[Federal Register Volume 63, Number 120 (Tuesday, June 23, 1998)]
[Notices]
[Pages 34176-34184]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-16673]


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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:<a href="/cdn-cgi/l/email-protection" class="__cf_email__" data-cfemail="6f180e03030a1d41020e1d162f0a1f0e">[email protected]</a>m   Arlington, VA  
                                 ail.epa.gov.                           
James Tompkins................  Rm. 239, CM #2, 703-                    
                                 305-5687, e-mail:                      
                                 <a href="/cdn-cgi/l/email-protection#63170c0e13080a0d104d09020e0610230613020e020a690f4d0613024d040c15"><span class="__cf_email__" data-cfemail="13677c7e63787a7d603d79727e7660537663727e727a">[email protected]</span>
l.epa.gov</a>.                             
Stephanie Willett.............  Rm. 202, CM #2, 703-    Do.             
                                 305-5419, e-                           
                                 mail:willett.stephani                  
                                 <a href="/cdn-cgi/l/email-protection#88edc8edf8e9e5e9e1e4a6edf8e9a6efe7fe"><span class="__cf_email__" data-cfemail="3f5a7f5a4f5e525e5653115a4f5e11585049">[email protected]</span></a>.                     
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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:
    <a href="/cdn-cgi/l/email-protection#a4cbd4d489c0cbc7cfc1d0e4c1d4c5c9c5cdc88ac1d4c58ac3cbd2"><span class="__cf_email__" data-cfemail="422d32326f262d21292736022732232f232b2e6c2732236c252d34">[email protected]</span></a>


    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


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