[Federal Register Volume 62, Number 43 (Wednesday, March 5, 1997)]
[Notices]
[Pages 10050-10053]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-4879]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-700; FRL-5586-1]
Rhone-Poulenc Ag Company; Pesticide Tolerance Petition Filing
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice of filing.
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SUMMARY: This notice announces the filing of a pesticide petition
proposing to establish tolerances for residues of thiodicarb and its
metabolite in or on leafy vegetables, broccoli, cabbage and
cauliflower. The notice includes a summary of the petition prepared by
the petitioner, Rhone-Poulenc Ag Company.
DATES: Comments, identified by the docket control number [PF-700], must
be received on or before, April 4, 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, Crystal
Mall #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 must be submitted either as an ASCII file avoiding the use of
special characters and any form of encryption. Comments and data will
also be acceped on disks in Wordperfect in 5.1 file format or ASCII
file format. All comments and data in electronic form must be
identified by the docket control number [PF-700]. Electronic comments
on this notice may be filed online at many Federal Depository
Libraries. Additional information on electronic submissions can be
found below this document.
Information submitted as a comment concerning this notice 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. No CBI should be submitted through e-mail. A copy of the
comment that does not contain CBI must be submitted for inclusion in
the public record.
[[Page 10051]]
Information not marked confidential may be disclosed publicly by EPA
without prior notice.
FOR FURTHER INFORMATION CONTACT: Dennis H. Edwards, Jr. Product Manager
(PM 19), Registration Division, (7505C), Office of Pesticide Programs,
Environmental Protection Agency, 401 M St., SW., Washington, DC. Office
location, telephone number and e-mail address: Rm., 207, Crystal Mall
#2, 1921 Jefferson Davis Highway, Arlington, VA.; Telephone: 703-305-
6386, e-mail: edwards.dennis@epamail.epa.gov.
SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions (PP)
6F3417 and 7F3516 from Rhone-Poulenc Ag Company, P.O. Box 12014, 2 T.W.
Alexander Drive, Research Triangle Park, NC 27709. These petitions
propose, pursuant to section 408(d) of the Federal Food, Drug and
Cosmetic Act (FFDCA), 21 U.S.C. section 346a, to amend 40 CFR part 180
by establishing tolerances for the combined residues of the insecticide
thiodicarb (Dimethyl N,N-[thiobis[[(methylimino) carbonyl]oxy]] bis
[ethanimidothioate]) and its metabolite methomyl (S-methyl N
[(methylcarbamoyl)oxy]-thioacetimadate) in or on the following raw
agricultural commodities: leafy vegetables at 35 parts per million
(ppm), broccoli at 7 ppm, cabbage at 7 ppm, and cauliflower at 7 ppm.
The proposed analytical method is HPLC.
As required by section 408(d) of the FFDCA, as recently amended by
the Food Quality Protection Act (FQPA), Rhone-Poulenc Ag Company
included in the petition a summary of the petitions and authorization
for the summary to be published in the Federal Register in a notice of
receipt of the petition. The summary represents the views of Rhone-
Poulenc Ag Company; EPA is in the process of evaluating the petition.
As required by section 408(d)(3), EPA is including the summary as a
part of this notice of filing. EPA may have made minor edits to the
summary for the purpose of clarity.
I. Petition Summary
A. Residue Chemistry
The metabolism of thiodicarb in plants and animals is adequately
understood. Adequate analytical methods are available for enforcement
purposes. There are no livestock feed items associated with this
petition; there are no problems of secondary residues in meat, milk,
poultry or eggs.
B. Toxicological Profile
1. Acute toxicity. EPA evaluation of the three acute oral toxicity
studies in rats indicated the LD50 in males and females to be >50
miligrams/kilograms (mg/kg). Based on the results of these studies,
thiodicarb is placed in Toxicity Category II. The acute dermal toxicity
study in rabbits resulted in a LD50 of >2,000 mg/kg for both males
and females. The acute inhalation LC50 was found to be >0.56 mg/l
in male and female rats. The primary eye irritation study showed iridal
involvement and moderate to severe conjunctival irritation. All
positive reactions cleared within 4 days and eyes had returned to a
normal appearance by day 7 following treatment. There was no irritation
in the primary dermal irritation study. Thiodicarb was a weak dermal
sensitizer in guinea pigs.
Conclusion. Based on the acute toxicity data cited above, Rhone-
Poulenc Ag Company concludes that thiodicarb does not pose any acute
dietary risks.
2. Mutagenicity. Mutagenicity studies completed include Salmonella
typhimurium mammalian microsome reverse mutation assay (negative),
Saccharomyces cerevisiae reverse mutation (negative), mitotic crossing
over (negative) and gene conversion (positive in strain D7 and negative
in strain D4), primary DNA damage in Escherichia coli (negative), mouse
lymphoma gene mutation assay (equivocal positive), chromosomal
aberration assay in CHO cells (negative), UDS assay with primary rat
hepatocytes (negative), in vivo micronucleus test in mouse bone marrow
(negative) and dominant lethal test in rats (negative).
Conclusion. Thiodicarb was tested in a variety of mutagenicity
assays and was negative in all but the mouse lymphoma assay, in which
there was only a weak to equivocal response and for mitotic gene
conversion in Saccharomyces cerevisiae. EPA has previously concluded
that overall there is low concern for the mutagenicity of thiodicarb.
3. Metabolism. The metabolism of thiodicarb has been studied in
several animal and plant species and studies submitted and accepted by
EPA. The metabolism in plants and animals is adequately understood for
the purposes of this tolerance.
4. Chronic effect. Based on the available chronic toxicity data,
the Health Effects Division-RfD/Peer Review Committee of the EPA
recommended in their RfD/Peer Review Report (Ghali, June 18, 1996) that
the Reference Dose (RfD) for thiodicarb remain unchanged from the
previously established value of 0.03 mg/kg/day. The recently completed
rat studies support the no observed effect level (NOEL) of 3 mg/kg/day
established in previous studies. An Uncertainty Factor (UF) of 100 was
applied to account for both the interspecies extrapolation and
intraspecies variability.
5. Carcinogenicity. The potential oncogenicity of thiodicarb has
been fully evaluated by the EPA's Health Effects Division
Carcinogenicity Peer Review Committee (CPRC) (Taylor and Rinde, June
10, 1996). The committee determined that the available database was
adequate for the determination of the carcinogenicity of thiodicarb in
animals and concluded that thiodicarb should be classified in Group B2.
While Rhone-Poulenc disagrees with the classification of thiodicarb and
the interpretation of the study results (as described below) Rhone-
Poulenc agrees with the risk characterization procedure recommended by
the CPRC and concurs that the recommended procedures are fully adequate
to protect humans from dietary exposure to thiodicarb.
The CPRC recommended that a margin of exposure methodology be
applied for the estimation of human risk because the findings observed
in the oncogenicity studies occurred only at the highest doses tested
in the studies and in the case of mice the highest dose tested may even
have been excessive. In addition, there was no evidence of
genotoxicity.
a. Rhone-Poulenc feels that the results in the most recent
oncogenicity study in rats should not be considered indicative of a
carcinogenic response in the Leydig cells of the rats for the following
reasons:
i. Compared to the control groups, both sexes at the high dose
level displayed fewer tumors and there were fewer with multiple benign
and malignant tumors.
ii. There was a statistically significant decrease in pituitary
adenomas in the high dose animals relative to controls (10 percent vs
56 percent ) indicating more high dose than control animals had normal
pituitaries at the end of the study. The incidence of pituitary
adenomas is well below the historical control range (10 percent vs a
range of 43 to 80 percent ). Pituitary activity is known to be critical
in the regulation of benign Leydig cell tumor formation through the
secretion of luteinizing hormone. Increased pituitary activity in aged
male rats would be expected to secondarily result in increased benign
Leydig cell tumor formation.
iii. There was no statistical increase in benign interstitial cell
tumors relative to the concurrent controls when all
[[Page 10052]]
animals were included in the statistical analysis.
iv. There is clear evidence that exposure to 900 ppm thiodicarb
resulted in increased survival for male rats relative to controls. The
2 year survival rate for high dose males was 1.3 times that of controls
(58 percent vs 45 percent, respectively). Benign interstitial cell
tumors are very common age related tumors. Because survival was 1.3
times higher in the high dose group than in controls, the high dose
animals should be expected to have a higher raw incidence of common age
related tumors.
v. Benign interstitial cell tumors do not transform into a more
aggressive form with time.
vi. Benign interstitial cell tumors are very common in rats and
highly uncommon in humans. There is an absence of epidemiological
evidence that Leydig cell tumors in rats are relevant for human health
risk assessment. The Food and Drug Administration (FDA), and European
regulatory authorities in general do not consider these findings to be
relevant for human health risk assessment. Numerous scientific
symposia/discussions have been held regarding the lack of relevance of
rat Leydig cell changes for human risk assessment.
b. Rhone-Poulenc feels that the results in the most recent mouse
oncogenicity study should not be considered indicative of a
carcinogenic response in the liver cells of the mice for the following
reasons:
i. The evidence shows that thiodicarb is not oncogenic in mice at
doses which do not exceed the maximum tolerated dose (MTD).
ii. There was no evidence to suggest liver oncogenicity in the
first mouse study at doses up to 10 mg/kg/day or in the second study at
doses up to 70 mg/kg/day.
iii. In the second study where there was evidence suggestive of an
oncogenic response in the liver, the MTD was significantly exceeded
based on increased mortality in females and a dramatic body weight gain
depression in the males. The body weight gains for males at 1,000 mg/
kg/day were 54 percent of the control male gains during the first year
of the study. The body weight gains for the 1,000 mg/kg/day group
females were 85 percent of controls for the same time period.
Survivability at 97 weeks was also significantly decreased in males (41
percent versus 58 percent in control males) and females (24 percent
versus 51 percent in control females).
iv. Other evidence that the MTD was exceeded included severe and
sustained liver toxicity demonstrated by increased liver weights,
hepatocyte hypertrophy, single cell necrosis and hemosiderin deposition
by 52 weeks and increased bilirubin and ALT, increased liver weight,
hepatocyte hypertrophy, bile duct hyperplasia, hepatocyte pleomorphism
and hemosiderin deposition at 97 weeks of treatment.
Conclusion. The oncogenicity studies with thiodicarb fully conform
to the currently accepted guidelines for this study type. Rhone-Poulenc
Ag Company believes that the results of the studies provide only
minimal evidence that the compound is oncogenic in rodents. After
analysis of the data, EPA scientists recently determined that a margin
of exposure of 100 applied to the lowest NOEL from the chronic studies
with thiodicarb would provide adequate safety for any risks to humans.
Rhone-Poulenc agrees with this risk assessment approach and is
confident that it will provide adequate safety for all human population
subgroups including infants and children.
6. Teratology. Several teratology studies exist on thiodicarb in
rats, rabbits, and mice. These are reviewed below:
a. A teratology study in rats was conducted at doses of 0, 0.5,
1.0, 3, and 100 mg/kg/day. No signs of teratogenicity were observed.
b. A teratology study was conducted in rats at doses of 0, 1, 10
and 30 mg/kg/day. No signs of teratogenicity were observed.
Data from both studies can be (and were by EPA) used to derive
maternal and developmental NOELs and lowest observed effect levels
(LOELs). Based on data from both studies, the maternal NOEL and LOEL
were determined to be 10 and 20 mg/kg/day, respectively. The
developmental NOEL and LOEL were determined to be 3 and 10 mg/kg/day,
respectively, based on delayed ossification of sternebrae.
c. A teratology study in rabbits was conducted at doses of 0, 5, 20
and 40 mg/kg/day. No signs of teratogenicity were observed. The NOEL
and LOEL for maternal toxicity were determined to be 20 and 40 mg/kg/
day, respectively. The developmental NOEL was determined to be 40 mg/
kg/day. As this was the highest level tested, no LOEL for developmental
toxicity was determined.
d. A teratology study in mice was conducted at doses of 0, 50, 100
and 200 mg/kg/day. No signs of teratogenicity were observed. The
maternal NOEL and LOEL were determined to be 100 and 200 mg/kg/day,
respectively. As no fetal effects were observed at all, the
developmental NOEL can be considered to be 200 mg/kg/day.
Conclusion. Based on all the studies above, Rhone-Poulenc Ag
Company does not believe that thiodicarb is a teratogen, or that it
presents any unreasonable risk to children.
7. Reproductive effects. Two reproduction studies were recently
conducted with thiodicarb; one dose-rangefinding study and one
definitive study.
a. In the dose-rangefinding study, rats were administered
thiodicarb in their diets at concentrations of 0, 200, 600, 1,800, and
3,000 ppm. Maternal toxicity, as evidenced by decreased pup viability
at birth and day 4, was seen at the three highest doses. Also at the
three highest doses, decreased pup growth occurred. Therefore, the NOEL
for both maternal and fetal effects was determined to be 200 ppm.
b. In the definitive study, thiodicarb was administered in the
diets of rats at concentrations of 0, 100, 300, and 900 ppm. Fetal body
weight gain at 100 ppm was significantly decreased when compared with
concurrent controls resulting in the conclusion that, strictly
speaking, no NOEL was reached for fetal effects in this study. An
independent expert consulting firm was contracted with to statistically
derive from these data a conservative NOEL for all effects. These
experts concluded that a conservative NOEL for all effects would be 80
ppm, equivalent to an average daily dose of 5.20 mg/kg/day. EPA
subsequently utilized a Benchmark Dose approach to estimate the NOEL
for this study, and ultimately concluded that, based on all the data
and all the different analyses of the data, 100 ppm is at or near the
NOEL for reproductive/developmental toxicity. It is significant, too,
that this NOEL is higher than the NOEL from the chronic toxicity/
oncogenicity study in rats, where the NOEL is used to determine the
Reference Dose for thiodicarb.
Conclusion. Based on the studies cited above, Rhone-Poulenc Ag
Company believes that thiodicarb does not pose an unreasonable risk of
reproductive effects to parents or their offspring. Further, as none of
the effects observed in the cited studies are classically related to
any specific endocrine mechanism, Rhone-Poulenc Ag Company believes
that thiodicarb is not an endocrine disrupter.
C. Aggregate Exposure/Cumulative Effects
The Dietary Analysis for the Proposed Use of thiodicarb on leafy
vegetables has been run by EPA and summarized in a document dated June
17, 1991 (Schaible, S.A.). Using the Theoretical
[[Page 10053]]
Maximum Residue Contributions (TMRC) calculated from the tolerances and
estimated consumption data for various populations (very conservative
estimates) a value of 0.019213 is obtained for the TMRC which
represents 64.0 percent of the established reference dose was reached
for the overall U.S. population. The Dietary Analysis for the Proposed
Use of thiodicarb on broccoli, cabbage and cauliflower has been run by
EPA and summarized in a document dated July 9, 1990 (Briggs, R.). Using
the TMRC calculated from the tolerances and estimated consumption data
for various populations (very conservative estimates). A value of
0.015225 is obtained for the TMRC which represents 50.8 percent of the
established reference dose utilized for the overall U.S. population.
None of the population subgroups exceeded the 100 percent level of the
reference dose. This value includes all pending and published
tolerances, including apples, tomatoes and peppers for which Rhone-
Poulenc Ag Company does not currently have a registration. This is a
large overestimation of the actual dietary exposure to thiodicarb
because it assumes 100 percent of crops treated and maximum residue
levels present.
The FQPA of 1996 lists three other potential sources of exposure to
the general population that must be addressed, these are pesticides in
drinking water, exposure from non-occupational sources, and the
potential cumulative effect of pesticides with similar toxicological
modes of action. Based on the available studies of thiodicarb in the
environment which show a short half-life in soil (1.5 days), Rhone-
Poulenc Ag Company does not anticipate residues of thiodicarb in
drinking water. There is no established Maximum Concentration Level or
Health Advisory Level for thiodicarb under the Safe Drinking Water Act.
The potential for non-occupational exposure to the general public
is also insignificant. There are no residential lawn or garden uses for
thiodicarb products where the general population may be exposed via
inhalation or dermal routes.
Rhone-Poulenc concludes that consideration of a common mechanism of
toxicity is not appropriate at this time since there is no reliable
data to indicate that the toxic effects caused by thiodicarb would be
cumulative with those of any other compound. Based on this point,
Rhone-Poulenc has considered only the potential risks of thiodicarb in
it's exposure assessment.
D. Safety Determinations
1. U.S. population in general. Using the very conservative exposure
estimates described above, the conclusion reached is that aggregate
exposure to thiodicarb will utilize no more than 64 percent of the
established reference dose. Rhone-Poulenc Ag Company has conducted a
preliminary Dietary Risk Exposure Study (DRES) with TAS, Inc. which
utilizes actual data (where available) for percent crops treated and
residue data from FDA and Cal-EPA monitoring programs (no detectable
residues of thiodicarb were observed in these databases, so as a
conservative estimate, all methomyl residues were assumed to result
from thiodicarb use). Only registered and conditionally registered uses
(including leafy vegetables, broccoli, cabbage and cauliflower) were
included in the analysis. The study concluded that chronic exposure
estimates are well below the endpoints of concern. Chronic exposure
estimates are 0.1 percent of the RfD or less for all population groups.
Based on this study and the above points, Rhone-Poulenc Ag Company
believes there is a reasonable certainty that no harm will result from
aggregate exposure to thiodicarb.
2. Infants and children. Referring to the conclusions and summary
in the Developmental and Reproductive Toxicity section stated above,
Rhone-Poulenc Ag Company believes there is no additional sensitivity
for infants and children and that an additional safety factor for
infants and children is not warranted. The RfD of 0.03 mg/kg/day is
appropriate for assessing aggregate risk to this subpopulation. For the
infant and children (1 to 6 years of age) populations only 0.1 percent
of the reference dose was used in the DRES study discussed above.
Based on the completeness and reliability of the toxicology data
and the dietary analysis Rhone-Poulenc Ag Company concludes that there
is a reasonable certainty that no harm will result to infants and
children from aggregate exposure to thiodicarb residues.
E. International Tolerances
There are no Codex maximum residue levels established for
thiodicarb on leafy vegetables, broccoli, cabbage or cauliflower.
II. Public Record
EPA invites interested persons to submit comments on this notice of
filing. Comments must bear a notification indicating the docket control
number [PF-700].
A record has been established for this notice under docket control
number [PF-700] (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 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
notice record which will also include all comments submitted directly
in writing. The official notice 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, Pesticide and pest, Reporting and
recordkeeping requirements.
Dated: February 10, 1997.
Stephen L. Johnson,
Director, Registration Division, Office of Pesticide Programs.
[FR Doc. 97-4879 Filed 3-4-97; 8:45 am]
BILLING CODE 6560-50-F
