicity than the parent compound.
2. Non-dietary exposure. Thiazopyr is not registered for any use
which could result in non-occupational, non-dietary exposure to the
general population.
D. Cumulative Effects
There is no reliable information to indicate that thiazopyr has a
common mechanism of toxicity with any other chemical compound.
Thiazopyr is based on a totally new class of chemistry, thus EPA should
consider only the potential risks of thiazopyr in its exposure
assessment.
E. Safety Determination
1. U.S. population. Using the conservative exposure assumptions
described above, and based on the completeness and reliability of the
toxicity data, Rohm and Haas has concluded that aggregate exposure to
thiazopyr will utilize 4.37 percent of the RfD for the U.S. population.
EPA generally has no concern for exposures below 100 percent of the RfD
because the RfD represents the level at or below which daily aggregate
dietary exposure over a lifetime will not pose appreciable risks to
human health. Therefore, Rohm and Haas concludes that there is a
reasonable certainty that no harm will result from aggregate exposure
to thiazopyr residues.
The complete toxicology profile of thiazopyr shows no evidence of
physiological effects characteristic of the disruption of the hormone
estrogen. Based on this observation thiazopyr does not meet the
criteria for an estrogenic compound.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of thiazopyr, EPA
considers data from developmental toxicity studies in the rat and
rabbit and a 2-generation reproduction study in the rat. The
developmental toxicity studies are designed to evaluate adverse effects
on the developing organism resulting from pesticide exposure during
prenatal development to one or both parents. Reproduction studies
provide information relating to effects from exposure to the pesticide
on the reproductive capability of mating animals, data on systemic
toxicity, and the survival, growth and development of the offspring.
Based on the current toxicological data requirements, the database
relative to pre- and post-natal effects for children is complete. The
NOEL at 0.8 mg/kg/day from the dog study, which was used to calculate
the RfD (discussed above), is already lower than the NOEL's from the
developmental studies in rats and rabbits by a factor of more than 100
fold. Therefore, Rohm and Haas concludes that an additional uncertainty
factor is not warranted and that the RfD at 0.008 mg/kg/day is
appropriate for assessing aggregate risk to infants and children.
F. International Tolerances
There are no Codex maximum residue levels [MRL] established for
residues of thiazopyr.
G. Other Considerations/Conclusions
Thiazopyr will be a useful addition for weed control in citrus
growing areas, particularly where annual grass pressures are high,
because it provides control against aggressive grass weeds at
significantly lower use rates than existing products. Thiazopyr has a
new unique mode of action and offers benefits in integrated pest
management programs to counter the potential for weed resistance.
Thiazopyr is extremely safe around citrus trees, including young citrus
trees.
Therefore, permanent tolerances should be established for residues
of thiazopyr in orange (whole fruit) at 0.05 ppm and grapefruit (whole
fruit) at 0.05 ppm.
II. Administrative Matters
Interested persons are invited to submit comments on this notice of
filing. Comments must bear a notation indicating the docket number,
[PF-673]. All written comments filed in response to this petition will
be available in the Public Response and Program Resources Branch, at
the Virginia address given above from 8 a.m. to 4 p.m., Monday through
Friday, except legal holidays.
A record has been established for this notice under docket number
[PF-673] 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 a.m. to
4:30 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 22202.
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 of filing 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
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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 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: November 14, 1996.
Donald R. Stubbs,
Acting Director, Registration Division, Office of Pesticide Programs.
[FR Doc. 96-29930 Filed 11-21-96; 8:45 am]
BILLING CODE 6560-50-F
