FLUORIDE ACTION NETWORK PESTICIDE PROJECT
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Flutolanil (AgrEvo). June 23, 1998. Pesticide Tolerance Petition. Federal Register.
http://www.epa.gov/fedrgstr/EPA-PEST/1998/June/Day-23/p16673.htm
[Federal Register: June 23, 1998 (Volume 63, Number 120)]
[Notices]
[Page 34176-34184]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr23jn98-52]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-813; FRL-5795-1]
Notice of Filing of Pesticide Petitions
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
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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-813, must
be received on or before July 23, 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 by following
the instructions under ``SUPPLEMENTARY INFORMATION.'' No confidential
business information should be submitted through e-mail.
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: The product manager listed in the
table below:
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Office location/
Product Manager telephone number Address
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Mary Waller................... Rm. 247, CM #2, 703- 1921 Jefferson
308-9354, e- Davis Hwy,
mail:waller.mary@epam Arlington, VA
ail.epa.gov.
James Tompkins................ Rm. 239, CM #2, 703-
305-5687, e-mail:
tompkins.james@epamai
l.epa.gov.
Stephanie Willett............. Rm. 202, CM #2, 703- Do.
305-5419, e-
mail:willett.stephani
e@epamail.epa.gov.
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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
petition.
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-813] (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:
opp-docket@epamail.epa.gov
Electronic comments must be submitted as an ASCII file avoiding the
[[Page 34177]]
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
requirements.
Dated: June 12, 1998.
James Jones,
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. AgrEvo USA Company
PP 4F4380
EPA has received a pesticide petition (PP [4F4380]) from AgrEvo USA
Company, 2711 Centerville Road, Wilmington, DE 19808 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 flutolanil in or on the raw agricultural commodity of
rice grain at 2.0 parts per million (ppm), rice straw at 12.0 ppm and
in or on the processed commodities of rice hulls at 7.00 ppm and rice
bran at 3.0 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 supports granting of
the petition. Additional data may be needed before EPA rules on the
petition.
A. Residue Chemistry
1. Plant and animal metabolism. The metabolism of flutolanil in
plants and animals is adequately understood for the purposes of this
petition. Animal studies in rats, ruminants, and poultry indicate that
flutolanil is metabolized primarily to desisopropylflutolanil and its
conjugates. Plant metabolism studies have been conducted in rice,
cucumber, and peanuts. The metabolic profile for flutolanil was similar
in all three crops. The major route of degradation was 4'-0-
dealkylation to desisopropylflutolanil, followed by conjugation. Other
metabolites may occur at very low levels due to hydroxylation and
oxidation of the side chain, hydroxylation of the aniline ring, and
methylation of the hydroxyl groups. These minor metabolites were also
subject to conjugation. The residues of concern are the parent
flutolanil and desisopropylflutolanil.
2. Analytical method. The analytical method designated as AU-95R-04
has been independently validated and is adequate for enforcement
purposes. A multi-residue method for flutolanil has been previously
submitted. It has the following disclaimer: The method is for use only
by experienced chemists who have demonstrated knowledge of the
principles of trace organic analysis and have proven skills and
abilities to run a complex residue analytical method obtaining accurate
results at the part per million level (PPML). Users of this method are
expected to perform additional method validation prior to using the
method for either monitoring or enforcement. The method can detect
gross misuse.
3. Magnitude of residues. 24 field trials consisting of foliar
applications to rice were conducted in California, Louisiana, Texas,
Arkansas, Arizona, Missouri, and Mississippi. Applications of
flutolanil formulated as 50WP or 70WP were made at a total seasonal
rate of 1.0 lb active ingredient (a.i) per acre resulted in flutolanil-
derived residues ranging from below the limit of detection (<0.05 ppm)
to 1.66 ppm in whole rice grain and hulled rice and from 0.95 ppm to
11.28 ppm in rice straw.
A processing study was also conducted in Louisiana in which the
50WP formulation of flutolanil was applied to rice following label
directions at a total rate of 1.0 lb active ingredient per acre.
Residues of flutolanil were observed in all processed commodities and
ranged from <0.05 ppm in polished rice to 1.37 ppm in grain dust below
420 microns.
B. Toxicological Profile
1. Acute toxicity. A battery of acute studies was conducted: the
acute oral LD<INF>50</INF> in rat and mice were >10,000 milligram/
kilograms (mg/kg), Toxicity category IV; acute dermal LD<INF>50</INF>
in rat was >2,000 mg/kg, Toxicity category III; and acute inhalation
LC<INF>50</INF> in rat was >5.98 milligram/liter (mg/l), Toxicity
category III. There was slight eye irritation; no dermal irritation;
and no dermal sensitization.
2. Genotoxicty. Flutolanil has been tested in a battery of in-vitro
and in-vivo assays. No evidence of genotoxicity was noted in gene
mutation assays with Salmonella, E. coli, or mouse lymphoma cells; a
mouse micronucleus assay or in an in-vitro unscheduled DNA synthesis
assay. A weak positive response was noted in an in-vitro cytogenetics
assay in Chinese hamster lung cells but no evidence of clastogenicity
was noted in an in-vitro cytogenetics assay in human lymphocytes. The
overall weight of evidence indicates that flutolanil is not genotoxic.
3. Reproductive and developmental toxicity. A 3-generation rat
reproduction study was conducted at dietary concentrations of 0, 1,000
and 10,000 ppm. The NOEL for this study is considered to be 1,000 ppm
(63 milligram/kilograms/day (mg/kg/day), based on reduced pup weights
late in lactation at 10,000 ppm. Because the Agency considered this
study supplementary, a 2-generation rat reproduction study subsequently
was conducted at dietary concentrations of 200, 2,000, and 20,000 ppm.
No adverse findings were noted at any dose level and the NOEL was
considered to be 20,000 ppm 1,936 mg/kg/day. The Agency, however, has
concluded that the NOEL of the original study 63 mg/kg/day should
continue to be used for risk assessment.
Developmental toxicity (teratology) studies were conducted in both
rats and rabbits at dose levels of 0, 40, 200, and 1,000 mg/kg/day. No
significant maternal or developmental toxicity was noted in either
study. Thus, both the maternal and developmental NOEL's for both rats
and rabbits were considered to be 1,000 mg/kg/day highest dose tested
(HDT).
4. Subchronic toxicity. A 90-day rat feeding study was conducted at
dose levels of 500, 4,000 and 20,000 ppm. The NOEL in this study was
considered to be 500 ppm (37 mg/kg/day for males and 44 mg/kg/day for
females) based on increased liver weights at 4,000 ppm and slightly
decreased body weights at 20,000 ppm.
[[Page 34178]]
In a 90-day oral toxicity study in dogs, flutolanil was
administered via capsule at dose levels of 0, 80, 400 and 2,000 mg/kg/
day. The NOEL was determined to be 80 mg/kg/day based on enlarged
livers and increased glycogen deposition at 400 and 2,000 mg/kg/day,
and increased alkaline phosphatase and cholesterol levels and thyroid/
parathyroid organ weights at 2,000 mg/kg/day.
In a 21-day dermal toxicity study, flutolanil was applied dermally
to rats for 15-days over a 21-day interval at dose levels of 0 and
1,000 mg/kg/day. No evidence of dermal irritation or systemic toxicity
was observed. Thus, the NOEL was considered to be 1,000 mg/kg/day.
5. Chronic toxicity. In a 2-year chronic toxicity/oncogenicity
study, flutolanil was administered to rats at dietary levels of 0, 40,
200, 2,000 and 10,000 ppm. The NOEL was considered to be 2,000 ppm
(86.9 mg/kg/day for males and 103.1 mg/kg/day for females) based on
reduced body weight gain in males and increased liver weights in
females at 10,000 ppm. No evidence of carcinogenicity was observed.
In a 78-week carcinogenicity study, flutolanil was administered to
mice at dietary concentrations of 0, 300, 1,500, 7,000 and 30,000 ppm.
The NOEL was considered to be 7,000 ppm (735 mg/kg/day for males) and
1,500 ppm (162 mg/kg/day for females) based on decreased body weight
gains at the higher level(s). No evidence of carcinogenicity was
observed.
A 2-year chronic toxicity study was conducted in beagle dogs at
dose levels of 0, 50, 250, and 1,250 mg/kg/day. The NOEL was considered
to be 250 mg/kg/day based on decreased weight gain at 1,250 mg/kg/day.
6. Animal metabolism. Studies in rats, ruminants, and poultry
suggest that flutolanil is not well-absorbed following oral
administration. Once absorbed, however, it is rapidly metabolized,
primarily to desisopropylflutolanil and its conjugates, and rapidly
excreted via urine and feces.
7. Endocrine disruption. No special studies have been conducted to
investigate the potential of flutolanil to induce estrogenic or other
endocrine effects. However, no evidence of such effects has been
observed in the subchronic, chronic, or reproductive studies previously
discussed. Thus, the potential for flutolanil to cause endocrine
effects is considered to be minimal.
C. Aggregate Exposure
1. Dietary exposure. Includes food and drinking water--i. Food.
Time-limited tolerances have been previously established for flutolanil
in or on rice commodities, and tolerances with no time limitations are
established for peanut commodities, meat, milk, and eggs. Potential
dietary exposures to flutolanil from these food commodities were
assessed using the exposure one software system (TAS, Inc.) and food
consumption data from the 1977-1978 USDA Continuing Surveys of Food
Consumption by Individuals (CSFCI). For the purposes of this
assessment, it was assumed that 100% of all of the above commodities
were at the existing tolerance levels for flutolanil.
ii. Drinking water. The potential for flutolanil to leach into
groundwater has been assessed in two terrestrial field dissipation
studies, a long-term terrestrial field dissipation study, and an
aquatic field dissipation study. Under field conditions, the half-life
of flutolanil varied from 101 to 123 days in the long-term field soil
dissipation study, which was consistent with the other field studies,
and was approximately 180 days in the aquatic environment. Flutolanil
strongly adsorbs to soil following application and did not exhibit
mobility under either terrestrial or aquatic conditions. The water
solubility of flutolanil is quite low ( 5.0 ppm). Based on these
environmental fate data and the conditions of use, the potential for
movement of flutolanil into groundwater is very low, and as such the
potential contribution of any such residues to the total dietary intake
of flutolanil will be negligible. No maximum contaminant level (MCL) or
Health Advisory Level for residues of flutolanil in drinking water has
been established.
2. Non-dietary exposure. As prostar 50WP (EPA Reg No. 45639-153) is
a professional turf and ornamental fungicide, flutolanil is used
primarily (>95%) on golf courses for control of brown patch disease
(Rhizoctonia solani). Very limited use of prostar 50WP may occur on
commercial ornamental turf by professional lawn care applicators or on
sod farms. The product is rarely, if ever, used on homeowner turf due
to the fact that the diseases it controls (Brown patch, Fry ring, snow
molds) occur in high-fertility, high-maintenance turf (e.g. golf
courses), not in homeowner lawns. Thus, non-dietary exposure to
flutolanil would be minimal. Furthermore, no dermal toxicity endpoints
of concern have been identified for flutolanil. Thus, an assessment of
non-dietary exposure and risk is not considered to be necessary.
D. Cumulative Effects
Flutolanil has demonstrated only minimal toxicity in animal
studies. The mechanism of this toxicity is unknown. Furthermore, there
are no available data to indicate that flutolanil has a common
mechanism of toxicity with other substances. Thus, only the potential
risks from flutolanil are being considered in this document.
E. Safety Determination
1. U.S. population. Based on the existing and proposed tolerances
in rice, peanuts, and secondary commodities, the Theoretical Maximum
Residue Contribution (TMRC) of the current action is estimated to be
0.001124 mg/kg/day for the U.S. population in general. This exposure
would utilize less than 1% of the RfD. There is generally no concern
for exposures below 100% of the RfD since the RfD represents the
exposure level at or below which daily exposure over a lifetime will
not pose any appreciable risks to human health. Therefore, there is a
reasonable certainty that no harm will result to the U.S. population in
general from aggregate exposure to flutolanil.
2 Infants and children. Data from reproductive and developmental
toxicity studies are generally used to assess the potential for
increased sensitivity of infants and children. No evidence of
developmental toxicity was noted in rats or rabbits, even at the limit
dose of 1,000 mg/kg/day. Reduced pup weights in the absence of parental
toxicity were noted at the HDL (10,000 ppm) in a 3-generation rat
reproduction study. However, no such effects were noted in a subsequent
reproduction study, even at a HDT (20,000 ppm). Furthermore, the
reduced weight gain in the first study began late in the lactation
period, at a time when the pups were likely ingesting significant
quantities of diet. Feed intake is much higher in young animals than in
adults and the apparent increase in sensitivity may simply reflect the
higher test material intake in these pups on a mg/kg basis compared to
the adults. Thus, AgrEvo believes that the overall weight of evidence
does not indicate any special concern for infants and children, and
that no additional safety factor is necessary.
Based on the existing and proposed tolerances in rice, peanuts, and
secondary commodities, the Theoretical Maximum Residue Contribution
(TMRC) from the current petition is estimated to be 0.006218 mg/kg/day
for the most highly exposed sub-population, non-nursing infants (less
[[Page 34179]]
than 1-year old).. This exposure would utilize less than 1 % of the
RfD. Therefore, there is a reasonable certainty that no harm will
result to infants or children from aggregate exposure to flutolanil.
F. International Tolerances
No CODEX tolerances have been established or proposed for residues
of flutolanil. (Mary Waller).
2. Bayer Corporation
PP 6F4631
EPA has received a pesticide petition (PP 6F4631) from Bayer
Corporation, 8400 Hawthorn Road, P.O. Box 4913, Kansas City, MO 64120-
0013 proposing pursuant to section 408(d) of the Federal Food, Drug,
and Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 CFR 180.527 by
establishing tolerances for inadvertent residues of N-(4-fluorophenyl)-
N-(1-methylethyl)-2- [[5-(trifluoromethyl)-1,3,4-thiadiazol-2-
yl]oxy]acetamide [hereafter referred to as flufenacet, the proposed
common chemical name] and metabolites containing the 4-fluoro-N-
methylethyl benzenamine moiety in or on the raw agricultural
commodities of Crop Group 15 (cereal grains), Crop Group 16 (forage,
stover and hay of cereal grains), Crop Group 17 (grass forage, and
grass hay), alfalfa forage, alfalfa hay, alfalfa seed, clover forage,
and clover hay at 0.1 parts per million (ppm) when present therein as a
result of the application of flufenacet to field corn and soybeans as a
herbicide. 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 supports granting of
the petition. Additional data may be needed before EPA rules on the
petition.
A. Residue Chemistry
1. Plant metabolism. The nature of the residue in field corn,
soybeans, livestock and rotational crops is adequately understood. The
residues of concern for the tolerance expression are N-(4-
fluorophenyl)-N-(1-methylethyl)-2-[[5-(trifluoromethyl)-1,3,4-
thiadiazol-2-yl]oxy]acetamide parent and its metabolites containing the
4-fluoro-N-methylethyl benzenamine moiety. Based on the results of
animal metabolism studies it is unlikely that secondary residues would
occur in animal commodities from the use of flufenacet on field corn
and soybeans.
2. Analytical method. An adequate analytical method, gas
chromatography/mass spectrometry with selected ion monitoring, is
available for enforcement purposes. Because of the long lead time from
establishing these tolerances to publication of the enforcement
methodology in the Pesticide Analytical Manual, Vol. II, the analytical
methodology is being made available in the interim to anyone interested
in pesticide enforcement when requested from: Calvin Furlow, Public
Information and Records Integrity Branch, Information Resources and
Services Division (7502C), Office of Pesticide Programs, Environmental
Protection Agency, 401 M St., SW., Washington, DC 20460. Office
location and telephone number: Room 119E, CM #2, 1921 Jefferson Davis
Highway, Arlington, VA 22202, (703-305-5937).
3. Magnitude of residues. Time limited tolerances exist for the
combined residues of flufenacet, N-(4-fluorophenyl)-N-(1-methylethyl)-
2-[[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]oxy]acetamide and its
metabolites containing the 4-fluoro-N-methylethyl benzenamine moiety in
or on field corn grain at 0.05 ppm, field corn forage at 0.4 ppm, field
corn stover at 0.4 ppm, and soybean seed at 0.1 ppm. The petitioner,
Bayer Corporation has amended its petition (PP 6F4631) to include
tolerances for residues of N-(4-fluorophenyl)-N-(1-methylethyl)-2-[[5-
(trifluoromethyl)-1,3,4-thiadiazol-2-yl]oxy]acetamide and its
metabolites containing the 4-fluoro-N-methylethyl benzenamine moiety at
0.1 ppm for residues in or on the raw agricultural commodities of Crop
Group 15 (cereal grains), Crop Group 16 (forage, stover and hay of
cereal grains), Crop Group 17 (grass forage and grass hay), alfalfa
forage, alfalfa hay, alfalfa seed, clover forage, and clover hay. The
proposed tolerance levels are adequate to cover residues likely to be
present in rotational crops planted after corn or soybeans which were
treated with flufenacet.
B. Toxicological Profile
1. Acute toxicity. A rat acute oral study with a LD<INF>50</INF> of
1,617 milligrams/kilograms for males and 589 mg/kg for females.
2. Genotoxicty. Flufenacet was negative for mutagenic/genotoxic
effects in a Gene mutation/In vitro assay in bacteria, a Gene mutation/
In vitro assay in chinese hamster lung fibroblasts cells, a
Cytogenetics/In vitro assay in chinese hamster ovary cells, a
Cytogenetics/In vivo mouse micronucleus assay, and an In vitro
unscheduled DNA synthesis assay in primary rat hepatocytes.
3. Reproductive and developmental toxicity. A two-generation rat
reproduction study with a parental systemic no observed effect level
(NOEL) of 20 ppm [1.4 mg/kg/day in males and 1.5 mg/kg/day in females]
and a reproductive NOEL of 20 ppm [1.3 mg/kg/day] and a parental
systemic lowest observed effect level (LOEL) of 100 ppm [7.4 mg/kg/day
in males and 8.2 mg/kg/day in females] based on increased liver weight
in F1 females and hepatocytomegaly in F1 males and a reproductive LOEL
of 100 ppm [6.9 mg/kg/day] based on increased pup death in early
lactation (including cannibalism) for F1 litters and the same effects
in both F1 and F2 pups at the high dose level of 500 ppm [37.2 mg/kg/
day in F1 males and 41.5 mg/kg/day in F1 females, respectively]. A rat
developmental study with a maternal NOEL of 25 mg/kg/day and with a
maternal LOEL of 125 mg/kg/day based on decreased body weight gain
initially and a developmental NOEL of 25 mg/kg/day and a developmental
LOEL of 125 mg/kg/day based on decreased fetal body weight, delayed
development [mainly delays in ossification in the skull, vertebrae,
sternebrae, and appendages], and an increase in the incidence of extra
ribs. A rabbit developmental study with a maternal NOEL of 5 mg/kg/day
and a maternal LOEL of 25 mg/kg/day based on histopathological finds in
the liver and a developmental NOEL of 25 mg/kg/day and a developmental
LOEL of 125 mg/kg/day based on increased skeletal variations.
4. Subchronic toxicity. A 84-day rat feeding study with a No
Observed Effect Level ( NOEL) less than 100 ppm [6.0 mg/kg/day] for
males and a NOEL of 100 ppm [7.2 mg/kg/day] for females and with a
Lowest Observed Effect Level (LOEL) of 100 ppm [6.8 mg/kg/day] for
males based on suppression of thyroxine (T4) level and a LOEL of 400
ppm [28.8 mg/kg/day] for females based on hematology and clinical
chemistry findings. A 13-week mouse feeding study with a NOEL of 100
ppm [18.2 mg/kg/day for males and 24.5 mg/kg/day for females] and a
LOEL of 400 ppm [64.2 mg/kg/day for males and 91.3 mg/kg/day for
females] based on histopathology of the liver, spleen and thyroid. A
13-week dog dietary study with a NOEL of 50 ppm [1.70 mg/kg/day for
males and 1.67 mg/kg/day for females] and a LOEL of 200 ppm [6.90 mg/
kg/day for males and 7.20 mg/kg/day for females] based on evidence that
the bio-transformation capacity of the liver has been exceeded, (as
indicated by increase in LDH, liver weight, ALK and hepatomegaly),
globulin and spleen pigment in females, decreased T4 and
[[Page 34180]]
ALT values in both sexes, decreased albumin in males, and decreased
serum glucose in females. A 21-day rabbit dermal study with the dermal
irritation NOEL of 1,000 mg/kg/day for males and females and a systemic
NOEL of 20 mg/kg/day for males and 150 mg/kg/day for females and a
systemic LOEL of 150 mg/kg/day for males and 1,000 mg/kg/day for
females based on clinical chemistry data (decreased T4 and FT4 levels
in both sexes) and centrilobular hepatocytomegaly in females.
5. Chronic toxicity. A 1-year dog chronic feeding study with a NOEL
was 40 ppm [1.29 mg/kg/day in males and 1.14 mg/kg/day in females] and
a LOEL of 800 ppm [27.75 mg/kg/day in males and 26.82 mg/kg/day in
females] based on increased alkaline phosphatase, kidney, and liver
weight in both sexes, increased cholesterol in males, decreased T2, T4
and ALT values in both sexes, and increased incidences of microscopic
lesions in the brain, eye, kidney, spinal cord, sciatic nerve and
liver. A rat chronic feeding/carcinogenicity study with a NOEL less
than 25 ppm [1.2 mg/kg/day in males and 1.5 mg/kg/day in females] and a
LOEL of 25 ppm [1.2 mg/kg/day in males and 1.5 mg/kg/day in females]
based on methemoglobinemia and multi-organ effects in blood, kidney,
spleen, heart, and uterus. Under experimental conditions the treatment
did not alter the spontaneous tumor profile. In a mouse carcinogenicity
study the NOEL was less than 50 ppm [7.4 mg/kg/day] for males and the
NOEL was 50 ppm [9.4 mg/kg/day] for females and the LOEL was 50 ppm
[7.4 mg/kg/day] for males and the LOEL was 200 ppm [38.4 mg/kg/day] for
females based on cataract incidence and severity. There was no evidence
of carcinogenicity for flufenacet in this study.
6. Animal metabolism. A rat metabolism study showed that radio-
labeled flufenacet was rapidly absorbed and metabolized by both sexes.
Urine was the major route of excretion at all dose levels and smaller
amounts were excreted via the feces. A 55-day dog study with
subcutaneous administration of Thiadone [flufenacet metabolite]
supports the hypothesis that limitationsin glutathione interdependent
pathways and antioxidant stress result in metabolic lesions in the
brain and heart following flufenacet exposure.
7. Endocrine disruption. EPA is required to develop a screening
program to determine whether certain substances (including all
pesticides and inerts) may have an effect in humans that is similar to
an effect produced by a naturally occurring estrogen, or such other
effect. The Agency is currently working with interested stakeholders,
including other government agencies, public interest groups, industry
and research scientists in developing a screening and testing program
and a priority setting scheme to implement this program. Congress has
allowed 3 years from the passage of FQPA (August 3, 1999) to implement
this program. At that time, EPA may require further testing of this
active ingredient and end use products for endocrine disrupter effects.
Based on the toxicological findings for flufenacet relating to
endocrine disruption effects, flufenacet should be considered as a
candidate for evaluation as an endocrine disrupter when the criteria
are established.
C. Aggregate Exposure
In examining aggregate exposure, FFDCA section 408 requires that
EPA take into account available and reliable information concerning
exposure from the pesticide residue in the food in question, residues
in other foods for which there are tolerances, residues in groundwater
or surface water that is consumed as drinking water, and other non-
occupational exposures through pesticide use in gardens, lawns, or
buildings (residential and other indoor uses).
1. Dietary exposure--i. Food. Dietary exposure to residues of a
pesticide in a food commodity are estimated by multiplying the average
daily consumption of the food forms of that commodity by the tolerance
level or the anticipated pesticide residue level. The Theoretical
Maximum Residue Contribution (TMRC) is an estimate of the level of
residues consumed daily if each food item contained pesticide residues
equal to the tolerance. In evaluating food exposures, varying
consumption patterns of major identifiable subgroups of consumers,
including infants and children is taken into account. The TMRC is a
``worst case'' estimate since it is based on the assumptions that food
contains pesticide residues at the tolerance level and that 100% of the
crop is treated by pesticides that have established tolerances. Using
tolerance levels and percent crop treated, the residues in the diet
(food only) are calculated to be 0.0001 milligrams/kilogram of body
weight per day (mg/kg bwt/day) or 2.6% of the RfD for the general U.S.
population and 0.00023 mg/kg bwt/day or 5.8% of the RfD for children
aged 1-6 years.
ii. Drinking water. Residues of flufenacet in drinking water may
comprise up to 0.0039 mg/kg bwt/day (0.0040-0.0001 mg/kg bwt/day) for
the U.S. population and 0.0038 mg/kg bwt/day (0.00400-0.00023 mg/kg
bwt/day) for children 1-6 years old (the group exposed to the highest
level of flufenacet residues in both food and water). The drinking
water levels of concern (DWLOCs) for chronic exposure to flufenacet in
drinking water calculated for the U.S. population was 136 parts per
billion (ppb) assuming that an adult weighs 70 kg and consumes a
maximum of 2 liters of water per day. For children (1-6 years old), the
DWLOC was 37.7 ppb assuming that a child weighs 10 kg and consumes a
maximum of 1 liter of water per day. The drinking water estimated
concentration (DWECs) for groundwater (parent flufenacet and degradate
thiadone) calculated from the monitoring data is 0.03 ppb for chronic
concentrations which does not exceed DWLOC of 37.7 ppb for children (1-
6 years old). The DWEC for surface water based on the computer models
PRZM 2.3 and EXAMS 2.97.5 was calculated to be 14.2 ppb for chronic
concentration (parent flufenacet and degradate thiadone) which does not
exceed the DWLOC of 37.7 ppb for children (1-6 years old).
2. Non-dietary exposure. There are no non-food uses of flufenacet
currently registered under the Federal Insecticide, Fungicide and
Rodenticide Act, as amended. No non-dietary exposures are expected for
the general population.
D. Cumulative Effects
Flufenacet is structurally a thiadiazole. EPA is not aware of any
other pesticides with this structure. For flufenacet, EPA has not yet
conducted a detailed review of common mechanisms to determine whether
it is appropriate, or how to include this chemical in a cumulative risk
assessment. After EPA develops a methodology to address common
mechanism of toxicity issues to risk assessments, the Agency will
develop a process (either as part of the periodic review of pesticides
or otherwise) to reexamine these tolerance decisions. Unlike other
pesticides for which EPA has followed a cumulative risk approach based
on a common mechanism of toxicity, flufenacet does not appear to
produce a toxic metabolite produced by other substances. For the
purposes of these tolerance actions; therefore, EPA has not assumed
that flufenacet has a common mechanism of toxicity with other
substances.
E. Safety Determination
1. U.S. population--i. Acute risk. The acute endpoint for
flufenacet and its metabolites is 75 mg/kg/day. The acute
[[Page 34181]]
exposure for flufenacet and its metabolites is 0.0015 mg/kg/day for
the general U.S. population and 0.002 mg/kg/day for children 1-6 years
of age. The DWLOC for acute exposure to flufenacet in drinking water
calculated for the U.S. population was 2.87 ppm and for children (1-6
years old) was 813 ppb. These figures were calculated as follows.
First, the acceptable acute exposure to flufenacet in drinking water
was obtained by subtracting the acute dietary food exposures from the
ratio of the acute LOEL to the acceptable margin of exposure (MOE) for
aggregate exposure. Then, the DWLOCs were calculated by multiplying the
acceptable exposure to flufenacet in drinking water by estimated body
weight (70 kg for adults, 10 kg for children) and then dividing by the
estimated daily drinking water consumption (2 L/day for adults, 1 L/day
for children). The Agency's SCI-Grow model estimates peak levels of
flufenacet and its metabolite thiadone in groundwater to be 15.3 ppb.
PRZM/EXAMS estimates peak levels of flufenacet and its metabolite
thiadone in surface water to be 17 ppb. EPA's acute drinking water
level of concern is well above the estimated exposures for flufenacet
in water for the U.S. population and subgroup with highest estimated
exposure.
ii. Chronic risk. The chronic endpoint for flufenacet is 0.004 mg/
kg bwt/day. Using tolerance levels and percent crop treated, the
residues in the diet (food only) are calculated to be 0.0001 mg/kg bwt/
day or 2.6% of the Reference dose (RfD) for the general U.S. population
and 0.00023 mg/kg bwt/day or 5.8% of the RfD for children aged 1-6
years. Therefore, residues of flufenacet in drinking water may comprise
up to 0.0039 mg/kg bwt/day (0.0040-0.0001 mg/kg bwt/day) for the U.S.
population and 0.0038 mg/kg bwt/day (0.00400-0.00023 mg/kg bwt/day) for
children 1-6 years old (the group exposed to the highest level of
flufenacet residues in both food and water). The DWLOCs for chronic
exposure to flufenacet in drinking water calculated for the U.S.
population was 136 ppb assuming that an adult weighs 70 kg and consumes
a maximum of 2 liters of water per day. For children (1-6 years old),
the DWLOC was 37.7 ppb assuming that a child weighs 10 kg and consumes
a maximum of 1 liter of water per day. The drinking water estimated
concentration (DWECs) for groundwater (parent flufenacet and degradate
thiadone) calculated from the monitoring data is 0.03 ppb for chronic
concentrations which does not exceed the DWLOC of 37.7 ppb for children
(1-6 years old). The DWEC for surface water based on the computer
models PRZM 2.3 and EXAMS 2.97.5 was calculated to be 14.2 ppb for
chronic concentration (parent flufenacet and degradate thiadone) which
does not exceed the DWLOC of 37.7 ppb for children (1-6 years old). EPA
concludes that there is a reasonable certainty that no harm will result
from aggregate exposure to flufenacet residues.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of flufenacet, EPA
considered data from developmental toxicity studies in the rat and
rabbit and a two-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 and data on systemic
toxicity. FFDCA section 408 provides that EPA shall apply an additional
tenfold margin of safety for infants and children in the case of
threshold effects to account for pre- and post-natal toxicity and the
completeness of the database unless EPA determines that a different
margin of safety will be safe for infants and children. Although there
is no indication of increased sensitivity to young rats or rabbits
following pre- and/or post-natal exposure to flufenacet in the standard
developmental and reproductive toxicity studies, an additional
developmental neurotoxicity study, which is not normally required, is
needed to access the susceptibility of the offspring in function/
neurological development. Therefore, EPA has required that a
developmental neurotoxicity study be conducted with flufenacet and a
threefold safety factor for children and infants will be used in the
aggregate dietary acute and chronic risk assessment. Although there is
no indication of additional sensitivity to young rats or rabbits
following pre- and/or post-natal exposure to flufenacet in the
developmental and reproductive toxicity studies; the Agency concluded
that the FQPA safety factor should not be removed but instead reduced
because:
(i) There was no assessment of susceptibility of the offspring in
functional/neurological developmental and reproductive studies.
(ii) There is evidence of neurotoxicity in mice, rats, and dogs.
(iii) There is concern for thyroid hormone disruption.
F. International Tolerances
There are no Codex Alimentarius Commission (Codex) Maximum Residue
Levels (MRLs) for flufenacet. (James A. Tompkins).
3. FMC Corporation
PP 8F4970
EPA has received pesticide petitions (PP 8F4970) from FMC
Corporation, 1735 Market Street,Philadelphia, PA 19103, proposing
pursuant to section 408 (d) of the Federal Food, Drug, and Cosmetic
Act, 21 U.S.C. 346a(d), to amend 40 CFR 180.418 by establishing a
tolerance for residues of the insecticide zeta-cypermethrin
(<plus-minus><greek-a>-Cyano(3-phenoxyphenyl)methyl ( <plus-minus>)
cis, trans 3-(2,2-dichloroethenyl)-2,2-
dimethylcyclopropanecarboxylate)in or on the raw agricultural commodity
Brassica vegetables, head and stem at 2.0 ppm and Brassica vegetables,
leafy at 14.0 ppm; and the leafy vegetables (except Brassica
vegetables) group at 10.0 ppmn. 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
supports granting of the petition. Additional data may be needed before
EPA rules on the petition.
A. Residue Chemistry
1. Plant metabolism. The metabolism of cypermethrin in plants is
adequately understood. Studies have been conducted to delineate the
metabolism of radio labelled cypermethrin in various crops all showing
similar results. The residue of concern is the parent compound only.
2. Analytical method. There is a practical analytical method for
detecting and measuring levels of cypermethrin in or on food with a
limit of detection that allows monitoring of food with residues at or
above the levels set in these tolerances (Gas Chromatography with
Electron Capture Detection (GC/ECD).
3. Magnitude of residues. Crop field trial residue data from
studies conducted at the maximum label rates for head and stem Brassica
vegetables, leafy Brassica greens, and leafy vegetables (except
Brassica vegetables) group, show that the proposed zeta-cypermethrin
tolerances on Brassica vegetables, head and stemat 2.0 ppm and Brassica
vegetables, leafy at 14.0 ppm; and the leafy vegetables (except
Brassica vegetables) group at 10.0 ppm will not be exceeded when the
zeta-cypermethrin products labeled for these uses are used as directed.
[[Page 34182]]
B. Toxicological Profile
1. Acute toxicity. For the purposes of assessing acute dietary
risk, FMC has used the no-observed-effected label (NOEL) of 3.8 mg/kg/
day based on the NOEL of 7.5 mg/kg/day from the cypermethrin chronic
feeding/oncogenicity study in rats and a correction factor of two to
account for the differences in the percentage of the biologically
active isomer. The LOEL of 50.0 mg/kg/day was based on neurological
signs which were displayed during week one of the study. This acute
dietary end point is used to determine acute dietary risks to all
population subgroups.
2. Genotoxicity. The following genotoxicity tests were all
negative: in vivo chromosomal aberration in rat bone marrow cells; in
vitro cytogenic chromosome aberration; unscheduled DNA synthesis;CHO/
HGPTT mutagen assay; weakly mutagenic: gene mutation (Ames).
3. Reproductive and developmental toxicity. No evidence of
additional sensitivity to young rats was observed following pre- or
postnatal exposure to zeta-cypermethrin.
i. A 2-generation reproductive toxicity study with zeta-
cypermethrin in rats demonstrated a NOEL of 7.0 mg/kg/day and a LOEL of
27.0 mg/kg/day for parental/systemic toxicity based on body weight,
organ weight, and clinical signs. There were no adverse effects in
reproductive performance. The NOEL for reproductive toxicity was
considered to be > 45.0 mg/kg/day the highest dose tested (HDT).
ii. A developmental study with zeta-cypermethrin in rats
demonstrated a maternal NOEL of 12.5 mg/kg/day and a LOEL of 25 mg/kg/
day based on decreased maternal body weight gain, food consumption and
clinical signs. There were no signs of developmental toxicity at 35.0
mg/kg/day, the higest dose level tested (HDLT).
iii. A developmental study with cypermethrin in rabbits
demonstrated a maternal NOEL of 100 mg/kg/day and a LOEL of 450 mg/kg/
day based on decreased body weight gain. There were no signs of
developmental toxicity at 700 mg/kg/day, the HDLT.
4. Subchronic toxicity-- Short- and intermediate-term toxicity. The
NOEL of 3.8 mg/kg/day based on the NOEL 7.5 mg/kg/day from the
cypermethrin chronic feeding/oncogenicity study in rats and a
correction factor of two to account for the biologically active isomer
would also be used for short-and intermediate-term MOE calculations (as
well as acute, discussed in (1) above). The LOEL of 50.0 mg/kg/day was
based on neurological signs which were displayed during week one of the
study.
5. Chronic toxicity. The reference dose (RfD) of 0.0125 mg/kg/day
for zeta-cypermethrin is based on a NOEL of 2.5 mg/kg/day from a
cypermethrin rat reproduction study and an uncertainty factor of 200
(used to account for the differences in the percentage of the
biologically active isomer). The endpoint effect of concern was based
on consistent decreased body weight gain in both sexes at the LOEL of
7.5 mg/kg/day.
Cypermethrin is classified as a Group C chemical (possible human
carcinogen with limited evidence of carcinogenicity in animals) based
upon limited evidence for carcinogenicity in femalemice; assignment of
a Q* has not been recommended.
6. Animal metabolism. The metabolism of cypermethrin in animals is
adequately understood. Cypermethrin has been shown to be rapidly
absorbed, distributed, and excreted in rats when administered orally.
Cypermethrin is metabolized by hydrolysis and oxidation.
7. Metabolite toxicology. The Agency has previously determined that
the metabolites of cypermethrin are not of toxicological concern and
need not be included in the tolerance expression.
8. Endocrine disruption. No special studies investigating potential
estrogenic or other endocrine effects of cypermethrin have been
conducted. However, no evidence of such effects were reported in the
standard battery of required toxicology studies which have been
completed and found acceptable. Based on these studies, there is no
evidence to suggest that cypermethrin has an adverse effect on the
endocrine system.
C. Aggregate Exposure
1. Dietary exposure--i. Food. Permanent tolerances, in support of
registrations, currently exist for residues of zeta-cypermethrin on
cottonseed; pecans; lettuce, head; onions, bulb; and cabbage and
livestock commodities of cattle, goats, hogs, horses, and sheep. For
the purposes of assessing the potentialdietary exposure for these
existing and the subject proposed tolerances, FMC has utilized
available information on anticipated residues, monitoring data and
percent crop treated as follows:
ii. Acute exposure and risk. Acute dietary exposure risk
assessments are performed for a food-use pesticide if a toxicological
study has indicated the possibility of an effect of concern occurring
as a result of a 1-day or single exposure. For the purposes of
assessing acute dietary risk for zeta-cypermethrin, FMC has used the
NOEL of 3.8 mg/kg/day based on the NOEL of 7.5 mg/kg/day from the
cypermethrin chronic feeding/oncogenicity study in rats and a
correction factor of two to account for the differences in the
percentage of the biologically active isomer. The LOEL of 50.0 mg/kg/
day was based on neurological signs which were displayed during week
one of this study. This acute dietary endpoint is used to determine
acute dietary risks to all population subgroups. Available information
on anticipated residues, monitoring data and percent crop treated was
incorporated into a Tier 3 analysis, using Monte Carlo modeling for
commodities that may be consumed in a single serving. These assessments
show that the margins of exposure (MOE) are significantly greater than
the EPA standard of 100 for all subpopulations. The 95th percentile of
exposure for the overall U. S. population was estimated to be 0.000708
mg/kg/day (MOE of 5364); 99th percentile 0.002677 mg/kg/day (MOE of
1420); and 99.9th percentile 0.012098 mg/kg/day (MOE of 314). The 95th
percentile of exposure for all infants <1- year old was estimated to be
0.000264 mg/kg/day (MOE of 14394); 99th percentile 0.00189 mg/kg/day
(MOE of 2011); and 99.9th percentile 0.018164 mg/kg/day (MOE of 209).
The 95th percentile of exposure for nursing infants <1-year old was
estimated to be 0.000026 mg/kg/day (MOE of 147540); 99th percentile
0.000484 mg/kg/day (MOE of 7843); and 99.9th percentile 0.002004 mg/kg/
day (MOE of 1896).The 95th percentile of exposure for non-nursing
infants < 1- year old was estimated to be 0.000367mg/kg/day (MOE of
10342); 99th percentile 0.005649 mg/kg/day (MOE of 673); and 99.9th
percentile 0.019823 mg/kg/day (MOE of 192). The 95th percentile of
exposure for children 1 to 6-years old (the most highly exposed
population subgroup) and children 7 to 12-years old was estimated to
be, respectively, 0.000742 mg/kg/day (MOE of 5120) and 0.00748 mg/kg/
day (MOE of 5077); 99th percentile 0.003061 mg/kg/day (MOE of 1241) and
0.002638 (MOE of 1440); and 99.9th percentile 0.031769 mg/kg/day (MOE
of 120) and 0.013432 (MOE of 283). Therefore, FMC concludes that the
acute dietary risk of zeta-cypermethrin, as estimated by the dietary
risk assessment, does not appear to be of concern.
iii. Chronic exposure and risk. RfD of 0.0125 mg/kg/day for zeta-
cypermethrin is based on a NOEL of 2.5 mg/kg/day from a cypermethrin
rat reproduction
[[Page 34183]]
study and an uncertainty factor of 200 (used to account for the
differences in the percentage of the biologically active isomer). The
endpoint effect of concern was based on consistent decreased body
weight gain in both sexes at the LOEL of 7.5 mg/kg/day. A chronic
dietary exposure/risk assessment has been performed for zeta-
cypermethrin using the above RfD. Available information on anticipated
residues, monitoring data and percent crop treated was incorporated
into the analysis to estimate the anticipated residue contribution
(ARC). The ARC is generally considered a more realistic estimate than
an estimate based on tolerance level residues. The ARC are estimated to
be 0.000098 mg/kg body weight/day (mg/kg/bwt/day) and utilize 0.8 % of
the RfD for the overall U. S. population. The ARC for non-nursing
infants (<1-year) and nursing infants (<1-year) are estimated to be
0.00016 mg/kg/day and 0.00001 mg/kg/day and utilizes 1.3 % and 0.1 % of
the RfD, respectively. The ARC for children 1-6 years old (subgroup
most highly exposed) and children 7-12 years old are estimated to be
0.000172 mg/kg bwt/day and 0.000092 mg/kg bwt/day and utilizes 1.4 %
and 0.7 % of the RfD, respectively. Generally speaking, the EPA has no
cause for concern if the total dietary exposure from residues for uses
for which there are published and proposed tolerances is less than 100
% of the RfD. Therefore, FMC concludes that the chronic dietary risk of
zeta-cypermethrin, as estimated by the dietary risk assessment, does
not appear to be of concern.
2. Drinking water. Laboratory and field data have demonstrated that
cypermethrin is immobile in soil and will not leach into groundwater.
Other data show that cypermethrin is virtually insoluble in water and
extremely lipophilic. As a result, FMC concludes that residues reaching
surface waters from field runoff will quickly adsorb to sediment
particles and be partitioned from the water column. Further, a
screening evaluation of leaching potential of a typical pyrethroid was
conducted using EPA's Pesticide Root Zone Model (PRZM3). Based on this
screening assessment, the potential concentrations of a pyrethroid in
groundwater at depths of 1 and 2 meters are essentially zero (<0.001
part per billion (PPB). Surface water concentrations for pyrethroids
were estimated using PRZM3 and Exposure Analysis Modeling System
(EXAMS) using standard EPA cotton runoff and Mississippi pond
scenarios. The maximum concentration predicted in the simulated pond
was 0.052 PPB. Concentrations in actual drinking water would be much
lower than the levels predicted in the hypothetical, small, stagnant
farm pond model since drinking water derived from surface water would
normally be treated before consumption. Based on these analyses, the
contribution of water to the dietary risk estimate is negligible.
Therefore, FMC concludes that together these data indicate that
residues are not expected to occur in drinking water.
3. Non-dietary exposure. Zeta-cypermethrin is registered for
agricultural crop applications only, therefore non-dietary exposure
assessments are not warranted.
D. Cumulative Effects
In consideration of potential cumulative effects of cypermethrin
and other substances that may have a common mechanism of toxicity, to
our knowledge there are currently no available data or other reliable
information indicating that any toxic effects produced by cypermethrin
would be cumulative with those of other chemical compounds; thus only
the potential risks of cypermethrin have been considered in this
assessment of its aggregate exposure. FMC intends to submit information
for the EPA to consider concerning potential cumulative effects of
cypermethrin consistent with the schedule established by EPA at 62 FR
42020 (August 4, 1997) (FRL 5734-6) and other EPA publications pursuant
to the Food Quality Protection Act.
E. Safety Determination
1. U.S. population. Based on a complete and reliable toxicology
database, the RfD for zeta-cypermethrin is 0.0125 mg/kg/day, based on a
NOEL of 2.5 mg/kg/day and a LOEL of 7.5 mg/kg/day from the cypermethrin
rat reproduction study and an uncertainty factor of 200. Available
information on anticipated residues, monitoring data and percent crop
treated was incorporated into an analysis to estimate the ARC for 26
population subgroups. The ARC is generally considered a more realistic
estimate than an estimate based on tolerance level residues. The ARC
are estimated to be 0.000098 mg/kg/bwt/day and utilize 0.8 of the RfD
#or the overall U. S. population. The ARC for non-nursing infants (<1-
year) and nursing infants (<1- year) are estimated to be 0.00016 mg/kg/
day and 0.00001 mg/kg/day and utilizes 1.3 % and 0.1 % of the RfD,
respectively. The ARC for children 1-6 years old (subgroup most highly
exposed) and children 7-12 years old are estimated to be 0.000172 mg/kg
bwt/day and 0.000092 mg/kg bwt/day and utilizes 1.4 % and 0.7 % of the
RfD, respectively. Generally speaking, the EPA has no cause for concern
if the total dietary exposure from residues for uses for which there
are published and proposed tolerances is less than 100 % of the RfD.
Therefore, FMC concludes that the chronic dietary risk of zeta-
cypermethrin, as estimated by the aggregate risk assessment, does not
appear to be of concern.
For the overall U.S. population, the calculated margins of exposure
(MOE) at the 95th percentile was estimated to be 5364; 1420 at the 99th
percentile; and 314 at the 99.9th percentile. For all infants < 1-year
old, the calculated MOE at the 95th percentile was estimated to be
14394; 2011 at the 99th percentile; and 209 at the 99.9th percentile.
For nursing infants < 1-year old, the calculated MOE at the 95th
percentile was estimated to be 147540; 7843 at the 99th percentile; and
1896 at the 99.9th percentile. For non-nursing infants < 1-year old,
the calculated MOE at the 95th percentile was estimated to be 10342;
673 at the 99th percentile; and 192 at the 99.9th percentile. For the
most highly exposed population subgroup, children 1- 6 years old, and
for children 7-12 years old, the calculated MOEs at the 95th percentile
were estimated to be, respectively, 5120 and 5077; 1241 and 1440 at the
99th percentile; and 120 and 283 at the 99.9th percentile. Therefore,
FMC concludes that there is reasonable certainty that no harm will
result from acute exposure to zeta-cypermethrin.
2. Infants and children--i. General. In assessing the potential for
additional sensitivity of infants and children to residues of zeta-
cypermethrin, FMC considered data from developmental toxicity studies
in the rat and rabbit, and a 2-generation reproductive study in the
rat. The data demonstrated no indication of increased sensitivity of
rats to zeta-cypermethrin or rabbits to cypermethrin in utero and/or
postnatal exposure to zeta-cypermethrin or cypermethrin. 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 and data on systemic
toxicity. FFDCA section 408 provides that EPA may apply an additional
margin of safety for infants and children in the case of threshold
effects to account for pre- and post-natal toxicity and the
completeness of the database.
[[Page 34184]]
ii. Developmental toxicity studies. In the prenatal developmental
toxicity studies in rats and rabbits, there was no evidence of
developmental toxicity at the HDT (35.0 mg/kg/day in rats and 700 mg/
kg/day in rabbits). Decreased body weight gain was observed at the
maternal LOEL in each study; the maternal NOEL was established at 12.5
mg/kg/day in rats and 100 mg/kg/day in rabbits.
iii. Reproductive toxicity study. In the 2-generation reproduction
study in rats, offspring toxicity (body weight) and parental toxicity
(body weight, organ weight, and clinical signs) was observed at 27.0
mg/kg/day and greater. The parental systemic NOEL was 7.0 mg/kg/day and
the parental systemic LOEL was 27.0 mg/kg/day. There were no
developmental (pup) or reproductive effects up to 45.0 mg/kg/day, HDT.
iv. Pre- and post-natal sensitivity--a. Pre-natal. There was no
evidence of developmental toxicity in the studies at the HDT in the rat
(35.0 mg/kg/day) or in the rabbit (700 mg/kg/day). Therefore, there is
no evidence of a special dietary risk (either acute or chronic) for
infants and children which would require an additional safety factor.
b. Post-natal. Based on the absence of pup toxicity up to dose
levels which produced toxicity in the parental animals, there is no
evidence of special post-natal sensitivity to infants and children in
the rat reproduction study.
c. Conclusion. Based on the above, FMC concludes that reliable data
support use of the standard 100-fold uncertainty factor, and that an
additional uncertainty factor is not needed to protect the safety of
infants and children. As stated above, aggregate exposure assessments
utilized significantly less than 1 % of the RfD for either the entire
U. S. population or any of the 26 population subgroups including
infants and children. Therefore, it may be concluded that there is
reasonable certainty that no harm will result to infants and children
from aggregate exposure to cypermethrin residues.
3. Subchronic toxicity-- Short- and intermediate-term toxicity. The
NOEL of 3.8 mg/kg/day based on the NOEL 7.5 mg/kg/day from the
cypermethrin toxicity/oncogenicity study in rats and a correction
factor of two to account for the biologically active isomer would also
be used for short- and intermediate-term MOE calculations (as well as
acute, discussed in (E.1.) above). The LOEL of this study of 50.0 mg/
kg/day was based on neurological signs observed in the first week of
the study.
F. International Tolerances
There are no Codex, Canadian, or Mexican residue limits for
residues of zeta-cypermethrin in or on Brassica, head and stem
vegetables; Brassica, leafy vegetables; and leafy vegetables (except
Brassica vegetables) group. (Stephaine Willette).
[FR Doc. 98-16673 Filed 6-22-98; 8:45 am]
BILLING CODE 6560-50-F