[Federal Register Volume 63, Number 193 (Tuesday, October 6, 1998)]
[Notices]
[Pages 53656-53669]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-26782]


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ENVIRONMENTAL PROTECTION AGENCY

[PF-837; FRL-6033-8]


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-837, must 
be received on or before November 5, 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 to: opp-
[email protected]. Follow 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:

[[Page 53657]]



------------------------------------------------------------------------
                                   Office location/
        Product Manager            telephone number          Address
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Edith Minor...................  Rm. 229, CM #2, 703-    1921 Jefferson
                                 305-7390, e-            Davis Hwy,
                                 mail:minor.edith@epam   Arlington, VA
                                 ail.epa.gov.
Joanne Miller.................  Rm. 229, PM #23, 703-
                                 306-6224, e-mail:
                                 miller.joanne@epamail
                                 .epa.gov.
Joseph Tavano.................  Rm. 214, 703-305-6411,  Do.
                                 e-
                                 mail:tavano.joseph@ep
amail.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-837] (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:
    [email protected]


    Electronic comments must be submitted as an ASCII file avoiding the 
use of special characters and any form of encryption. Comments 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: September 29, 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. Griffin Corporation

PP 7F4837

    EPA has received a pesticide petition (PP 7F4837) from Griffin 
Corporation, P.O. Box 1847, Valdosta, GA 31603-1847, 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 to establish an exemption from 
the requirement of a tolerance for propazine 2-chloro-4,6-
bis(isopropylamine)-s-triazine and its two chloro metabolites, 2-amino-
4-chloro, 6-isopropylamino-s-triazine (G-30033) and 2,4-diamino-6-
chloro-s-triazine (G-28273) in or on the raw agricultural commodities 
sorghum, stover, forage, and grain at 0.25 parts per million (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 metabolism. In sorghum, metabolism occurs by the three 
following reactions: N-dealkylation of the side-chains, hydrolytic 
dehalogenation or nucleophilic displacement of the 2-chloro group with 
glutathione (GSH). The dehalogenation and formation of GSH conjugates 
are the two predominant pathways and only small amounts of the chloro 
residues were found in forage and stover. No chloro residues were 
detected in sorghum grain in two propazine metabolism studies that were 
conducted. Griffin believes the metabolism is well characterized in 
plants and animals and the pathways of metabolism are very similar to 
those defined for other triazines. The metabolism profile supports the 
use of an analytical enforcement method that accounts for parent 
propazine and its two chloro metabolites, 2-amino-chloro-6-isopropyl-
amino-s-triazine (G-30033) and 2-chloro-4,6-di-amino-s-triazine (G-
28273) in the raw agricultural commodity (RAC's) of grain sorghum and 
further supports the current tolerance of 0.25 ppm to include the two 
chloro metabolites.
    2. Analytical method. A practical analytical method has been 
submitted. as a part of the sorghum residue study. The method involves 
extraction, evaporation solid phase clean-up column and quantitation by 
high performance liquid chromotography (HPLC) equipped with a 
ultraviolet ray (UV) detector. One aliquot is used for assaying for 
propazine and G-30033 and another aliquot is used for quantitating G-
27283. The limit of quanitation (LOQ) for propazine and each of its 
chloro metabolites in each raw agricultural commodities (RAC) and each 
chloro residue is 0.05 ppm.
    3. Magnitude of residues. A total of 13 sorghum field residue 
trails were conducted in the major sorghum growing areas of the United 
States. No quantifiable residues of parent or the two chloro 
metabolites were detected in the RAC's of the 13 field residue studies 
when treated at the 1x rate. Only four samples for sorghum forage 
contained residues of G-28273 which were quantifiable and residues 
ranged from 0.05 ppm to 0.087 ppm. The treatment rate for these studies 
exceeded the maximum proposed use rate and the extrapolated range of 
residues for the four samples was 0.024 to 0.069 ppm.
    The RAC's of sorghum are only used as feed for cattle and poultry. 
Only the grain is fed to chickens and there were no chloro residues 
present in grain; therefore no chloro residues would be expected in 
eggs and poultry products. The level of chloro residues in forage

[[Page 53658]]

and fodder are sufficiently low in the metabolism and residue studies 
to demonstrate that any potential transfer of propazine and its chloro 
metabolites to milk and meat is not expected.
    For rotational crops, no chloro residues were present in root and 
grain crops when planted more than 129 days after treatment. Chloro 
residues were present in leafy vegetables grown in soils with pH values 
above 7 and under inclimate growing conditions. One field sample of 
wheat forage contained low levels of parent propazine but this sample 
was taken at an interval shorter than will be proposed on the label for 
plant back and, in addition, the pH of the soil was above 7.
    An amendment of the current tolerance of 0.25 ppm to include parent 
propazine and its two chloro metabolites, G-30033 and G-28273, is 
proposed for each of the RAC's of grain sorghum. The metabolism and 
field residue results show that chloro residues of propazine should not 
exceed 0.25 ppm in any of the RAC's. Potential transfer of propazine 
and its two chloro metabolites to milk and meat is not expected. 
Therefore, tolerances in milk, meat, poultry and eggs are not required. 
The data show that root and grain crops can be rotated with sorghum 
treated with propazine, but leafy vegetable crops should not be rotated 
with sorghum in soils with pH values above 7.

B. Toxicological Profile

    1. Acute toxicity. A complete battery of acute toxicity studies for 
propazine technical was completed. The acute oral toxicity study 
resulted in a LD50 of greater than 5,050 milligram kilogram 
(mg/kg) for both sexes. The acute dermal toxicity in rabbits resulted 
in an LD50 in either sex of greater than 5,050 mg/kg. The 
acute inhalation study in rats resulted in an LC50 of 
greater than 1.22 mg/l. Propazine was non-irritating to the skin of 
rabbits in the primary dermal irritation study. In the primary eye 
irritation study in rabbits, no irritation was noted. The dermal 
sensitization study in guinea pigs indicated that propazine is not a 
sensitizer. Based on these results, propazine technical is placed in 
toxicity Category III.
    2. Reproductive and developmental toxicity. The potential maternal 
and developmental toxicity of propazine were evaluated in rabbits. 
Propazine technical was suspended in corn oil and administered orally 
by gavage to three groups of 20 artificially inseminated New Zealand 
White rabbits as a single daily dose from gestation days 6-18. In the 
range-finding study, rabbits were dosed at levels of 0, 10, 50, 100, 
200, and 400 milligram kilogram day (mg/kg/day). Maternal toxicity was 
exhibited by decreased defecation, body weight losses and decreased 
food consumption during the treatment period at 50, 100, 200 and 400 
mg/kg/day. Abortions also occurred at levels of 200 and 400 mg/kg/day. 
Dose levels of 0, 2, 10, and 50 mg/kg/day were selected based on the 
results of this study. In the definitive study, no test article related 
deaths occurred at any dose level tested. The only clinical sign 
observed was decreased defecation in the 50 mg/kg/day group. Inhibition 
of body weight gain occurred during the first 6 days of dosing and 
inhibition of food consumption occurred throughout the treatment period 
in the 50 mg/kg/day group. No other treatment related findings were 
noted in the dams at any dose level. Intrauterine parameters were 
unaffected by treatment. There were no treatment related effects on 
fetal malformations or developmental variations.
    The data from the developmental toxicity studies on propazine show 
no evidence of a potential for developmental effects (malformations or 
variations) at doses that are not maternally toxic. The no observed 
adverse effect level (NOAEL) for maternal toxicity in rabbits was 10 
mg/kg/day and the NOAEL for developmental toxicity was 50 mg/kg/day.
    3. Subchronic toxicity.. No test article related deaths occurred at 
any dose level. Very minimal dermal irritation was noted in the 100 and 
1,000 mg/kg/day females. Body weight gain was slightly inhibited in the 
high dose group during weeks 0-1 (both sexes) and 2-3 (males only). 
There were no treatment related effects on the clinical observations, 
food consumption, hematology and serum chemistry parameters or organ 
weights were observed at any dose level. Macroscopic and microscopic 
examinations revealed no treatment related lesions at any dose level.
    Based on the 21 day dermal study in rats, the NOAEL for systemic 
toxicity was 100 mg/kg/day due to reduced body weight gain at 1,000 mg/
kg/day.
    4. Chronic toxicity. Griffin conclude that the body weight gain and 
survival data clearly indicate that the high dose female rats exceeded 
the maximum tolerance dose (MTD), and therefore the high dose female 
group should be excluded from any risk assessment or weight-of-evidence 
arguments concerning this study. Additionally, the incidence of mammary 
gland tumors in all doses in this study were within the range of 
current laboratory historical control incidences and those reported by 
the breeder, Charles River. No adverse treatment related effects were 
observed at levels below the MTD.
    5. Animal metabolism. The absorption, distribution, excretion, and 
metabolism of propazine (ring-UL-14C propazine) was 
investigated in Sprague-Dawley CD rats. One group of rats was 
administered a single oral dose at 1.0 mg/kg (low dose), one group was 
administered a single oral dose at 100 mg/kg (high dose), and a third 
group was administered fourteen consecutive oral daily doses of non-
radioactive propazine at 1.0 mg/kg, followed by a single oral dose of 
14C-propazine at 1.0 mg/kg (consecutive dose group). A 
fourth group of animals (3 rats/sex) was administered a single oral 
dose of the vehicle only (corn oil), and served as controls. Since 
propazine is not soluble in water, it was not possible to include an 
intravenous dose group.
    Excretion patterns were very similar in all dose groups. Nearly all 
of the radioactivity administered was recovered in the excreta within 
24 to 48 hours after dosing. The majority of the administered 
radioactivity was excreted in the urine (66.2 - 70.5%), and this 
finding shows that the majority of the administered dose was 
bioavailable and rapidly absorbed from the gastrointestinal tract. High 
performance liquid chromotography (HPLC) analysis of the urine 
indicated a similar profile among all dose groups and both sexes. The 
excretion of radioactivity in the feces was significantly lower than in 
the urine (range: 19.9 -28.6%) in all dose groups and both sexes. 
Analysis of this radioactivity demonstrated a relatively consistent 
pattern among the various dose groups with females containing a 
quantitatively higher level of the parent compound. The recovery of 
expired radioactivity was shown in a pilot study to be negligible 
(<0.1%), indicating little or no 14CO2 production 
during the metabolism of propazine.
    7 days post-treatment all animals were sacrificed and the total 
radioactive residue was quantified in bone, brain, fat (visceral), 
gastrointestinal tract (including contents), heart, kidney, liver, 
lung, muscle (thigh), ovary, plasma, red blood cells (RBC), skin, 
spleen, testis, thyroid, uterus, and residual carcass. Highest 
concentrations were found in the RBCs of all dose groups (0.472 - 0.577 
ppm parent equivalents at 1.0 mg/kg and 44.649 - 55.287 ppm at 100 mg/
kg). Residue concentration in the remaining tissues ranged from 0.007 
to 0.468 ppm at the low and consecutive dose groups, and from 0.859 to 
13.246 ppm at the high dose. Mean body burdens for the low,

[[Page 53659]]

high, and consecutive dose groups accounted for 10.3, 5.9 and 7.1% of 
the dose, respectively. Material balances were quantitative and 
accounted for 102.5, 101.1 and 96.3% of the dose, respectively.
    Metabolite characterization of excreta indicated a 
biotransformation pathway consistent with historical metabolism of 
alkylated s-triazines. Confirmed metabolite identification showed that 
propazine was metabolized via N-dealkylation mechanisms and excreted in 
urine primarily as the G-27283 metabolite (approximately 27% of the 
total dose). Unmetabolized parent propazine was the predominant 
identified compound in the feces (13.8% in the high dose male group). 
The fact that a greater percentage of administered 14C-
propazine was found in the feces of the high dose group probably 
indicated some degree of saturation of the absorption mechanism.
    Propazine technical is not metabolized to breakdown products which 
accumulate in sufficient quantities that can be reasonably expected to 
present any chronic dietary risk.
    6. Metabolite toxicology. The hydroxy metabolite of atrazine, an 
analog of propazine has been shown not to exhibit carcinogenic effects.
    7. Endocrine disruption. There is no evidence that propazine has 
endocrine-modulation characteristics as demonstrated by the lack of 
endocrine effects in developmental, subchronic and chronic studies.

C. Aggregate Exposure

    1. Dietary exposure--Food. A dietary risk exposure study dietary 
risk evaluation system (DRES) for Griffin for the purpose of estimating 
dietary exposure to propazine residues. Grain sorghum is the only 
proposed food or food use of propazine. Therefore, there exists no 
potential for human consumption of crops treated with propazine. 
Sorghum (grain, forage and stover) is, however, fed to livestock. Grain 
is the only sorghum commodity fed to poultry. There are no chloro 
residues, the residues of toxicological concern, in the grain. In turn, 
there is no potential for poultry to be exposed to propazine or related 
residues. Beef and dairy cattle are fed all sorghum commodities: grain, 
forage, stover, and aspirated grain fractions. Therefore, in evaluating 
potential human dietary exposure to propazine, the potential exposure 
via secondary residues in meat and milk must be considered. The total 
chloro residues for a goat dosed at 9.9 ppm in a metabolism study were 
low. Specifically, the highest total residue was observed in milk 
(0.162 ppm), while the lowest residue of <0.002 ppm was observed in 
kidney.
    These tissue to feed ratios can then be combined with the worst-
case diets derived from a sorghum only ration which includes propazine 
residues at the tolerance level of 0.25 ppm. (It should be noted that 
this worst-case diet is not a ration that would be fed to cattle). The 
results of this indicate that even under theoretically worst-case 
conditions all meat and milk residues are extremely low (all less than 
0.01 ppm; the LOQ in plant matrices is 0.05 ppm). In turn, there is no 
potential for dietary exposure to propazine via secondary residues in 
meat and milk. Therefore, tolerances for meat and milk are not required 
for propazine.
    2. Drinking water. Griffin conclude that environmental fate and 
behavior studies, including aerobic soil metabolism, field lysimeter, 
and long term soil dissipation, indicate little potential for propazine 
to reach surface or groundwater from its proposed use on grain sorghum. 
Griffin concludes that there is little potential for dietary exposure 
to propazine residues in water exists.
    3. Non-dietary exposure. There are no residential uses for 
propazine in the U.S. therefore, there is no potential for residential 
exposure.
    4.  Non-occupational. A registration application is pending for use 
of propazine in greenhouses on certain ornamental plants. The container 
sizes in which the product is to be distributed and channel of 
distribution make it unlikely that this use would result in any non-
occupational exposure.

D. Cumulative Effects

    Because of the benefits of propazine, most of the propazine use on 
sorghum will be substituted for other triazines and since the proposed 
use rate is lower than the other triazines the cumulative will not 
increase and could possibly be reduced as a result of registering 
propazine for use on grain sorghum.

E. Safety Determination

    The reference dose (RfD) is based on the rat chronic study. Using 
the NOAEL of 5 mg/kg/day in this study and an uncertainty factor (UF) 
of 300, an RfD of 0.02 mg/kg/day was established as the chronic dietary 
endpoint.
    1. U.S. population--General U.S. population. In the DRES analysis 
referenced above, it was determined that there is no potential exposure 
to propazine via dietary, water, or non-occupational routes.
    2. Infants and children. In assessing the potential for additional 
sensitivity of infants and children to residues of propazine, the 
available developmental toxicity study and the potential for endocrine 
modulation by propazine were considered. The data from the 
developmental toxicity studies on propazine show no evidence of a 
potential for developmental effects (malformations or variations) at 
doses that are not maternally toxic. The developmental no observed 
adverse effect levels (NOAELs) and LOAELs were at higher dose levels 
(less toxic), indicating no increase in susceptibility of developing 
organisms. No evidence of endocrine effects were noted in any study. It 
is therefore concluded that propazine poses no additional risk for 
infants and children and no additional uncertainty factor is warranted.
    Federal food, drug and cosmetic act (FFDCA) section 408 provides 
that an additional safety factor for infants and children may be 
applied in the case of threshold effects. Since, as discussed in the 
previous section, the toxicology studies do not indicate that young 
animals are any more susceptible than adult animals and the fact that 
the current RfD calculated from the NOAEL from the rat chronic study 
already incorporates a 300x uncertainty factor, Griffin believes that 
an adequate margin of safety is therefore provided by the RfD 
established by EPA.
    There is no evidence that propazine has endocrine-modulation 
characteristics as demonstrated by the lack of endocrine effects in 
developmental, subchronic, and chronic studies.
    There is no potential exposure to propazine via dietary, water, or 
non-occupational routes based on the proposed use on grain sorghum. No 
additional uncertainty factor for infants and children is warranted 
based on the completeness and reliability of the database, the 
demonstrated lack of increased risk to developing organisms, and the 
lack of endocrine-modulating effects.

F. International Tolerances

    There are no Codex Alimentarius Commission (CODEX) maximum residue 
levels (MRLs) established for residues of propazine and its chloro 
metabolites in or on raw agricultural commodities.

2. K-1 Chemical U.S.A., Inc.

 PP 7F4821

    EPA has received an amendment to pesticide petition (PP 7F4821) 
from K-I Chemical U.S.A., Inc., proposing pursuant to section 408(d) of 
the Federal Food, Drug, and Cosmetic Act, 21 U.S.C.

[[Page 53660]]

346a(d), to amend 40 CFR part 180 by establishing a tolerance for 
residues of herbicide and harvest aid fluthiacet-methyl in or on the 
raw agricultural commodities cottonseed at 0.02 parts per million (ppm) 
and cotton, gin by-products at 0.5 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.
    On April 14, 1997, EPA announced receipt of a pesticide petition 
(PP 7F4821) from K-1 Chemical U.S.A., Inc., 11 Martine Avenue, 9th 
Floor, White Plains, NY 10606, proposing pursuant to section 408(d) of 
the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. 346a(d), to amend 
40 CFR part 180 by establishing a tolerance for residues of the 
herbicide fluthiacet-methyl: Acetic acid, [[2-chloro-4-fluoro-5-
[(tetrahydro-3-oxo-1H,3H-[1,3,4]thiadiazolo[3,4-a] pyridazin-1-
ylidene)amino]phenyl]thio]-methyl ester in or on the raw agricultural 
commodities field corn grain and sweet corn grain (K + CWHIR) at 0.02 
ppm and corn forage and fodder at 0.05 ppm.
    On September 4, 1997 K-I Chemical, U.S.A., Inc., amended PP 7F4821 
to include a proposed tolerance for popcorn grain at 0.02 ppm.
    On August 14, 1998 K-I Chemical U.S.A., Inc. amended PP 7F4821 to 
include proposed tolerances for cottonseed at 0.02 ppm and for cotton, 
gin by-products at 0.5 ppm. EPA has determined that the amended 
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 residues in corn is 
adequately understood following application of fluthiacet-methyl. 
Residue levels and the metabolic pathway are consistent with those in 
soybeans. Parent fluthiacet-methyl was the primary component of the 
residue seen in corn grain, forage, fodder and silage. Results of these 
studies have been submitted to the EPA.
    2. Analytical method. K-I Chemical has submitted practical 
analytical methods (AG-603B and AG-624) for detecting and measuring the 
level of fluthiacet-methyl in or on corn, corn commodities, cotton, 
cotton commodities, and in animal tissues with a limit of detection 
that allows monitoring residues at or above the levels set for the 
proposed tolerance. The limit of quantitation of the crop method is 
0.01 ppm in corn, corn commodities, cotton, and cotton commodities, 
0.05 ppm in animal tissues and 0.01 ppm in milk. The crop method 
involves extraction, filtration, and solid phase clean up. Residue 
levels of fluthiacet-methyl are determined by gas chromatographic 
analysis utilizing a nitrogen phosphorus detector and a fused-silica 
column. The animal tissue method involves extraction, filtration, and 
partition. Determination of residue levels in animal tissues is by high 
performance liquid chromotography (HPLC) with ultraviolet ray (UV) 
detection via column switching using C1 and C18 columns. The analyte of 
interest in animal tissues and milk is the major animal metabolite CGA-
300403. Residues of fluthiacet-methyl in corn are determined by gas 
chromatography.
    3. Magnitude of residues. The residue of concern in corn is 
fluthiacet-methyl per se. Twenty-one field residue studies were 
conducted with corn grown in nineteen States. Fifteen of the studies 
were on field corn and six on sweet corn. No studies were conducted 
with popcorn, however K-I believes that the data on field and sweet 
corn support a tolerance in popcorn as well. Because the proposed use 
rate and pattern is the same for popcorn, it is reasonable to conclude 
that residues in popcorn grain will not exceed the proposed tolerance 
of 0.02 ppm. Residues in field and sweet corn forage after the day of 
application were less than the proposed tolerance of 0.05 ppm. Popcorn 
forage is not a fed commodity. Nonetheless, residues in popcorn forage 
or fodder are not expected to exceed the proposed tolerance of 0.05 
ppm. The proposed tolerances of 0.02 ppm in field corn, sweet corn, and 
popcorn grain and 0.05 ppm in field corn and sweet corn forage and 
fodder are adequate to cover residues likely to occur when Action 
herbicide is applied to corn as directed.
    This position is based on 180.34(d) of the CFR which states that 
``If the pesticide chemical is not absorbed into the living plant or 
animal when applied (is not systemic), it may be possible to make a 
reliable estimate of the residues to be expected on each commodity in a 
group of related commodities on the basis of less data than would be 
required for each commodity in the group, considered separately''. And, 
180.34(e) states that ``each of the following groups of crops lists raw 
agricultural commodities that are considered to be related for the 
purpose of paragraph (d) of this section; field corn, popcorn, sweet 
corn (each in grain form)''.
    Residues of fluthiacet-methyl in treated field and sweet corn grain 
and sweet corn ears were less than the method limit of quanitation 
(LOQ) (<0.01 ppm). Because the proposed use rate and pattern is the 
same for popcorn, it is reasonable to conclude that residues in popcorn 
grain will not exceed the proposed tolerance of 0.02 ppm. Residues in 
field, and sweet corn forage -after the day of application were less 
than the proposed tolerance of 0.05 ppm. Popcorn forage is not a feed 
commodity. Nonetheless, residues in popcorn forage or fodder are not 
expected to exceed the proposed tolerance of 0.05 ppm. The proposed 
tolerances of 0.02 ppm in field corn, sweet corn, and popcorn grain and 
0.05 ppm in field corn, sweet corn forage, and fodder are adequate to 
cover residues likely to occur when fluthiacet-methyl herbicide is 
applied to corn as directed.
    Twelve cotton field residue trials were conducted in which 
fluthiacet-methyl 4.75% Wettable Powder (WP) was applied as two 
broadcast foliar sprays, 7 days apart. No residues were detected 
(<0.01ppm) in undelinted seed, delinted seed, hulls, meal, or refined 
oil nor was there concentration of residues in processed fractions, 
even at 3x and 5x rates in 3 day PHI ( preharvest interval) samples. 
Fluthiacet-methyl residues were present in field trash at 0.32 and 
0.11ppm at 3 and 8 day PHIs, respectively, and in gin trash at 0.1 0 
and .086 ppm at 4 and 7 day PHIs, respectively, in the 1x treatment 
rate. Results were similar in two additional trials in which the 
magnitude of residues was compared following application of the 4.75% 
WP and 10.3% emulsifiable concentrate (EC) formulations of fluthiacet-
methyl. Residues from the proposed use of fluthiacet-methyl on cotton 
will not exceed the proposed tolerances of 0.02 ppm and 0.5 ppm for 
fluthiacet-methyl residues in/on the raw agricultural commodities 
cottonseed and cotton, gin by-products.

B. Toxicological Profile

    1. Acute toxicity--i. A rat acute oral study with an 
LD50 > 50,000 milligram/kilogram (mg/kg).
    ii. A rabbit acute dermal study with an LD50 > 2,000 mg/
kg.
    iii. A rat inhalation study with an LC50 > 5.05 mg/
liter.

[[Page 53661]]

    iv. A primary eye irritation study in the rabbit showing moderate 
eye irritation.
    v. A primary dermal irritation study in the rabbit showing no skin 
irritation.
    vi. A primary dermal sensitization study in the Guinea pig showing 
no sensitization.
    2. Acute neurotoxicity study in rats. Neurotoxic effects were not 
observed. The no observed adverse effect level (NOAEL) was 2,000 mg/kg.
    3. Genotoxicty. In vitro gene mutation tests: Ames test -negative; 
Chinese hamster V79 test - negative; rat hepatocyte DNA repair test - 
negative; E. Coli lethal DNA damage test - negative. In vitro 
chromosomal aberration tests: Chinese hamster ovary -positive at 
cytotoxic doses; Chinese hamster lung - positive at cytotoxic doses; 
human lymphocytes - positive at cytotoxic doses. In vivo chromosome 
aberration tests: Micronucleus assays in rat liver - negative; mouse 
bone marrow test - negative.
    4. Reproductive and developmental toxicity. Teratology study in 
rats with a maternal and developmental NOAEL equal to or greater than 
1,000 milligram/kilogram/day (mg/kg/day). Teratology study in rabbits 
with a maternal NOAEL greater than or equal to 1,000 mg/kg/day and a 
fetal NOAEL of 300 mg/kg based on a slight delay in fetal maturation. 
2-generation reproduction study in rats with a NOAEL of 36 mg/kg/day, 
based on liver lesions in parental animals and slightly reduced body 
weight development in parental animals and pups. The treatment had no 
effect on reproduction or fertility.
    5. Subchronic toxicity. 90-day subchronic neurotoxicity study in 
rats. The NOAEL was 0.5 mg/kg/day based on reduced body/weight/gain 
(bwt/gain). No clinical or morphological signs of neurotoxicity were 
detected at any dose level. 28 day dermal toxicity study in rats with a 
NOAEL equal to or higher than the limit dose of 1,000 mg/kg.
    6 week dietary toxicity study in dogs with a NOAEL of 162 
milligram/kilogram/day (mg/kg/day) in males and 50 mg/kg/day in females 
based on decreased body weight gain and modest hematological changes.
    90 day subchronic dietary toxicity study in rats with a NOAEL of 
6.2 mg/kg/day based on liver changes and hematological effects.
    6. Chronic toxicity. 24 month combined chronic toxicity/ 
carcinogenicity study in rats with a NOAEL of 2.1 mg/kg/day. Based on 
reduced bwt development and changes in bone marrow, liver, pancreas and 
uterus the MTD was exceeded at 130 mg/kg/day. A positive trend of 
adenomas of the pancreas in male rats treated at 130 mg/kg/day and 
above may be attributable to the increased survival of the rats treated 
at high doses. 18 month oncogenicity study in mice with a NOAEL of 0. 
14 mg/kg/day. Based on liver changes, the MTD was reached at 1.2 mg/kg/
day. The incidence of hepatocellular tumors was increased in males 
treated at 12 and 37 mg/kg/day.
    7. Animal metabolism. The results from hen and goat metabolism 
studies, wherein fluthiacet-methyl was fed at exaggerated rates, showed 
that the transfer of fluthiacet-methyl residues from feed to tissues, 
milk and eggs is extremely low. No detectable residues of fluthiacet-
methyl (or metabolite CGA-300403) would be expected in meat, milk, 
poultry, or eggs after feeding the maximum allowable amount of treated 
corn and soybeans. This conclusion is based on residue data from the 
corn and soybean metabolism and field residue chemistry studies coupled 
with the residue transfer from feed to tissues, milk and eggs obtained 
in the goat and hen metabolism studies.
    8. Endocrine disruption. Based on the results of short-term, 
chronic, and reproductive toxicity studies there is no indication that 
fluthiacet-methyl might interfere with the endocrine system. 
Considering further the low environmental concentrations and the lack 
of bioaccumulation, there is no risk of endocrine disruption in humans 
or wildlife.

C. Aggregate Exposure

    Aggregate exposure includes exposure from dietary exposure from 
food and drinking water; and non-dietary exposure from non-dietary uses 
of pesticides products containing the active ingredient, fluthiacet-
methyl.
    1. Dietary exposure. Dietary exposure consists of exposures from 
food and drinking water.
    2. Food. In this assessment, K-1 Chemical has conservatively 
assumed that 100% of all soybeans and corn used for human consumption 
would contain residues of fluthiacet-methyl and all residues would be 
at the level of the proposed tolerances. The potential dietary exposure 
to fluthiacet-methyl was calculated on the basis of the proposed 
tolerance which is based on an limit of quantitation (LOQ) of 0.01 ppm 
in soybeans and 0.02 ppm in corn (2x LOQ). The anticipated residues in 
milk, meat and eggs resulting from feeding the maximum allowable amount 
of soybean and corn commodities to cattle and poultry were calculated, 
and the resulting quantities were well below the analytical method LOQ. 
Therefore, tolerances for milk, meat and eggs are not required. 
Assuming 100% crop treated values, the chronic dietary exposure of the 
general U.S. population to fluthiacet-methyl would correspond to 2.3% 
of the Reference dose (RfD).
    3. Drinking water. Although fluthiacet-methyl has a slight to 
medium leaching potential; the risk of the parent compound to leach to 
deeper soil layers is negligible under practical conditions in view of 
the fast degradation of the product. For example, the soil metabolism 
half-life was extremely short, ranging from 1.1 days under aerobic 
conditions to 1.6 days under anaerobic conditions. Even in the event of 
very heavy rainfalls immediately after application, which could lead to 
a certain downward movement of the parent compound, parent fluthiacet-
methyl continues to be degraded during the transport into deeper soil 
zones. Considering the low application rate of fluthiacet-methyl, the 
strong soil binding characteristics of fluthiacet-methyl and its 
degradates, and the rapid degradation of fluthiacet-methyl in the soil, 
there is no risk of ground water contamination with fluthiacet-methyl 
or its metabolites. Thus, aggregate risk of exposure to fluthiacet-
methyl does not include drinking water.
    4. Non-dietary exposure. Fluthiacet-methyl is not registered for 
any other use and is only proposed for use on agricultural crops. Thus, 
there is no potential for non-occupational exposure other than 
consumption of treated commodities containing fluthiacet-methyl 
residue.

D. Cumulative Effects

    A cumulative exposure assessment is not appropriate at this time 
because there is no information available to indicate that effects of 
fluthiacet-methyl in mammals would be cumulative with those of another 
chemical compound.

E. Safety Determination

    1. U.S. population. Using very conservative exposure assumptions 
coupled with toxicity data for fluthiacet-methyl, K-1 Chemical 
calculated that aggregate, chronic exposure to fluthiacet-methyl will 
utilize no more than 1.42% of the RfD for the U.S. population, 2.47% 
for nursing infants less than 1 year old, 5.09% for non-nursing infants 
greater than 1 year, and 3.5% for children ages 1-6 years. Because the 
actual anticipated residues are well below tolerance levels and the 
percent crop treated with fluthiacet-methyl is expected to be less than 
100% of planted corn, cotton or soybeans, a more realistic estimate is 
that dietary exposure will be many times less than the conservative 
estimate previously

[[Page 53662]]

noted (the margins of exposure (MOE) will be accordingly higher). 
Exposures below 100% of the RfD are generally not of concern because 
the RfD represents the level at or below which daily aggregate dietary 
exposure over a lifetime will not pose appreciable risks to human 
health. K-1 Chemical concludes that there is a reasonable certainty 
that no harm will result to infants and children from chronic aggregate 
exposure to residues of fluthiacet-methyl.
    Also the acute dietary risk to consumers will be far below any 
significant level; the lowest NOAEL from a short term exposure scenario 
comes from the teratology study in rabbits with a NOAEL of 300 mg/kg. 
This NOAEL is 2,000-fold higher than the chronic NOAEL which provides 
the basis for the RfD (see above). Acute dietary exposure estimates 
which are based on a combined food survey from 1989 to 1992 predict MOE 
of at least one million for 99.9% of the general population and for 
women of child bearing age. MOE of 100 or more are generally considered 
satisfactory. Therefore, K-1 Chemical concludes that there is a 
reasonable certainty that no harm will result from acute aggregate 
exposure to fluthiacet-methyl residues
    2. Infants and children. In assessing the potential for additional 
sensitivity of infants and children to residues of fluthiacet-methyl, 
K-1 Chemical considered data from developmental toxicity studies in the 
rat and rabbit and a 2-generation reproduction study in the rat. A 
slight delay in fetal maturation was observed in a teratology study in 
rabbits at a daily dose of 1,000 mg/kg. In a 2-generation reproduction 
study fluthiacet-methyl did not affect the reproductive performance of 
the parental animals or the physiological development of the pups. The 
NOAEL was 500 ppm for maternal animals and their offspring, which is 
50,000 fold higher than the RfD.

F. International Tolerances

     No international tolerances have been established under CODEX for 
fluthiacet-methyl.

3. Rohm and Haas Company

PP 8F5004 and 8F5006

    EPA has received pesticide petitions (PP 8F5004 and 8F5006) from 
Rohm and Haas Company, 100 Independence Mall West., 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 methoxyfenozide[benzoic acid, 3-methoxy-2-methyl-,2-
(3,5-dimethylbenzoyl)-2-91,1-dimethylethyl) hydrazide in or on the raw 
agricultural commodity cottonseed at 2.0 parts per million (ppm), 
cotton gin trash at 25 ppm, pome fruit at 1.25 ppm, meat, kidney, meat 
by-products and milk of cattle, goats, sheep, and hogs at 0.02 ppm and 
in fat and liver at 0.1 ppm. The tolerance expression for kidney and 
liver includes the glucuronide conjugate of methoxyfenozide (RH-1518). 
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 ofthe petition. 
Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

    1. Plant metabolism. The metabolism of methoxyfenozide in plants 
(apples,cotton, and grapes) is adequately understood for the purposes 
of these tolerances. The metabolism of methoxyfenozide in all crops was 
similar and involves cleavage of the methoxyl side chain to the free 
phenol, RH-117236,or oxidation of the alkyl substituents of the 
aromatic rings primarily at the benzylic positions. In all crops, 
parent compound comprised the majority of the total dosage. None of the 
metabolites were in excess of 10 of the total dosage.
    2. Analytical method. High performance liquid chromatographic 
(HPLC) analytical methods using ultraviolet (UV) or mass selective (MS) 
detection have been validated for cottonseed, cotton gin trash, 
cottonseed processed fractions, pome fruit, apple processed fractions 
and meat, kidney, liver, fat and milk. The methods involve extraction 
by blending with solvents, purification of the extracts by liquid-
liquid partitions and final purification of the residues using solid 
phase extraction column chromatography. The limit of quantitation (LOQ) 
is 0.01 parts per million (ppm) for cottonseed processed fractions 
(meal, hulls and oil), 0.025 ppm for cottonseed, 0.05 ppm for gin 
trash, 0.01 ppm for pome fruit and apple processed fractions (wet 
pomace and juice), 0.01 ppm for meat, kidney, liver, fat and milk. For 
residues of the gluronide conjugate metabolite of methoxyfenozide (RH-
1518), the limit of quantitation in liver and kidney is 0.02 ppm.
    3. Magnitude of residues. A total of twelve cotton residue trials 
were conducted in the U.S. with the 80WP formulation of INTREPID at a 
maximum seasonal rate of 2.0 lb. a.i./A (i.e., 5 applications at 0.4 
lb. a.i./A). The label pre-harvest interval (PHI) is 14 days. In all 
cases, cotton was harvested at 14-16 days after the last application. 
Methoxyfenozide residues in cottonseed ranged from 0.1-1.75 ppm. The 
average residue from all GAP trials is 0.5 0.40 ppm. 
Residues of methoxyfenozide in gin trash ranged from 3.84 to 22.3 ppm 
with an average of 12.1 6.35 ppm. Residues did not 
concentrate in meal, hulls and refined oil.
    4. Pome fruit. Six pears and twelve apples trials were conducted in 
1996 and 1997 with INTREPID 80WP at an application rate of 0.3 lb. AI/
acre for a total of six applications. Samples of fruit collected 14-15 
days after the last application. Residues of methoxyfenozide in apples 
ranged from 0.16 to 1.18 ppm and in pears from 0.26 to 0.93 ppm. The 
average residue in apples is 0.53 0.28 ppm and in pears is 
0.43 0.24 ppm. The combined apple and pear residue average 
is 0.50 0.26 ppm. Residues of methoxyfenozide did not 
concentrated in apple juice but did concentrate in wet apple pomace.
    5. Cattle feeding study. A 28 day feeding study was conducted in 
which dairy cows were fed daily doses of 0, 15, 45 and 150 ppm 
methoxyfenozide. Tissues and milk samples were collected analyzed using 
validated analytical methods. The analytes of concern included parent 
methoxyfenozide in all matrices and its metabolite, RH-1518, the 
glucuronic acid conjugate of the free phenol in kidney and liver. 
Overall, average methoxyfenozide residues (or sum of methoxyfenozide 
and RH-1518 residues for kidney and liver) were < 0.05 ppm in the 
tissues (fat, muscle and kidney) from the 45 ppm dose level except in 
liver (0.066 ppm). In milk, methoxyfenozide average residues were less 
than the LOQ, 0.01 ppm, at the 45 ppm dose levels.

B. Toxicological Profile

    1. Acute toxicity--methoxyfenozide has low acute toxicity. 
Methoxyfenozide was practically non-toxic by ingestion of a single oral 
dose in rats and mice (LD50 < 5,000 milligram/kilogram (mg/
kg)) and was practically non-toxic by dermal application 
(LD50 < 5,000 mg/kg). Methoxyfenozide was not significantly 
toxic to rats after a 4 hours inhalation exposure with an 
LC50 value of > 4.3 mg/L (highest attainable concentration), 
is not considered to be a primary eye irritant or a skin irritant and 
is not a dermal sensitizer. An acute neurotoxicity study in rats did 
not produce any neurotoxic or neuropathologic effects with a No

[[Page 53663]]

observed adverse effect level (NOAEL) > 2,000 mg/kg.
    2. Genotoxicty. Methoxyfenozide tested negative (non-mutagenic, 
non-genotoxic) in a battery of in vitro and in vivo assays, which 
included an Ames assay with and without metabolic activation, a CHO/
HGPRT assay, an in vitro chromosome aberration assay in CHO cells with 
and without a metabolic activation, an in vivo micronucleus assay in 
mouse bone marrow cells.
    3. Reproductive and developmental toxicity. NOAEL for developmental 
and maternal toxicity to methoxyfenozide were established at 1,000 
milligrams/kilogram/day (mg/kg/day) highest dose tested (HDT) in both 
the rat and rabbit. No signs of developmental toxicity were exhibited.
    In a 2-generation reproduction study in the rat, the reproductive/
developmental toxicity NOAEL of 1,552 mg/kg/day was 100-fold higher 
than the parental (systemic) toxicity NOAEL of 200 ppm (15.5 mg/kg/
day).
    4. Subchronic toxicity. The NOAEL in a 90-day rat feeding study was 
1,000 ppm (69.3 mg/kg/day for males, 72.4 mg/kg/day for females). The 
lowest-observed-effect-level (LOAEL) was 5,000 ppm (353 mg/kg/day for 
males, 379 mg/kg/day for females). Increased liver weight and liver 
histopathology were observed at the LOAEL of 5,000 ppm. Methoxyfenozide 
did not produce neurotoxic or neuropathologic effects when administered 
in the diets of rats for 3 months at concentrations up to and including 
the limit dose of 20,000 ppm (NOAEL = 1,318 mg/kg/day for males, 1,577 
mg/kg/day for females).
    i. In a 90-day feeding study with mice, the NOAEL was 2,500 ppm 
(428 and 589 mg/kg/day for males and females, respectively). The LOAEL 
was 7,000 ppm (1,149 and 1,742 mg/kg/day for males and females, 
respectively). Decreases in body weight gain (bwt/gain) were noted in 
both sexes of mice at the LOAEL of 7,000 ppm.
    ii. A 90 day dog feeding study gave a NOAEL of 3,000 ppm, the 
highest dose tested (HDT) (198 and 209 mg/kg/day for males and females, 
respectively). Extension of treatment of the low dose animals for 6 
weeks at 15,000 ppm (422 and 460 mg/kg/day for males and females, 
respectively) produced no signs of systemic toxicity.
    Methoxyfenozide did not produce toxicity in the rat when 
administered dermally for 4 weeks at doses up to and including the 
limit dose of 1,000 mg/kg/day. These findings correlate with the low 
dermal penetration observed with 14C-methoxyfenozide, 
formulated as the wettable powder, (i.e., after 24 hours 1-3% of the 
administered dose was systemically absorbed).
    5. Chronic toxicity--i. The NOAEL in a 1 year feeding study in dogs 
was 300 ppm (9.8 and 12.6 mg/kg/day for male and females, 
respectively). The LOAEL was 3,000 ppm (106 and 111 mg/kg/day for male 
and females, respectively) based on minimal hematological effects.
    ii. An 18 month mouse carcinogenicity study showed no signs of 
carcinogenicity at dosage levels up to and including 7,000 ppm (1,020 
and 1,354 mg/kg/day for male and females, respectively), HDT.
    iii. In a combined rat chronic/oncogenicity study, the NOAEL for 
chronic toxicity was 200 ppm (10.2 and 11.9 mg/kg/day for males and 
females, respectively) and the LOAEL was 8,000 ppm (411 and 491 mg/kg/
day for males and females, respectively). No carcinogenicity was 
observed at the dosage levels up to 20,000 ppm (1,045 and 1,248 mg/kg/
day for males and females, respectively).
    6. Animal metabolism. In toxicokinetic and metabolism studies in 
the rat, methoxyfenozide was rapidly absorbed following oral exposure 
with peak plasma levels occurring within 0.5 hour of administration. 
Methoxyfenozide does not bioaccumulate in that the compound is rapidly 
and almost completely eliminated within 24 hours. Methoxyfenozide was 
extensively metabolized in rats. Including parent compound, 32 
metabolites, of which 26 were identified, were isolated from the rat 
urine and feces. The primary pathway of methoxyfenozide metabolism 
involves demethylation of the A-ring methoxyl moiety to form the 
corresponding A-ring phenol, RH-117,236, which is readily conjugated 
with glucuronic acid to RH-1518. Hydroxylation on the B-ring methyl 
moieties is also an important metabolic pathway.
    7. Metabolite toxicology. Common metabolic pathways for 
methoxyfenozide have been identified in both plants (apple, cotton and 
grape), and animals (,goat, hen, rat). Extensive degradation and 
elimination of polar metabolites occurs in animals such that residues 
are unlikely to accumulate in humans or animals exposed to these 
residues through the diet. The rapid metabolism and excretion of 
methoxyfenozide in part accounts for the compound's overall low 
toxicity profile in animals. The main metabolite of methoxyfenozide in 
plants and animals, the A-ring phenol, RH-117,236, produced no toxicity 
in mice (LD50 > 5,000 mg/kg) and was negative when tested in 
the Ames mutagenic assay. Other metabolites of methoxyfenozide (e.g., 
glucuronides) would be expected to produce minimal to no toxicity given 
structure activity considerations.
    8. Endocrine disruption. Based on structure-activity information as 
well as the lack of developmental and reproductive toxicity, 
methoxyfenozide is unlikely to exhibit estrogenic activity. No 
indicators of estrogenic or other endocrine effects were observed in 
mammalian chronic studies or in mammalian and avian reproduction 
studies. Methoxyfenozide is within a class of chemistry 
(diacylhydrazines) that is not known to bind to mammalian steroid 
receptors. Overall, the weight of evidence provides no indication that 
methoxyfenozide has endocrine activity in vertebrates.

C. Aggregate Exposure

    1. Dietary exposure. Tolerances are proposed for the residues of 
methoxyfenozide in or cottonseed, cotton gin trash, pome fruit, apple 
pomace, and livestock commodities. Risk assessments were conducted by 
Rohm and Haas to assess dietary exposures and risks from 
methoxyfenozide as follows:
    2. Acute exposure and risk. No acute endpoint of concern was 
identified for methoxyfenozide and no acute risk assessment is 
required.
    3. Chronic exposure and risk. For chronic dietary risk assessment, 
the proposed tolerance values and anticipated (average) residues are 
used and the assumption that 100% of all cotton and pome fruit will 
contain residues of methoxyfenozide at the tolerance or anticipated 
residue levels. The Reference dose (RfD) used for the chronic dietary 
analysis is 0.1 mg/kg/day based on the NOAEL of 9.8-10.0 mg/kg/day from 
the rat and dogs chronic studies. Potential chronic exposures were 
estimated using NOVIGEN'S Dietary Exposure Evaluation Model (DEEM 
Version 5.03b) which uses USDA food consumption data from the 1989-1992 
survey. With the proposed tolerances and anticipated residue levels for 
methoxyfenozide, the percentage of the RfD utilized is as follows:

[[Page 53664]]



----------------------------------------------------------------------------------------------------------------
          Population Subgroups                     Tolerance Levels                  Anticipated Residues
----------------------------------------------------------------------------------------------------------------
                                                      Total % RfD                         Total %RfD
----------------------------------------------------------------------------------------------------------------
U.S. Population - 48 States.............                                 1.7                                 0.3
Nursing Infants < 1 year old............                               1.5.7                                 0.7
Non-Nursing Infants < 1 year old2.......                                19.0                                 1.7
Children 1-6 years old..................                                 6.8                                 1.3
Children 7-12 years old.................                                .2.7                                 0.7
----------------------------------------------------------------------------------------------------------------

    The chronic dietary risks from these uses do not exceed EPA's level 
of concern.
    4. Drinking water. Submitted environmental fate studies suggest 
that methoxyfenozide is moderately persistent and mobile, and could 
potentially leach to groundwater and runoff to surface water under 
certain environmental conditions. However, in terrestrial field 
dissipation and orchard dissipation studies, residues of 
methoxyfenozide showed minimal mobility and remained associated with 
the upper layers of soil. Foliar interception (up to 70% of the total 
dosage applied) by target crops reduces the ground level residues of 
methoxyfenozide.
    Acute and chronic exposures to methoxyfenozide in drinking water 
were estimated using the GEENEC V1.2 and SCI-GROW models, as directed 
in OPP's Interim Approach for Addressing Drinking Water Exposure. 
GEENEC is a highly conservative model used to estimate residue 
concentrations in surface water. SCI-GROW is an equally conservative 
model used to estimate residue concentrations in shallow, highly 
vulnerable ground water (i.e., sites with sandy soils and depth to 
ground water of 10 to 20 feet). As indicated in EPA's drinking water 
exposure guidance, a very small percentage of people in the U.S. would 
derive their drinking water from such sources. GEENEC (56 Day average) 
and SCI-GROW water exposure values for methoxyfenozide utilize 1% or 
less of the RfD for adults and children.
    There is no established Maximum Concentration Level (MCL) for 
residues of methoxyfenozide in drinking water. No drinking water health 
advisory levels have been established for methoxyfenozide. There is no 
entry for methoxyfenozide in the ``Pesticides in Groundwater Database'' 
(EPA 734-12-92-001, September 1992).
    5. Chronic exposure and risk. There are insufficient water-related 
exposure data to complete a comprehensive drinking water assessment for 
methoxyfenozide at this time. However, in order to mitigate the 
potential for methoxyfenozide to leach into groundwater or runoff to 
surface water, precautionary language has been incorporated into the 
proposed product label. Also, to the best of our knowledge, previous 
experience at EPA with more persistent and mobile pesticides for which 
there were available data to perform quantitative risk assessments 
demonstrated that drinking water exposure was typically a small 
percentage of the total dietary exposure. This observation holds even 
for pesticides detected in wells and drinking water at levels nearing 
or exceeding established MCLs. Considering the precautionary language 
on the label and our knowledge of previous experience with persistent 
chemicals, no risk from residues of methoxyfenozide in drinking water 
is anticipated.
    6. Non-dietary exposure. Methoxyfenozide is not currently 
registered for any indoor or outdoor residential uses; therefore, no 
non-dietary residential exposure is anticipated.

D. Cumulative Effects

    Cumulative exposure to substances with common mechanism of 
toxicity: The methodologies to resolve the complex scientific issues 
concerning common mechanism of toxicity in a meaningful way are not 
available at this time. EPA has begun a pilot process to study this 
issue further through the examination of particular classes of 
pesticides. The Agency hopes that the results of this pilot process 
will increase the Agency's scientific understanding of this question 
such that EPA will be able to develop and apply scientific principles 
for better determining which chemicals have a common mechanism of 
toxicity and evaluating the cumulative effects of such chemicals. The 
Agency anticipates, however, that even as its understanding of the 
science of common mechanisms increases, decisions on specific classes 
of chemicals will be heavily dependent on chemical specific data, much 
of which may not be presently available.
    Although at present the Agency does not know how to apply the 
information in its files concerning common mechanism issues to most 
risk assessments, there are pesticides for which the common mechanism 
issues can be resolved. These pesticides include pesticides that are 
toxicologically dissimilar to existing chemical substances (in which 
case the Agency can conclude that it is unlikely that a pesticide 
shares a common mechanism of activity with other substances) and 
pesticides that produce a common toxic metabolite (in which case common 
mechanism of activity will be assumed).
    At this time, no data are available to determine whether 
methoxyfenozide [benzoic acid, 3-methoxy-2-methyl-, 2-(3,5-
dimethylbenzoyl)-2-(1,1-dimethylethyl) hydrazide] has a common 
mechanism of toxicity with other substances. Thus, it is not 
appropriate to include this pesticide in a cumulative risk assessment. 
Unlike other pesticides for which EPA has followed a cumulative risk 
approach based on a common mechanism of toxicity, methoxyfenozide 
[benzoic acid, 3-methoxy-2-methyl-, 2-(3,5-dimethylbenzoyl)-2-(1,1-
dimethylethyl) hydrazide] does not produce a toxic metabolite produced 
by other substances. For the purposes of this tolerance action, 
therefore, methoxyfenozide [benzoic acid, 3-methoxy-2-methyl-, 2-(3,5-
dimethylbenzoyl)-2-(1,1-dimethylethyl) hydrazide] is assumed not to 
have a common mechanism of toxicity with other substances.

E. Safety Determination

    1. U.S. population--Acute exposure and risk. Since no acute 
endpoint of concern has been identified for methoxyfenozide, no acute 
risk assessment is required.
    2. Chronic exposure and risk. Using the conservative exposure 
assumptions described above and taking into account the completeness 
and reliability of the toxicity data, the percentage of the RfD that 
will be utilized by dietary (food only) exposure to residues of 
methoxyfenozide from the proposed tolerances is 1.7% (tolerance levels) 
and 0.3% (anticipated residues) for the U.S. population. Aggregate 
exposure (food and water) are not expected to exceed 100%. EPA 
generally has no concern for exposures below 100% of the RfD

[[Page 53665]]

because the RfD represents the level at or below which daily aggregate 
dietary exposure over a lifetime will not pose appreciable risks to 
human health. Rohm and Haas concludes that there is a reasonable 
certainty that no harm will result from aggregate exposure to 
methoxyfenozide residues to the U.S. population.
    3. Infants and children-- Safety factor for infants and children-- 
i. In general. The potential for additional sensitivity of infants and 
children to residues of methoxyfenozide are assessed using data from 
developmental toxicity studies in the rat and rabbit and 2-generation 
reproduction studies in the rat. The developmental toxicity studies are 
designed to evaluate adverse effects on the developing organism 
resulting from maternal pesticide exposure during gestation. 
Reproduction studies provide information relating to effects from 
exposure to the pesticide on the reproductive capability of mating 
animals and data on systemic toxicity.
    ii. Developmental toxicity studies-- Rats. In a developmental 
toxicity study in rats, the maternal (systemic) NOAEL was 1,000 mg/kg/
day HDT. The developmental (pup) NOAEL was > 1,000 mg/kg/day HDT).
    iii. Rabbits. In a developmental toxicity study in rats, the 
maternal (systemic) NOAEL was 1,000 mg/kg/day HDT. The developmental 
(pup) NOAEL was > 1,000 mg/kg/day HDT.
    iv. Reproductive toxicity study rats. In a multigeneration 
reproductive toxicity study in rats, the parental (systemic) NOAEL was 
15.5 mg/kg/day, based on liver effects at the LOAEL of 153 mg/kg/day. 
The reproductive (pup) NOAEL was 1,552 mg/kg/day HDT. No adverse 
reproductive effects were observed.
    v. Pre- and post-natal sensitivity--Pre-natal sensitivity. The 
developmental NOAELs of >1,000 mg/kg/day HDT from the developmental 
toxicity studies in rats and rabbits demonstrate that there is no 
developmental (prenatal) toxicity present for methoxyfenozide. 
Additionally, these developmental NOAELs are greater than 100-fold 
higher than the NOAEL of 9.8-10.0 mg/kg/day from the rat and dogs 
chronic studies which are the basis of the RfD.
    vi. Post-natal sensitivity. In the reproductive toxicity study in 
rats, the reproductive NOAEL (1,552 mg/kg/day) is about 100-fold higher 
than the parental NOAEL (15.5 mg/kg/day). These developmental and 
reproductive studies indicate that methoxyfenozide does not have 
additional pre- and post-natal sensitivity for infants and children in 
comparison to other exposed groups.
    vii. Acute exposure and risk. No acute endpoint was identified for 
methoxyfenozide, and therefore no acute risk assessment is required.
    viii. Chronic exposure and risk. For chronic dietary risk 
assessment, tolerances and anticipated residue values are used and the 
assumption that 100% of all cotton and pome fruit will contain residues 
at the tolerance or anticipated residue levels. The percentage RfD 
utilized from the proposed tolerances and anticipated residues is 
calculated using the Dietary Exposure Evaluation Model (Version 5.03b, 
licensed by Novigen Sciences Inc.) which uses USDA food consumption 
data from the 1989-1992 survey.
    With the proposed tolerances and anticipated residues for 
methoxyfenozide, the percentage of the RfD that will be utilized by 
dietary (food only) exposure to residues of methoxyfenozide is 9.0% 
(tolerance levels ) and 1.7% (anticipated residues) for non-nursing 
infants less than 1 year old. Aggregate exposure (food and water) are 
not expected to exceed 100%. Rohm and Haas concludes that there is a 
reasonable certainty that no harm will result from aggregate exposure 
to methoxyfenozide residues to non-nursing infants.

F. International Tolerances

    There are currently no CODEX, Canadian or Mexican maximum residue 
levels (MRLs) established for methoxyfenozide in cottonseed, gin trash, 
pome fruit, apple pomace, or livestock commodities so no harmonization 
issues are required for this action.

4. Valent U.S.A. Company

PP 8F5022

    EPA has received a pesticide petition (PP 8F5022) from Valent 
U.S.A. Company, 1333 North California Boulevard, Suite 600, Walnut 
Creek, CA 94596-8025., 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 pyriproxyfen, 
2-[ 1-methyl-2-(4-phenoxyphenoxy)ethoxy]pyridine in or on the raw 
agricultural commodity almond hulls at 2.0 parts per million (ppm), 
citrus fruits (crop group 10) at0.3 ppm, fruiting vegetables (crop 
group 8) at 0.1 ppm, tree nuts (crop group 14) at 0.02 ppm, and in the 
processed commodities citrus oil at 20 ppm and dried citrus pulp at 1.5 
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 metabolism-- Nature of the residues in food, feed and 
secondary residues. Metabolism of 14C-pyriproxyfen labelled 
in the phenoxyphenyl ring and in the pyridyl ring has been studied in 
cotton, apples, tomatoes, lactating goats, and laying hens (and rats). 
The major metabolic pathways in plants is aryl hydroxylation and 
cleavage of the ether linkage, followed by further metabolism into more 
polar products by further oxidation and/or conjugation reactions. 
However, the bulk of the radiochemical residue on RAC samples remained 
as parent. Comparing metabolites detected and quantified from apple, 
cotton, tomato, goat and hen (and rat) shows that there are no 
significant aglycones in plants which are not also present in the 
excreta or tissues of animals. The residue of concern is best defined 
as the parent, pyriproxyfen. Ruminant and poultry metabolism studies 
demonstrated that transfer of administered 14C-residues to 
tissues was low. Total 14C-residues in goat milk, muscle and 
tissues accounted for less than 2% of the administered dose, and were 
less than 1 parts per million (ppm) in all cases. In poultry, total 
14C residues in eggs, muscle and tissues accounted for about 
2.7% of the administered dose, and were less than 1 ppm in all cases 
except for gizzard.
    2. Analytical method--Priproxyfen and metabolites. Practical 
analytical methods for detecting and measuring residue levels of 
pyriproxyfen (and relevant metabolites) have been developed and 
validated in/on all appropriate agricultural commodities, respective 
processing fractions, milk, animal tissues, and environmental samples. 
The extraction methodology has been validated using aged radiochemical 
residue samples from metabolism studies. The methods have been 
validated in cottonseed, apples, soil, and oranges at independent 
laboratories. EPA has successfully validated the analytical method for 
analysis of cottonseed raw agricultural commodity. The limit of 
detection of pyriproxyfen in the methods is 0.01 ppm which will allow 
monitoring of food with residues at the levels proposed for the 
tolerances.
    3. Magnitude of residues--i. Almonds. Data from six field trials in 
almonds all conducted in 1997 in California showed that at the proposed 
maximum

[[Page 53666]]

application rate there were no detectable residues in nutmeats (>0.01 
ppm pyriproxyfen). In a single sample at twice the maximum rate, 
pyriproxyfen was measured just at the limit of detection (0.01 ppm). 
Almond hulls are exposed to application and are used as ruminant feed. 
In/on almond hulls, the average measured residue was 0.78 ppm (n = 
12,n-1 = 0.41 ppm) pyriproxyfen. A tolerance of 
0.02 ppm in/on tree nutmeats and 2.0 in/on almond hulls is proposed. 
The proposed nutmeat tolerance, twice the limit of detection, is 
completely consistent with previously submitted data on walnut 
nutmeats, and supports the proposed tree nut crop group tolerance.
    ii. Citrus. Thirteen field trials in oranges were conducted in 1996 
through 1998. Similarly, six field trials were conducted for lemons, 
and seven field trials were conducted for grapefruit. The proposed use 
pattern for the three citrus crops is identical. The analytical data 
show that the average measured residue in/on orange samples was 0.155 
ppm (n = 26, n-1 = 0.045 ppm) pyriproxyfen. 
Similarly, the analytical data show that the average measured residue 
in/on lemon samples was 0.128 ppm (n = 12, n-1 = 
0.073 ppm), and in/on grapefruit samples was 0.123 ppm (n = 14, 
n-1 = 0.025 ppm), pyriproxyfen. In one unfrozen 
sample of oranges, peel was analyzed separately from pulp demonstrating 
that the residue of pyriproxyfen is on the exterior of the citrus 
fruit. A processing study in oranges demonstrated that pyriproxyfen 
concentrated in orange oil (74-fold) and in dried orange pulp (6.3-
fold) but did not concentrate in orange juice (>0.03-fold). The highest 
average residue (HAR) from field trials was 0.22 ppm. All these data 
support proposed tolerances for pyriproxyfen in/on citrus fruit crop 
group at 0.3 ppm, citrus oil at 20 ppm, and dried citrus pulp at 1.5 
ppm
    iii. Peppers. Data from ten field trials in bell and non-bell 
peppers conducted in 1997 showed that the average measured residue was 
0.025 ppm (n = 20, n-1 = 0.24 ppm) pyriproxyfen. 
These data along with tomato data support a proposed fruiting vegetable 
crop group tolerance of 0.1 ppm.
    iv. Tomatoes. Data from thirteen field trials in tomatoes conducted 
in 1996 and 1997 showed that the average measured residue was 0.016 ppm 
(n = 26, n-1 = 0.010 ppm) pyriproxyfen. The 
proposed use pattern is identical to that proposed for peppers and 
allows a maximum seasonal application totaling 0.176 lb. ai/acre (80 
grams ai./acre), with a maximum single application rate of 0.066 lb. 
ai./acre (30 grams ai./acre), at a minimum 7 days interval between 
applications, and with the last application no less than 14 days before 
harvest. A processing study demonstrated that pyriproxyfen did not 
concentrate in tomato puree or tomato paste and no processed product 
tolerances are necessary. These data along with pepper data support a 
proposed fruiting vegetable crop group tolerance of 0.1 ppm.
    v. Secondary residues. Using proposed tolerances to calculate the 
maximum feed exposure to fed animals, and using the very low potential 
for residue transfer documented in the milk cow feeding residue study, 
finite, detectable secondary residues in animal tissues, milk, and eggs 
are not expected. Therefore, tolerances are not proposed for these 
commodities.
    vi. Rotational crops. The results of a confined rotational crops 
accumulation study indicate that no rotational crop planting 
restrictions or rotational crop tolerances are required.

B. Toxicological Profile

    1. Acute toxicity. The acute toxicity of technical grade 
pyriproxyfen is low by all routes. The compound is classified as 
Category III for acute dermal and inhalation toxicity, and Category IV 
for acute oral toxicity, and skin/eye irritation. Pyriproxyfen is not a 
skin sensitizing agent.
    2. Genotoxicty--pyriproxyfen does not present a genetic hazard. 
Pyriproxyfen was negative in the following tests for mutagenicity: Ames 
assay with and without S9, in vitro unscheduled DNA synthesis in HeLa 
S3 cells, in vitro gene mutation in V79 Chinese hamster cells, and in 
vitro chromosomal aberration with and without S9 in Chinese hamster 
ovary cells.
    3. Reproductive and developmental toxicity. Pyriproxyfen is not a 
developmental or reproductive toxicant. Developmental toxicity studies 
have been performed in rats and rabbits, and multigenerational effects 
on reproduction were tested in rats. These studies have been reviewed 
and found to be acceptable to the Agency.
    In the developmental toxicity study conducted with rats, technical 
pyriproxyfen was administered by gavage at levels of 0, 100, 300, and 
1,000 milligram kilogram body weight day (mg/kg/bwt/day) during 
gestation days 7-17. Maternal toxicity (mortality, decreased body 
weight gain and food consumption, and clinical signs of toxicity) was 
observed at doses of 300 mg/kg/bwt/day and greater. The maternal no 
observed adverse effect level (NOAEL) was 100 mg/kg/bwt/day. A 
transient increase in skeletal variations was observed in rat fetuses 
from females exposed to 300 mg/kg/bwt/day and greater. These effects 
were not present in animals examined at the end of the postnatal 
period, therefore, the NOAEL for prenatal developmental toxicity was 
100 mg/kg/bwt/day. An increased incidence of visceral and skeletal 
variations was observed postnatally at 1,000 mg/kg/bwt/day. The NOAEL 
for postnatal developmental toxicity was 300 mg/kg/bwt/day.
    In the developmental toxicity study conducted with rabbits, 
technical pyriproxyfen was administered by gavage at levels of 0, 100, 
300, and 1,000 mg/kg/bwt/day during gestation days 6-18. Maternal 
toxicity (clinical signs of toxicity including one death, decreased 
body weight gain and food consumption, and abortions or premature 
deliveries) was observed at oral doses of 300 mg/kg bw/day or higher. 
The maternal NOEL was 100 mg/kg bw/day. No developmental effects were 
observed in the rabbit fetuses. The NOAEL for developmental toxicity in 
rabbits was 1,000 mg/kg/bwt/day.
    In the rat reproduction study, pyriproxyfen was administered in the 
diet at levels of 0, 200, 1,000, and 5,000 ppm through 2-generations of 
rats. Adult systemic toxicity (reduced body weights, liver and kidney 
histopathology, and increased liver weight) was produced at the 5,000 
ppm dose (453 mg/kg/bwt/day in males, 498 mg/kg/bwt/day in females) 
during the pre-mating period. The systemic NOAEL was 1,000 ppm (87 mg/
kg/bwt/day in males, 96 mg/kg/bwt/day in females). No effects on 
reproduction were produced at 5,000 ppm, the highest dose tested (HDT).
    4. Subchronic toxicity. Subchronic oral toxicity studies conducted 
with pyriproxyfen technical in the rat, mouse and dog indicate a low 
level of toxicity. Effects observed at high dose levels consisted 
primarily of decreased body weight gain; increased liver weights; 
histopathological changes in the liver and kidney; decreased red blood 
cell counts, hemoglobin and hematocrit; altered blood chemistry 
parameters; and, at 5,000 and 10,000 ppm in mice, a decrease in 
survival rates. The NOAELs from these studies were 400 ppm (23.5 mg/kg/
bwt/day for males, 27.7 mg/kg/bwt/day for females) in rats, 1,000 ppm 
(149.4 mg/kg/bwt/day for males, 196.5 mg/kg/bwt/day for females) in 
mice, and 100 mg/kg/bwt/day in dogs.
    In a 4 week inhalation study of pyriproxyfen technical in rats, 
decreased body weight and increased

[[Page 53667]]

water consumption were observed at 1,000 mg/m3. The NOAEL in 
this study was 482 mg/m3.
    A 21 day dermal toxicity study in rats with pyriproxyfen technical 
did not produce any signs of dermal or systemic toxicity at 1,000 mg/
kg/bwt/day, the HDT. In a 21 day dermal study conducted with KNACK. 
Insect Growth Regulator the test material produced a NOAEL of 1,000 mg/
kg/bwt/day (HDT) for systemic effects, and a NOAEL for skin irritation 
of 100 mg/kg/bwt/day.
    5. Chronic toxicity. Pyriproxyfen technical has been tested in 
chronic studies with dogs, rats and mice. EPA has established a 
reference dose (RfD) for pyriproxyfen of 0.35 mg/kg/bwt/day, based on 
the NOAEL in female rats from the 2 year chronic/oncogenicity study. 
Effects cited by EPA in the RfD Tracking Report include negative trend 
in mean red blood cell volume, increased hepatocyte cytoplasm and 
cytoplasm:nucleus ratios, and decreased sinusoidal spaces.
    Pyriproxyfen is not a carcinogen. Studies with pyriproxyfen have 
shown that repeated high dose exposures produced changes in the liver, 
kidney and red blood cells, but did not produce cancer in test animals. 
No oncogenic response was observed in a rat 2 year chronic feeding/
oncogenicity study or in a 78 week study on mice. The oncogenicity 
classification of pyriproxyfen is ``E'' (no evidence of carcinogenicity 
for humans).
    Pyriproxyfen technical was administered to dogs in capsules at 
doses of 0, 30, 100, 300 and 1,000 mg/kg/bwt/day for 1 year. Dogs 
exposed to dose levels of 300 mg/kg/bwt/day or higher showed overt 
clinical signs of toxicity, elevated levels of blood enzymes and liver 
damage. The NOAEL in this study was 100 mg/kg/bwt/day.
    Pyriproxyfen technical was administered to mice at doses of 0, 120, 
600 and 3,000 ppm in diet for 78 weeks. The NOAEL for systemic effects 
in this study was 600 ppm (84 mg/kg/bwt/day in males, 109.5 mg/kg/bwt/
day in females), and a lowest observed adverse effect level (LOAEL) of 
3,000 ppm (420 mg/kg/bwt/day in males, 547 mg/kg/bwt/day in females) 
was established based on an increase in kidney lesions.
    In a 2 year study in rats, pyriproxyfen technical was administered 
in the diet at levels of 0, 120, 600, and 3,000 ppm. The NOAEL for 
systemic effects in this study was 600 ppm (27.31 mg/kg/bwt/day in 
males, 35.1 mg/kg/bwt/day in females). A LOAEL of 3,000 ppm (138 mg/kg/
bwt/day in males, 182.7 mg/kg/ bwt/day in females) was established 
based on a depression in body weight gainin females.
    6. Animal metabolism. The absorption, tissue distribution, 
metabolism and excretion of 14C-labeled pyriproxyfen were 
studied in rats after single oral doses of 2 or 1,000 mg/kg/bwt 
(phenoxyphenyl and pyridyl label), and after a single oral dose of 2 
mg/kg/bwt (phenoxyphenyl label only) following 14 daily oral doses at 2 
mg/kg/bwt of unlabelled material. For all dose groups, most (88-96%) of 
the administered radiolabel was excreted in the urine and feces within 
2 days after radiolabeled test material dosing, and 92-98% of the 
administered dose was excreted within 7 days. 7 days after dosing, 
tissue residues were generally low, accounting for no more than 0.3% of 
the dosed 14C. Radiocarbon concentrations in fat were the 
higher than in other tissues analyzed. Recovery in tissues over time 
indicates that the potential for bioaccumulation is minimal. There were 
no significant sex or dose-related differences in excretion or 
metabolism.
    7. Metabolite toxicology. Metabolism studies of pyriproxyfen in 
rats, goats and hens, as well as the fish bioaccumulation study 
demonstrate that the parent is very rapidly metabolized and eliminated. 
In the rat, most (88-96%) of the administered radiolabel was excreted 
in the urine and feces within 2 days of dosing, and 92-98% of the 
administered dose was excreted within 7 days. Tissue residues were low 
7 days after dosing, accounting for no more than 0.3% of the dosed 
14C. Because parent and metabolites are not retained in the 
body, the potential for acute toxicity from in situ formed metabolites 
is low. The potential for chronic toxicity is adequately tested by 
chronic exposure to the parent at the MTD and consequent chronic 
exposure to the internally formed metabolites.
    Seven metabolites of pyriproxyfen, 4'-OH-pyriproxyfen, 5''-OH-
pyriproxyfen, desphenyl-pyriproxyfen, POPA, PYPAC, 2-OH-pyridine and 
2,5-diOH-pyridine, have been tested for mutagenicity (Ames) and acute 
oral toxicity to mice. All seven metabolites were tested in the Ames 
assay with and without S9 at doses up to 5,000 micro-grams per plate or 
up to the growth inhibitory dose. The metabolites did not induce any 
significant increases in revertant colonies in any of the test strains. 
Positive control chemicals showed marked increases in revertant 
colonies. The acute toxicity to mice of 4'-OH-pyriproxyfen, 5''-OH-
pyriproxyfen, desphenyl-pyriproxyfen, POPA, and PYPAC did not appear to 
markedly differ from pyriproxyfen, with all metabolites having acute 
oral LD50 values greater than 2,000 mg/kg/bwt. The two 
pyridines, 2-OH-pyridine and 2,5-diOH-pyridine, gave acute oral 
LD50 values of 124 (male) and 166 (female) mg/kg/bwt, and 
1,105 (male) and 1,000 (female) mg/kg/bwt, respectively.
    8. Endocrine disruption. Pyriproxyfen is specifically designed to 
be an insect growth regulator and is known to produce juvenoid effects 
on arthropod development. However, this mechanism-of-action in target 
insects and other some arthropods has no relevance to any mammalian 
endocrine system. While specific tests, uniquely designed to evaluate 
the potential effects of pyriproxyfen on mammalian endocrine systems 
have not been conducted, the toxicology of pyriproxyfen has been 
extensively evaluated in acute, sub-chronic, chronic, developmental, 
and reproductive toxicology studies including detailed histopathology 
of numerous tissues. The results of these studies show no evidence of 
any endocrine-mediated effects and no pathology of the endocrine 
organs. Consequently, it is concluded that pyriproxyfen does not 
possess estrogenic or endocrine disrupting properties applicable to 
mammals.

C. Aggregate Exposure

    1. Dietary exposure. An evaluation of acute and chronic dietary 
exposure to include drinking water has been performed for the U.S. 
population and various sub-populations including infants and children. 
Because of the lack of identified toxic endpoints of concern for acute 
dietary exposure, the results of the acute evaluations are not reported 
in this analysis.
    2. Food. Chronic dietary exposure to pyriproxyfen residues was 
calculated for the U.S. population and 26 population subgroups assuming 
tolerance level residues and 100% of the crop treated. The results from 
several representative subgroups are listed below. Chronic dietary 
exposure was at or below 0.22 % of the reference dose with pome fruits, 
fruiting vegetables and citrus the commodities contributing the most to 
chronic exposure. Generally speaking, the Agency has no cause for 
concern if total residue contribution for published and proposed 
tolerances is less than 100% of the RfD.
    Tier I Calculated Chronic Dietary Exposures to the total U.S. 
Population and Selected Sub-Populations to Pyriproxyfen Residues in 
Food

[[Page 53668]]



----------------------------------------------------------------------------------------------------------------
           Population Subgroup                         Exposure                           Percent of
----------------------------------------------------------------------------------------------------------------
                                                    (mg/kg/bw/day)                            RfD
----------------------------------------------------------------------------------------------------------------
Total U.S. Population (all seasons).....                            0.000237                               0.067
Females (13+/Nursing)...................                            0.000310                               0.089
Females (20+ years, not preg. or nursing                            0.000188                               0.054
Children (1-6 Years)....................                            0.000544                               0.154
All Infants (<1 Year Old)...............                            0.000629                               0.180
Non-Nursing Infants (<1 Year Old).......                            0.000771                               0.220
Nursing Infants (<1 Year Old)...........                            0.000293                               0.084
----------------------------------------------------------------------------------------------------------------

    Acute dietary risk assessments are performed for a food use 
pesticide if a toxicological study has indicated the possibility of an 
effect of concern occurring as the result of a 1 day or single 
exposure. No acute dietary endpoint and dose was identified in the 
toxicology data base for pyriproxyfen, therefore the Agency has 
concluded that there is a reasonable certainty of no harm from acute 
dietary exposure.
    3. Drinking water. Since pyriproxyfen is applied outdoors to 
growing agricultural crops, the potential exists for pyriproxyfen or 
its metabolites to reach ground or surface water that may be used for 
drinking water. Because of the physical properties of pyriproxyfen, it 
is unlikely that pyriproxyfen or its metabolites can leach to potable 
groundwater. To quantify potential exposure from drinking water, 
surface water concentrations for pyriproxyfen were estimated using 
GENEEC 1.3. The average 56 day concentration predicted in the simulated 
pond water was 0.16 ppb. Using standard assumptions about body weight 
and water consumption, the chronic exposure to pyriproxyfen from this 
drinking water would be 4.57 x 10-6 and 1.6 x 
10-5 mg/kg/bwt/day for adults and children, respectively; 
0.0046 percent of the RfD (0.35 mg/Kg/day) for children. Based on this 
worse case analysis, the contribution of water to the dietary risk is 
negligible.
    4. Non-dietary exposure. Pyriproxyfen is the active ingredient in 
numerous registered products for household use -- primarily for indoor, 
non-food applications by consumers. The consumer uses of pyriproxyfen 
typically do not involve chronic exposure. Instead, consumers are 
exposed intermittently to a particular product (e.g., pet care pump 
spray) containing pyriproxyfen. Since pyriproxyfen has a relatively 
short elimination half-life, cumulative toxicological effects resulting 
from bioaccumulation are not plausible following short-term, 
intermittent exposures. Further, pyriproxyfen is short-lived in the 
environment and this indoor domestic use of pyriproxyfen provides only 
relatively short-term reservoirs. Thus, consumer use of these products 
results in acute and short term intermittent exposures. No acute 
dermal, or inhalation dose or endpoint was identified in the toxicity 
data for pyriproxyfen. Similarly, doses and endpoints were not 
identified for short and intermediate term dermal or inhalation 
exposure to pyriproxyfen. The Agency has concluded that there are 
reasonable certainties of no harm from acute, short term, and 
intermediate term dermal and inhalation occupational and residential 
exposures due to the lack of significant toxicological effects 
observed. Thus, no detailed exposure and risk analyses for non-dietary 
exposures to pyriproxyfen are necessary.

D Cumulative Effects

    Section 408(b)(2)(D)(v) requires that the Agency must consider 
``available information'' concerning the cumulative effects of a 
particular pesticide's residues and ``other substances that have a 
common mechanism of toxicity''. Available information in this context 
include not only toxicity, chemistry, and exposure data, but also 
scientific policies and methodologies for understanding common 
mechanisms of toxicity and conducting cumulative risk assessments. For 
most pesticides, although the Agency has some information in its files 
that may turn out to be helpful in eventually determining whether a 
pesticide shares a common mechanism of toxicity with any other 
substances, EPA does not at this time have the methodologies to resolve 
the complex scientific issues concerning common mechanism of toxicity 
in a meaningful way.
    There are no other pesticidal compounds that are structurally 
related to pyriproxyfen and have similar effects on animals. In 
consideration of potential cumulative effects of pyriproxyfen and other 
substances that may have a common mechanism of toxicity, there are 
currently no available data or other reliable information indicating 
that any toxic effects produced by pyriproxyfen would be cumulative 
with those of other chemical compounds. Thus, only the potential risks 
of pyriproxyfen have been considered in this assessment of aggregate 
exposure and effects.
    Valent will submit information for EPA to consider concerning 
potential cumulative effects of pyriproxyfen consistent with the 
schedule established by EPA at 62 FR 42020 (Aug. 4, 1997) and other 
subsequent EPA publications pursuant to the Food Quality Protection 
Act.

E. Safety Determination

    1. U.S. population--Chronic dietary exposure and risk-- Adult sub-
populations. Using the Tier I dietary exposure assessment procedures 
described above for pyriproxyfen, calculated chronic dietary exposure 
resulting from residue exposure from existing and proposed uses of 
pyriproxyfen is minimal. The estimated chronic dietary exposure from 
food for the overall U.S. population and many non-child/infant 
subgroups is from 0.000175 to 0.000310 mg/kg/bwt/day, 0.05 to 0.089% of 
the RfD. Addition of the small but worse case potential chronic 
exposure from drinking water (calculated above) increases exposure by 
only 4.57 x 10 -6 mg/kg/bwt/day and does not change the 
maximum occupancy of the RfD significantly. Generally, the Agency has 
no cause for concern if total residue contribution is less than 100% of 
the RfD. It can be concluded that there is a reasonable certainty that 
no harm will result to the overall U.S. population and many non-child/
infant subgroups from aggregate, chronic exposure to pyriproxyfen 
residues.
    2. Acute dietary exposure and risk-- Adult sub-populations. An 
acute dietary dose and endpoint was not identified. Thus, the risk from 
acute aggregate exposure is considered to be negligible. Non-Dietary 
Exposure and Aggregate Risk -- Adult Sub-Populations: Acute, short 
term, and intermediate term dermal and inhalation risk assessments for 
residential exposure are not required due to the lack of significant 
toxicological effects observed.
    3. Infants and children--i. Safety factor for infants and children. 
In

[[Page 53669]]

assessing the potential for additional sensitivity of infants and 
children to residues of pyriproxyfen, FFDCA section 408 provides that 
EPA shall apply an additional margin of safety, up to ten-fold, for 
added protection for infants and children in the case of threshold 
effects unless EPA determines that a different margin of safety will be 
safe for infants and children.
    The toxicological data base for evaluating pre- and post-natal 
toxicity for pyriproxyfen is complete with respect to current data 
requirements. There are no special pre- or post-natal toxicity concerns 
for infants and children, based on the results of the rat and rabbit 
developmental toxicity studies or the 2-generation reproductive 
toxicity study in rats. Valent concludes that reliable data support use 
of the standard 100-fold uncertainty factor and that an additional 
uncertainty factor is not needed for pyriproxyfen to be further 
protective of infants and children.
    ii. Chronic dietary exposure and risk-- Infants and children. Using 
the conservative Tier I exposure assumptions described above, the 
percentage of the RfD that will be utilized by chronic dietary (food 
only) exposure to residues of pyriproxyfen ranges from 0.000293 mg/kg/
bwt/day for Nursing Infants (<1 year old), up to 0.000771 mg/kg/bwt/day 
for Non-Nursing Infants (<1 year old), 0.084 to 0.220% of the RfD, 
respectively. Adding the worse case potential incremental exposure to 
infants and children from pyriproxyfen in drinking water (1.6 x 10 
-5 mg/kg/bwt/day) does not materially increase the 
aggregate, chronic dietary exposure and only increases the occupancy of 
the RfD by 0.0046% to 0.225% for Non-Nursing Infants (<1 year old). EPA 
generally has no concern for exposures below 100% of the RfD because 
the RfD represents the level at or below which daily aggregate dietary 
exposure over a lifetime will not pose appreciable risks to human 
health. It can be concluded that there is a reasonable certainty that 
no harm will result to infants and children from aggregate, chronic 
exposure to pyriproxyfen residues.
    iii. Acute dietary exposure and risk-- Infants and children. An 
acute dietary dose and endpoint was not identified. Thus, the risk from 
acute aggregate exposure is considered to be negligible. Non-Dietary 
Exposure and Aggregate Risk -- Infants and Children: Acute, short term, 
and intermediate term dermal and inhalation risk assessments for 
residential exposure are not required due to the lack of significant 
toxicological effects observed.

F. International Tolerances

    Pyriproxyfen is a New Compound scheduled for Toxicological and 
Residue evaluations at the 1999 JMPR. Therefore, there are no presently 
existing Codex MRLs for pyriproxyfen.
[FR Doc. 98-26782 Filed 10-5-98; 8:45 am]
BILLING CODE 6560-50-F