[Federal Register Volume 63, Number 231 (Wednesday, December 2, 1998)]
[Notices]
[Pages 66535-66540]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-31683]


-----------------------------------------------------------------------

ENVIRONMENTAL PROTECTION AGENCY

[PF-847; FRL-6043-2]


Notice of Filing of Pesticide Petitions

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

-----------------------------------------------------------------------

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-847, must 
be received on or before January 4, 1999.
ADDRESSES: By mail submit written comments to: Public Information and 
Records Branch (7502C), Information Resources and Services Division, 
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 (CBI) 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 
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. 119 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:

------------------------------------------------------------------------
                                   Office location/
        Product Manager            telephone number          Address
------------------------------------------------------------------------
Joanne I. Miller (PM 13)......  Rm. 237, CM #2, 703-    1921 Jefferson
                                 305-6224, e-mail:       Davis Hwy,
                                 M[email protected]   Arlington, VA
                                 .                       22202
Cynthia Giles-Parker (PM 22)..  Rm. 247, CM #2, 703-    Do.
                                 305-7740, e-mail:
                                 giles-
                                 [email protected]
                                 v.
------------------------------------------------------------------------


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 raw 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, as well as the public version, 
has been established for this notice of filing under docket control 
number PF-847 (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''.

[[Page 66536]]

    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. Comment and data 
will also be accepted on disks in Wordperfect 5.1/6.1 file format or 
ASCII file format. All comments and data in electronic form must be 
identified by the docket control number PF-847 and appropriate petition 
number. Electronic comments on this notice may be filed online at many 
Federal Depository Libraries.

    Authority: 21 U.S.C. 346a.

List of Subjects

    Environmental protection, Agricultural commodities, Food additives, 
Feed additives, Pesticides and pests, Reporting and recordkeeping 
requirements.

    Dated: November 13, 1998.

James Jones,
Director, Registration Division, Office of Pesticide Programs.

Summaries of Petitions

    Below petitioner summaries of the pesticide petitions are printed 
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. BASF Corporation

PP 7F4870

    EPA has received a pesticide petition (PP 7F4870) from BASF 
Corporation, P.O. Box 13528, Research Triangle Park, North Carolina 
27709-3528 proposing pursuant to section 408(d) of the Federal Food, 
Drug and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 
180 by establishing a tolerance for residues of quinclorac (3,7-
dichloro-8-quinolone carboxylic acid), in or on the raw agricultural 
commodity wheat and sorghum raw agricultural and food/feed commodities: 
0.5 parts per million (ppm) in or on wheat grain, 0.1 ppm in or on 
wheat straw, 1.0 ppm in or on wheat forage, 0.5 ppm in or on wheat hay, 
1.0 ppm in or on wheat bran, 1.5 ppm in or on wheat germ, 0.75 ppm in 
or on wheat shorts, 0.5 ppm in or on sorghum grain, 0.2 ppm in or on 
sorghum forage and 0.05 ppm in or on sorghum fodder. EPA has determined 
that the petition contains data or information regarding the elements 
set forth in section 408(d)(2) of the FFDCA; however, EPA has not fully 
evaluated the sufficiency of the submitted data at this time or whether 
the data supports granting of the petition. Additional data may be 
needed before EPA rules on the petition.

A. Residue Chemistry

    1. Plant and animal metabolism. The metabolism of quinclorac in 
plants and animals is well understood. Based on a nature of the residue 
study in wheat and supported by similar studies in rice and sorghum, 
the residue of concern from quinclorac use in non-oily grains consists 
only of the parent compound.
    2. Analytical method. An adequate analytical method for enforcement 
of the tolerances exists. The analytical method used for quantitative 
determinations was designed to measure quinclorac residues present as 
the parent compound.
    3. Magnitude of residues --(i) Raw agricultural commodities. Crop 
field trials were conducted in wheat and sorghum and treatments were 
made at the maximum proposed label rate. The maximum amount of 
quinclorac residue found in wheat and sorghum raw agricultural 
commodities are: wheat forage 0.88 ppm, wheat hay 032 ppm, wheat grain 
0.25 ppm, wheat straw 0.08 ppm, sorghum forage 0.15 ppm, sorghum grain 
0.26 ppm, sorghum fodder 0.05 ppm.
    (ii) Processed fractions. Processing studies were conducted for 
both wheat and sorghum to determine whether quinclorac residues 
concentrate during the commercial processing of these commodities. In 
sorghum, no concentration of residues was found in the production of 
flour and starch. In wheat, no concentration was found in the 
production of middlings and flour. Quinclorac residues concentrated 2-
fold in the production of bran, 3-fold in the production of germ, and 
only slightly, 1.3-fold, in shorts. No additional data were needed in 
support of residues in meat, milk, poultry, and eggs. Maximum residue 
levels in wheat and sorghum raw agricultural commodities and process 
fractions were well below levels of current rice tolerances (5 ppm for 
grain, 12 ppm for straw, and 15 ppm for bran) which originally dictated 
the animal feeding study dosing levels and subsequent setting of animal 
product tolerances.

B. Toxicological Profile

    1. Acute toxicity. Based on available acute toxicity data 
quinclorac does not pose any acute toxicity risks. Several acute 
toxicology studies place technical-grade quinclorac in Toxicity 
Category III for acute oral, acute dermal, acute inhalation toxicity, 
and for eye irritation. Technical 3,7-dichloro-8-quinoline carboxylic 
acid is in category IV for primary dermal irritation and is a skin 
sensitizer. The currently registered end use formulations of quinclorac 
(50% wettable powder and 75% dry flowable formulations) have tested 
negative for skin sensitization.
    2. Chronic feeding -- Nonrodent. A 1-year feeding study in dogs fed 
0, 34, 142, and 513 (males) and 0, 35, 140, and 469 (females) 
milligrams/kilogram/day (mg/kg/day) resulted in a No Observed Adverse 
Effect Level (NOAEL) of 140 mg/kg/day based on reduced body weight 
gains, adverse effect on food efficiency, hematological and clinical 
chemistry values, increased liver and kidney weights, and microscopic 
findings in liver and kidneys at 513 mg/kg/day (males) and 469 mg/kg/
day (females), the highest dosages tested (HDT).
    3. Chronic feeding/oncogenicity - Rats. A chronic feeding/
carcinogenicity study in rats fed dosages of 1, 56, 186, 385, and 487 
mg/kg/day (males) and 0, 60, 235, 478, and 757 mg/kg/day (females) 
resulted in a NOAEL of 478 mg/kg/day (females) and 385 mg/kg/day 
(males) based on slight decreases in weight for females at 757 mg/kg/
day (HDT) and an equivocal (uncertain) increase in acinar cell 
hyperplasia of the pancreas in males at 487 mg/kg/day (HDT). There were 
no carcinogenic effects noted for female rats under the conditions of 
the study up to 757 mg/kg/day (HDT).
    4. Oncogenicity - Mice. A carcinogenic study in mice fed dosages of 
0, 37.5, 150, 600, and 1,200 mg/kg/day resulted in no carcinogenic 
effects observed under the conditions of the study up to and including 
1,200 mg/kg/day (HDT) and a systemic NOAEL of 37.5 mg/kg/day based on a 
reduction of body weight at 150 mg/kg/day.
    5. Teratology - Rats. A developmental study in rats fed dosages of 
0, 24.4, 146, and 438 mg/kg/day (HDT) resulted in developmental 
toxicity NOAEL of 438 mg/kg/day and a maternal toxicity NOAEL of 146 
mg/kg/day based on reduced food consumption, increased water intake, 
and mortality at 438 mg/kg/day (HDT). Under the conditions of this 
study, quinclorac did not produce any sign of embryo/fetal toxicity and

[[Page 66537]]

did not alter fetal morphological development.
    6. Teratology - Rabbits. A developmental study in rabbits fed 
dosages of 0, 70, 200, and 600 mg/kg/day resulted in a developmental 
toxicity NOAEL of 200 mg/kg/day based on an increase in resorptions and 
postimplantation loss; a decrease in the number of live fetuses and 
decreased fetal body weights at the 600 mg/kg/day dose level (HDT). At 
all other treatment levels no embryo/fetal toxicity was observed. The 
maternal toxicity NOAEL is 70 mg/kg/day based on decreased body weight 
gain and food consumption at 200 mg/kg/day; and increased water 
consumption, increased mortality, and discoloration of the kidney at 
600 mg/kg/day.
    7. Two-generation reproduction - Rats. A 2-generation reproduction 
study with rats fed dosages of 0, 50, 200, and 600 mg/kg/day resulted 
in a reproductive NOAEL of 200 mg/kg/day based on reduced pup viability 
and pup weight, and delay in development (pinna unfolding and eye 
opening) at 600 mg/kg/day with a maternal NOAEL of 200 mg/kg/day based 
on reduced body weights at 600 mg/kg/day. At treatment levels of 50 and 
200 mg/kg/day no substance related finding were noted either in the 
parent animals or the offspring.
    8. Mutagenicity. All Salmonella Assays testing the appropriate 
technical 3,7-dichloro-8-quinoline carboxylic acid were negative. The 
3,7-dichloro-8-quinoline carboxylic acid was negative in the in vivo 
cytogenetics (Chinese hamster) at dose levels ranging from 2,000 to 
8,000 mg/kg and did not induce unscheduled DNA synthesis in the UDS 
assay at levels ranging from 101 to 1,520 -ug/ml.
    9. Metabolism - Rat. A metabolism study with rats receiving dosages 
of 15, 100, 600 and 1,200 mg/kg/day resulted in more than 90% of the 
administered radioactivity eliminated in the urine within 5 days (most 
within 24 hours) and 0.7 - 3.7% in the feces. Radioactivity was mainly 
associated with the unchanged parent compound. The glucuronic acid 
conjugate of quinclorac was a minor (2 - 5%) metabolite in urine.
    10. Reference dose. The established Reference Dose (RfD) for 
quinclorac is based on the 2-year feeding study in mice with a 
threshold NOAEL of 37.5 mg/kg/day. Using an uncertainty factor of 100, 
the RfD has been calculated to be 0.38 mg/kg/day.
    11. Cancer classification and risk assessment. The cancer 
classification of quinclorac has been reviewed by the FIFRA Scientific 
Advisory Panel (SAP). The Panel recommended that the compound be 
classified as a Group D carcinogen (not classifiable as to human 
carcinogenicity). The EPA Health Effects Peer Review Committee (PRC) 
evaluated the carcinogenic potential of quinclorac and the conclusions 
of the SAP and has classified quinclorac as a Group D carcinogen. Since 
quinclorac is not classified as a carcinogen, a cancer risk assessment 
was not necessary for approval of the currently established tolerances. 
Therefore, a cancer risk assessment for the proposed tolerances on 
wheat and sorghum is also not necessary.
    12. In addition to the data described above, BASF is submitting a 
21 day dermal study in the rat to supplement the quinclorac toxicology 
database. Results indicate that the NOAEL for quinclorac in this study 
is greater than 1,000 mg/kg body weight.

C. Aggregate Exposure / Cumulative Effects

    1. Chronic dietary exposure. BASF has estimated aggregate dietary 
exposure based on the Theoretical Maximum Residue Contribution (TMRC) 
calculation. The TMRC is a ``worst case'' estimate of dietary exposure 
since it is assumed that 100% of all crops for which tolerances are 
established are treated and that residues are at the tolerances level. 
Since the proposed label prohibits use in many wheat and sorghum 
producing states, the TMRC calculation results in a significant 
overestimate of human dietary exposure.
    The quinclorac TMRC for the overall U.S. population from the 
currently established rice and animal tolerances is 0.001485 mg/kg bwt/
day which represents 0.39% of the RfD. A preliminary estimate of 
dietary exposure to residues of quinclorac from the proposed tolerances 
in wheat and sorghum increases the TMRC by 0.000836 mg/kg bwt/day and 
accounts for approximately 0.22% of the RfD for the overall U.S. 
population.
    2. Acute dietary exposure. BASF has reviewed the toxicity database 
for quinclorac and has concluded that there is no acute dietary concern 
since there is no indication of any significant toxicity from a one day 
or single event oral exposure. The LD50 for technical 
quinclorac has been determined to be 3,060 mg/kg for males and 2,190 
mg/kg for females.
    3. Drinking water exposure. Other potential sources of exposure for 
the general population to residues of quinclorac are residues in 
drinking water and exposure from non-occupational sources. Based on the 
available studies used in EPA's assessment of environmental risk, BASF 
does not anticipate exposure to residues of quinclorac in drinking 
water. There is no established Maximum Concentration Level (MCL) for 
residues of quinclorac in drinking water under the Safe Drinking Water 
Act (SDWA).
    4. Non-occupational exposure. Quinclorac is not currently labeled 
for any nonagricultural use. An application for use of quinclorac on 
turfgrass is currently pending. The proposed turf registration 
restricts use of the product to certified commercial applicators and 
those under their direct supervision. Use of the product by typical 
uncertified homeowners will be prohibited. Therefore, potential for 
non-occupational exposure to the general population is significantly 
reduced compared to general use turf products. BASF is a member of the 
industry wide Outdoor Residential Exposure Task Force. The Task Force 
is currently generating data to assess exposure resulting from the use 
of turf products.

D. Cumulative Effects

    BASF has considered the potential for cumulative effects of 
quinclorac and other substances that have a common mechanism of 
toxicity. BASF is not aware of any other EPA registered active 
ingredient that is structurally similar to quinclorac or has a common 
mechanism of toxicity.

E. Safety Determination

    1. U.S. population. Using the conservative exposure assumptions 
described above and based on the completeness and the reliability of 
the toxicity data, BASF has estimated that aggregate exposure to 
quinclorac will utilize approximately 0.22% of the RfD for the U.S. 
population. BASF concludes that there is a reasonable certainty that no 
harm will result from the aggregate exposure to residues of quinclorac, 
including anticipated dietary exposure and non-occupational exposures.
    2. Infants and children. No signs of teratogenicity were observed 
in either the rat or rabbit Developmental studies. The NOAEL values 
from the Developmental studies are significantly higher than the NOAEL 
from the 2-year feeding study in mice (threshold NOAEL of 37.5 mg/kg/
day) used to establish the RfD.
    In the Reproductive Toxicity study, Quinclorac elicited signs of 
embryotoxicity only at dose levels where clear maternal toxicity was 
observed. Fertility and reproduction parameters were not affected even 
at the highest treatment levels (1,155 mg/kg/

[[Page 66538]]

day). The NOAEL values from the Reproduction study are significantly 
higher than the NOAEL from the 2-year feeding study in mice (threshold 
NOAEL of 37.5 mg/kg/day) used to establish the RfD.
    Based on the demonstrated lack of significant developmental or 
reproductive toxicity, BASF believes that the RfD used to assess safety 
to the general population is adequate to assess safety to children. The 
EPA evaluation of the established rice and animal tolerances concluded 
that for the subgroup exposed to the highest dietary risk, nonnursing 
infants less than 1 year old, the TMRC is 0.010065 mg/kg bwt/day or 
2.65 % of the RfD. The addition of the wheat and sorghum tolerances 
increases the TMRC for this subgroup to approximately 0.100726 mg/kg 
bwt/day or 2.82 % of the RfD. BASF concludes that there is a reasonable 
certainty that no harm will result to infants and children from 
aggregate exposure to the residues of quinclorac, including all 
anticipated dietary exposure and all other non-occupational exposures.

F. Endocrine Effects

    No specific tests have been conducted with quinclorac to determine 
whether the chemical may have an endocrine like effect in humans. 
However, there were no significant findings in other relevant tests 
(developmental and reproductive toxicity tests) which would suggest 
that quinclorac produces endocrine like effects.

G. International Tolerances

    A maximum residue level has not been established under the Codex 
Alimentarius Commission for quinclorac in wheat and sorghum. (Joanne I. 
Miller)

2. Novartis Crop Protection, Inc.

PP 2F4107

    EPA has received a pesticide petition (PP 2F4107) from Novartis 
Crop Protection, Inc., P.O. Box 18300, Greensboro, NC 28479-8300. 
proposing pursuant to section 408(d) of the Federal Food, Drug, and 
Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 by 
establishing a tolerance for residues of Difenconazole, [(2S,4R)/
(2R,4S)]/[2R,4R/2S,4S)] 1-(2-4-(4-chlorophenoxy)-2-chlorophenyl]-4-
methyl-1,3-dioxolan2yl-methyl)-1H-1,2,4-triazole in or on the raw 
agricultural commodity wheat grain, forage, and straw at 0.1 parts per 
million (ppm); cattle, eggs, goats, hogs, horses, poultry and sheep 
0.05; and milk at 0.01 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. The nature of the residue is adequately 
understood in plants and animals. The metabolism of difenoconazole has 
been studied in wheat, tomatoes, potatoes, and grapes. The metabolic 
pathway was the same in these four separate and distinct crops.
    2. Analytical method. Novartis has submitted a practical analytical 
method for detecting and measuring levels of difenoconazole in or on 
food with the limit of quantitation that allows monitoring of food with 
residues at or above the levels set in the proposed tolerances. EPA 
will provide information on this method to FDA. The method is available 
to anyone who is interested in pesticide residue enforcement from the 
Field Operations Division, Office of Pesticide Programs.
    3. Magnitude of residues. Data has been provided from fourteen 
spring and winter wheat residue trials conducted in major wheat growing 
states. Application rates were 24 grams a.i. and 48 grams a.i./100 kg 
seed (10.9 and 21.8 grams a.i./ 100 lb seed, respectively). A 
processing study was also conducted in which two foliar applications 
were made in addition to the seed treatment, in an attempt to generate 
grain samples containing measurable residues. Bran, middlings, shorts 
and germ, and patent flour were tested for residues.
    No residues of difenoconazole (<0.1 ppm) were detected in wheat 
grain or in any of the processed milled fractions, even when the higher 
seed treatment rate was coupled with two foliar treatments. The use of 
difenoconazole as a seed treatment will not result in detectable 
residues in grain or processed commodities. Similarly, no residues of 
difenoconazole (0.05 ppm) were detected on wheat forage or straw.
    No food additive tolerances are necessary for grain commodities. 
Tolerances in meat, milk, poultry or eggs were established for 
enforcement purposes.

B. Toxicological Profile

    The following mammalian toxicity studies were conducted and 
submitted in support of tolerances for difenoconazole.
    1. Acute toxicity. Difenoconazole has a low order of acute 
toxicity. The oral rat LD50 is 1,453 mg/kg. The rabbit acute 
dermal LD50 is > 2,010 mg/kg and the rat inhalation 
LC50 is > 3.285 mg/L. It is not a skin sensitizer in guinea 
pig and shows slight eye and dermal irritation in the rabbit.
    2. Genotoxicty. There was no evidence of the induction of point 
mutations in an Ames test.
    There was no evidence of mutagenic effects in a mouse lymphoma 
test.
    There was no evidence of mutagenic effects in a nucleus anomaly 
test with Chinese hamsters.
    There was no evidence of induction of DNA damage in a rat 
hepatocyte DNA repair test.
    There was no evidence of induction of DNA damage in a human 
fibroblast DNA repair test.
    3. Reproductive and developmental toxicity. An oral teratology 
study in rats had a maternal NOAEL of 16 mg/kg/day based on excess 
salivation and decreased body weight gain and food consumption. The 
developmental NOAEL of 85 mg/kg/day was based on effects seen secondary 
to maternal toxicity including slightly reduced fetal body weight and 
minor changes in skeletal ossification.
    An oral teratology study in rabbits had maternal NOAEL of 25 mg/kg/
day based on decreased body weight gain, death, and abortion. The 
developmental NOAEL of 25 mg/kg/day was based on effects seen secondary 
to maternal toxicity including slight increase in post-implantation 
loss and resorptions, and decreased fetal weight.
    A 2-generation reproduction study in rats had a parental and 
reproductive NOAEL of 25 ppm based on significantly reduced female body 
weight gain, and reductions in male pup weights at 21 days.
    4. Subchronic toxicity. A 13-week rat feeding study identified 
liver as a target organ and had a NOAEL of 20 ppm.
    A 13-week mouse feeding study identified liver as a target organ 
and had a NOAEL of 20 ppm.
    A 26-week dog feeding study identified liver and eye as target 
organs and had a NOAEL of 100 ppm.
    A 21-day dermal study in rabbits had a NOAEL of 10 mg/mg/day based 
on decreased body weight gain at 100 and 1,000 mg/kg/day.
    5. Chronic toxicity. A 24-month feeding study in rats had a NOAEL 
of 20 ppm based on liver toxicity at 500 and 2,500 ppm. There was no 
evidence of an oncogenic response.
    An 18-month mouse feeding study had an overall NOAEL of 30 ppm 
based on decreased body weight gain and liver toxicity at 300 ppm. 
There was an increase in liver tumors only at dose levels that exceeded 
the maximum

[[Page 66539]]

tolerated dose (MTD). The oncogenic NOAEL was 300 ppm.
    A 12-month feeding study in dogs had a NOAEL of 100 ppm based on 
decreased food consumption and increased alkaline phosphatase levels at 
500 ppm.
    6. Carcinogenicity. A 24-month feeding study in rats had a NOAEL of 
20 ppm based on liver toxicity at 500 and 2,500 ppm. There was no 
evidence of an oncogenic response.
    An 18-month mouse feeding study had an overall NOAEL of 30 ppm 
based on decreased body weight gain and liver toxicity at 300 ppm. 
There was an increase in liver tumors only at dose levels that exceeded 
the maximum tolerated dose (MTD). The oncogenic NOAEL was 300 ppm.
    7. Animal metabolism. The metabolism of difenoconazole is well 
understood. Studies with 14C-difenoconazole in the rat, goat, and hen 
demonstrate that the majority of the administered dose (76 to > 98%) is 
eliminated via the excreta as parent and metabolites. Very low 
concentrations of radioactivity, accounting for <1 to 4% of the applied 
dose, remain in tissues. The liver and kidney typically show the 
highest radioactivity, but in the rat, the highest concentration in any 
tissue was found in the fat.
    Concentrations in goat milk reached a plateau on Day 6 of the study 
at 0.043 ppm for the triazole label and 0.007 ppm for the phenyl label 
when goats were fed approximately 5 ppm for 10 days. Similarly, very 
little radioactivity was deposited in eggs; radioactivity reached a 
plateau of 0.248 to 0.299 ppm in yolks after 7 to 8 days, and 0.007 to 
0.153 ppm in whites after 5 days, in hens fed at a rate equivalent to 5 
ppm in the diet for 14 consecutive days. CGA-205375, an alcohol 
resulting from the deskelitalization of the dioxolane ring of 
difenoconazole, is a major metabolite found in animal tissues, excreta, 
milk, and eggs. The presence of CGA-71019, containing only the triazole 
ring, and CGA-189138, containing only the phenyl ring, indicates that 
bridge cleavage can occur in animals as well as plants. The metabolite 
patterns in the excreta of hens, goats, and rats were similar.
    8. Metabolite toxicology. The residue of concern for tolerance 
setting purposes is the parent compound. Metabolites of difenoconazole 
are considered to be of equal or lesser toxicity than the parent.
    9. Endocrine disruption. Developmental toxicity studies in rats and 
rabbits and a two-generation reproduction study in rats gave no 
specific indication that difenoconazole may have effects on the 
endocrine system with regard to development or reproduction. 
Furthermore, histologic investigations were conducted on endocrine 
organs (thyroid, adrenal, and pituitary, as well as endocrine sex 
organs) from long-term studies in dogs, rats, and mice. There was no 
indication that the endocrine system was targeted by difenoconazole, 
even when animals were treated with maximally tolerated doses over the 
majority of their lifetime.
    Difenoconazole has not been found in raw agricultural commodities 
at the limit of quantification. Based on the available toxicity 
information and the lack of detected residues, it is concluded that 
difenoconazole has no potential to interfere with the endocrine system, 
and there is no risk of endocrine disruption in humans.

C. Aggregate Exposure

    1. Dietary exposure -- Food. When the potential dietary exposure to 
difenoconazole from established and pending tolerances is calculated, 
the theoretical maximum residue concentration (TMRC) of 0.000473 mg/kg/
day utilizes 4.73% of the RfD for the overall U.S. population. For the 
most exposed population subgroups, children and non-nursing infants, 
the TMRC is 0.001252 mg/kg/day, utilizing 12.52% of the RfD followed by 
children (1-6 years) exposed to 11.24% of the RfD.
    Novartis has conducted another exposure analysis using additional 
crops and similar conservative assumptions. In this analysis, oats, 
barley, cotton and bananas (pending import tolerance) were included in 
addition to wheat. Tolerances or proposed tolerances were 0.1 ppm each 
for wheat, oats, and barley, and 0.2 ppm for bananas. Tolerances were 
0.01 ppm for milk and 0.05 ppm for all other commodities: beef, goat, 
horse, rabbit, sheep, pork, turkey, eggs, chicken, and other poultry. 
Very conservative assumptions were used to estimate residues (i.e. 100% 
of all wheat, oats, barley and imported bananas used for human 
consumption or forage was treated and all RACs contained tolerance 
level residues). These estimates result in a extreme overestimate of 
human dietary exposure. Calculated TMRC values from these assumptions 
utilize 4.73% of the RfD for the U.S. population and 12.52% of the RfD 
for non-nursing infants.
    2. Drinking water. Other potential sources of exposure of the 
general population to residues of pesticides are drinking water and 
non-occupational sources. Difenoconazole is currently used as a seed 
treatment and residues are, therefore, incorporated into the soil. The 
likelihood of contamination of surface water from run-off is 
essentially negligible. In addition, parent and aged leaching, soil 
adsorption/desorption, and radiolabeled pipe studies indicated that 
difenoconazole has a low potential to leach in the soil and it would 
not be expected to reach aquatic environments. For these reasons, and 
because of the low use rate, exposures to residues in ground water are 
not anticipated.
    3. Non-dietary exposure. Non-occupational exposure for 
difenoconazole has not been estimated since the current registration is 
limited to seed treatment. Therefore, the potential for non-
occupational exposure to the general population is insignificant.
    Novartis has considered the potential for cumulative effects of 
difenoconazole and other substances of common mechanism of toxicity. 
Novartis has concluded that consideration of a common mechanism of 
toxicity in aggregate exposure assessment is not appropriate at this 
time. Novartis has no information to indicate that the toxic effects 
(generalized liver toxicity) seen at high doses of difenoconazole would 
be cumulative with those of any other compound. Thus, Novartis is 
considering only the potential risk of difenoconazole from dietary 
exposure in its aggregate and cumulative exposure assessment.

D. Safety Determination

    1. U.S. population. Non-occupational exposure for difenoconazole 
has not been estimated since the current registration is limited to 
seed treatment. Therefore, the potential for non-occupational exposure 
to the general population is insignificant.
    Novartis has considered the potential for cumulative effects of 
difenoconazole and other substances of common mechanism of toxicity. 
Novartis has concluded that consideration of a common mechanism of 
toxicity in aggregate exposure assessment is not appropriate at this 
time. Novartis has no information to indicate that the toxic effects 
(generalized liver toxicity) seen at high doses of difenoconazole would 
be cumulative with those of any other compound. Thus, Novartis is 
considering only the potential risk of difenoconazole from dietary 
exposure in its aggregate and cumulative exposure assessment.
    If more realistic assumptions were used to estimate anticipated 
residues and appropriate market share, this percentage would be 
considerably lower, and would be significantly lower than 100%, even 
for the highest exposed population subgroup. EPA generally has no 
concern for exposures below 100%

[[Page 66540]]

of the RfD. Therefore, Novartis concludes that there is reasonable 
certainty that no harm will result from daily aggregate exposure to 
residues of difenoconazole over a lifetime.


    2. Infants and children. Developmental toxicity and two-generation 
toxicity studies were evaluated to determine if there is a special 
concern for the safety of infants and children from exposure to 
residues of difenoconazole. There was no evidence of embryo toxicity or 
teratogenicity, and no effects on reproductive parameters, including 
number of live births, birth weights, and post-natal development, at 
dose levels that did not cause significant maternal toxicity. In 
addition, there were no effects in young post-weaning animals that were 
not seen in adult animals in the 2-generation reproduction study. 
Therefore, Novartis concludes that it is inappropriate to assume that 
infants and children are more sensitive than the general population to 
effects from exposure to residues of difenoconazole.

E. International Tolerances

    There are no Codex maximum levels established for residues of 
difenoconazole. (Cynthia Giles-Parker)

FR Doc. 98-31683 Filed 12-1-98; 8:45 am
BILLING CODE 6560-50-F