[Federal Register Volume 62, Number 180 (Wednesday, September 17, 1997)]
[Notices]
[Pages 48848-48856]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-24692]


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ENVIRONMENTAL PROTECTION AGENCY

[PF-754; FRL-5735-8]


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 and/or amendment of regulations 
for residues of certain pesticide chemicals in or on various food 
commodities.

DATES: Comments, identified by the docket control number PF-754, must 
be received on or before October 17, 1997.

ADDRESSES: By mail submit written comments to: Public Information and 
Records Integrity Branch, Information Resources and Services Division 
(7506C), Office of Pesticides Programs, Environmental Protection 
Agency, 401 M St., SW., Washington, DC 20460. In person bring comments 
to: Rm. 1132, CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
    Comments and data may also be submitted electronically by following 
the instructions under ``SUPPLEMENTARY INFORMATION.'' No confidential 
business information should be submitted through e-mail.
    Information submitted as a comment concerning this document may be 
claimed confidential by marking any part or all of that information as 
``Confidential Business Information'' (CBI). CBI should not be 
submitted through e-mail. Information marked as CBI will not be 
disclosed except in accordance with procedures set forth in 40 CFR part 
2. A copy of the comment that does not contain CBI must be submitted 
for inclusion in the public record. Information not marked confidential 
may be disclosed publicly by EPA without prior notice. All written 
comments will be available for public inspection in Rm. 1132 at the 
address given above, from 8:30 a.m. to 4 p.m., Monday through Friday, 
excluding legal holidays.

FOR FURTHER INFORMATION CONTACT: By mail: Sidney Jackson, Product 
Manager (PM) 43, Minor Use, Inerts, Emergency Response Branch, 
Registration Division (7505C), Office of Pesticide Programs, 
Environmental Protection Agency, 401 M St., SW., Washington, DC 20460. 
Office location and telephone number: Rm. 274, CM#2, 1921 Jefferson 
Davis Highway, Arlington, VA., (703) 305-7610. e-mail: 
<a href="/cdn-cgi/l/email-protection#dfb5bebcb4acb0b1f1acb6bbb1baa69fbaafbeb2beb6b3f1baafbef1b8b0a9"><span class="__cf_email__" data-cfemail="5f353e3c342c3031712c363b313a261f3a2f3e323e3633713a2f3e71383029">[email protected]</span></a>.


[[Page 48849]]


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-754 (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''.
    Electronic comments can be sent directly to EPA at:
    <a href="/cdn-cgi/l/email-protection#412e31316c252e222a2435012431202c20282d6f2431206f262e37"><span class="__cf_email__" data-cfemail="90ffe0e0bdf4fff3fbf5e4d0f5e0f1fdf1f9fcbef5e0f1bef7ffe6">[email protected]</span></a>


    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 file format or ASCII 
file format. All comments and data in electronic form must be 
identified by the docket control number (insert docket number) 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: September 5, 1997.

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

Summaries of Petitions

    Below summaries of the pesticide petitions are printed. The 
summaries of the petitions were prepared by the petitioners. 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. DowElanco Products Co.

PP 5E4573

    EPA has received a pesticide petition (PP 5E4573) from the 
Interregional Research Project number 4 (IR-4), 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 Fenarimol, alpha-(2 chlorophenyl)-alpha-(4-chlorophenyl)-5-
pyrimidine methanol, in or on the raw agricultural commodity filbert 
(hazelnuts) at 0.02 parts per million (ppm).

A. Residue Chemistry

    1. Plant metabolism. The nature of the residue in fenarimol-treated 
filberts has not been directly determined. Radioactive metabolism 
studies with apples and cherries indicate that fenarimol is the only 
significant component of the residue in apples and cherries. The 
residue of concern is fenarimol.
    2. Analytical method. Analytical methodology used for filberts is a 
slight modification of the basic PAM II method for fenarimol (Method 
R039). Residues are extracted with methanol. Aqueous sodium chloride 
(5%) is added and the extract is partitioned with dichloromethane. 
Residues are cleaned up on a Florisil column and detected by GC/ECD. 
Recoveries ranged from 84-97% in samples fortified with fenarimol at 
0.02-0.2 ppm. The limit of detection via this method is >0.02 ppm.
    3. Magnitude of residues. IR-4 data from 4 residue trials show 
residues of fenarimol were <0.02 ppm in composite samples of filberts 
treated at 0.09 pounds active ingredient per acre (lb ai/A) and 
composite samples treated at 0.18 lb ai/A or two times the proposed 
maximum application rate. These data indicate that fenarimol residues 
would not be expected to accumulate to significant levels in filberts. 
Based on these results and for purposes of this petition, it is 
appropriate to base the magnitude of total terminal residues and 
proposed tolerance only on residues of the parent compound, fenarimol.

B. Toxicological Profile

    1. Acute toxicity. The acute oral lethal dose (LD)<INF>50</INF> in 
the rat is 2,500 milligrams (mg)/kilogram (kg) and the acute dermal 
LD<INF>50</INF> in the rabbit is >2,000 mg/kg. The inhalation lethal 
concentration (LC)<INF>50</INF> in the rat is >2.04 mg/liter(l) of air, 
which is the highest obtainable respirable aerosol concentration. 
Fenarimol produced no indications of dermal irritation in rabbits or 
sensitization in the guinea pig. End use formulations of fenarimol have 
similar low acute toxicity profiles.
    2. Genotoxicity. Fenarimol tested negative in several assay systems 
for gene mutation, structural chromosome aberration and other genotoxic 
effects. In a micronucleus test in the mouse, fenarimol did produce a 
significant increase in the percent of polychromatic erythrocytes with 
micronucleus at 24 hours but not at 48 or 72 hours. Moreover, a second 
test run at a higher dosage, which produced significant toxicity 
including death, was unequivocally negative.
    3. Reproductive and developmental toxicity. A developmental 
toxicity study in rabbits was negative for teratogenic effects at all 
doses tested (0, 5, 10, and 35 mg/kg). A developmental toxicity study 
in rats demonstrated hydronephrosis at 35 mg/kg (doses tested were 0, 
5, 10, and 35 mg/kg). A second developmental toxicity study in rats 
(with a postpartum evaluation) again demonstrated hydronephrosis at 35 
mg/kg. Maternal toxicity (decreased body weight) was also observed at 
the 35 mg/kg/day dose level. The no observed effect level (NOEL) for 
hydronephrosis and maternal toxicity is 13 mg/kg.
    A 3-generation reproduction study in rats dosed at 0, 12.5, 25 or 
50 ppm (equivalent to 0, 0.625, 1.25 or 2.5 mg/kg/day) demonstrated 
decreased fertility in males at 25 ppm and delayed parturition and 
dystocia in females at 25 and 50 ppm. The NOEL for reproductive effects 
was 12.5 ppm (0.625 mg/kg/day). The infertility effect in males is 
considered to be a species-specific effect mediated by the inhibition 
of aromatase an enzyme which catalyzes the conversion of testosterone 
to estradiol. Estradiol plays an essential role in the developmental 
and maintenance of sexual behavior in rats.
    Multigeneration reproduction studies in guinea pigs and mice were 
negative for reproductive effects at the highest dose levels tested 35 
mg/kg/day and 20 mg/kg/day, respectively. A NOEL of 35 mg/kg/day for 
reproductive effects relevant to humans was established based on the 
NOEL from the multi-generation reproduction study in guinea pigs.
    4. Chronic toxicity. A 2-year chronic toxicity/carcinogenicity 
study in rats fed diets containing 0, 50, 130, or 350 ppm (equivalent 
to 2.5, 6.5, or 17.5 mg/kg/day) with a systemic NOEL of 130 ppm

[[Page 48850]]

(equivalent to 6.5 mg/kg/day). An increase in fatty liver changes was 
observed in rats fed diets containing 350 ppm. There were no 
carcinogenic effects observed under the conditions of the study.
    A second 2-year carcinogenicity study was conducted in rats fed 
diets containing 0, 12.5, 25, or 50 ppm (equivalent to 0, 0.63, 1.25, 
or 2.5 mg/kg/day). There was no apparent effect on survival which was 
reduced in all treatment groups due to chronic respiratory disease. An 
increase incidence of fatty changes in the liver was observed at the 
top dose level of 50 ppm, and the NOEL was established as 25 ppm (1.2 
mg/kg/day) in this study. A third 2-year study carcinogenicity was 
conducted at the same dose levels as above. The incidence of liver 
lesions was similar in the treated and control groups, thus the NOEL 
for liver effects in this study was greater than 50 ppm (2.5 mg/kg/
day).
    A 2-year dietary feeding study in mice fed diets containing 
concentrations of 0, 50, 170, or 600 ppm equivalent to 0, 7, 24.3, or 
85.7 mg/kg/day). A 600 ppm dose level was shown to increase liver 
weight. There was no increase in cancer and no toxicologically 
significant treatment related effects were observed at any dose level. 
The NOEL was determined to be 600 parts per million(ppm) (85.7 mg/kg/
day).
    A 1-year chronic toxicity study in dogs fed diets containing 0, 
1.25, 12.5, or 125 mg/kg/day, the NOEL was 12.5 mg/kg/day based upon an 
increase in serum alkaline phosphatase, increased liver weights, an 
increase in p-nitroanisole o-demethylase activity, and mild hepatic 
bile stasis at the high dose level (125 mg/kg/day).
    Based on the chronic toxicity data, the Reference Dose (RfD) for 
fenarimol is established at 0.065 mg/kg/day. The RfD for fenarimol is 
based on a 2-year chronic feeding study in rats with a NOEL of 6.5 mg/
kg/day and an uncertainty factor of 100.
    There is no evidence to suggest that fernarimol effects any 
endocrine system or that fernarimol would elicit neurotoxic response.
    5. Animal metabolism. Metabolism studies conducted in rats show 
fenarimol is rapidly metabolized and excreted. Major metabolic pathways 
were oxidation of the carbinol-carbon atom, the phenyl rings and the 
pyrimidine ring.
    6. Carcinogenicity. Fenarimol is classified as Group ``E'' for 
carcinogenicity (no evidence of carcinogenicity) based on the results 
of the carcinogenicity studies. There was no evidence of 
carcinogenicity in 2-year feeding studies in mice and rats at the 
dosage levels tested. The doses tested were adequate for identifying a 
cancer risk. Thus, a cancer assessment would not be appropriate.

C. Aggregate Exposure

    1. Dietary (food) exposure. For the purposes of assessing the 
potential dietary exposure from use of fenarimol on filberts, an 
estimate of aggregate exposure is determined by basing the TMRC from 
previously established tolerances and the proposed tolerance on 
filberts for fenarimol at 0.02 parts per million(ppm) and assuming that 
100% of the filbert crop has a residue of fenarimol at the tolerance 
level.
    Exposure to humans to residues could also result if such residues 
are transferred to meat, milk, poultry or eggs. Since there is no 
livestock feed commodities associated with filberts, there is no 
reasonable expectation that measurable secondary residues of fenarimol 
will occur in meat, milk, poultry or eggs under the terms of the 
proposed use. Other established U.S. tolerances for fenarimol on food 
or feed crops in the United States are established under 40 CFR part 
180.421, 40 CFR part 185.3200 and 40 CFR part 186.3200. The use of a 
tolerance level and 100% of crop treated clearly results in an 
overestimate of human exposure and a safety determination for use of 
fenarimol on filberts that is based on a conservative exposure 
assessment.
    2. Drinking water. Based upon the available environmental studies 
conducted with fenarimol wherein it's properties show little potential 
for mobility in soil and extremely rapid photolysis in water, DowElanco 
concludes, there is no anticipated exposure to residues of fenarimol in 
drinking water.
    3. Non-dietary exposure. The proposed use on filberts involves 
application of fenarimol to a crop grown in an agricultural 
environment. Thus, the potential for non-occupational, non-dietary 
exposure to the general population is not expected to be significant.

D. Cumulative Effects

    DowElanco concludes that there is no evidence that there is a 
common mechanism of toxicity with any other chemical compound or that 
potential toxic effects of fenarimol would be cumulative with those of 
any other pesticide chemical. Thus DowElanco believes it is appropriate 
to consider only the potential risks of fenarimol in its exposure 
assessment.

E. Safety Determination

    1. U.S. population. DowElanco has concluded that aggregate exposure 
to fenarimol will utilize less than 2% of the RfD for the U.S. general 
population. 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. DowElanco concludes that there is a reasonable 
certainty that no harm will result from aggregate exposure to fenarimol 
residues in or on filberts. The complete toxicology profile for 
fenarimol shows no evidence of physiological effects characteristic of 
the disruption of the hormone estrogen. Based upon this observation, 
DowElanco concludes that fenarimol does not meet the criteria for an 
estrogenic compound.
    2. Infants and children. In assessing the potential for additional 
sensitivity of infants and children to residues of fenarimol, data from 
developmental toxicity studies in rats and rabbits and a 
multigeneration reproduction study in the rat are considered. The 
developmental toxicity studies are designed to evaluate adverse effects 
on the developing organism resulting from pesticide exposure during 
prenatal development to one or both parents. Reproduction studies 
provide information relating to effects from exposure to the pesticide 
on the reproductive capability and potential systemic toxicity of 
mating animals and on various parameters associated with the well-being 
of offspring.
    FFDCA section 408 provides that EPA may apply an additional safety 
factor for infants and children in the case of threshold effects to 
account for pre- and post-natal toxicity and the completeness of the 
data base. Based on the current toxicological data requirements, the 
data base for fenarimol relative to pre- and post-natal effects for 
children is complete. Further, for fenarimol, the NOEL in the chronic 
feeding study which was used to calculate the RfD (6.5 mg/kg/day used 
by EPA or 1.2 mg/kg/day used by The World Health Organization) is 
already lower than the NOELs from the developmental studies in rats and 
rabbits.
    Concerning the multi-generation reproduction study, the effects on 
reproduction are considered to be specific effect caused by aromatase 
inhibition. The aromatase enzyme promotes normal sexual behavior in 
rats and mice, but not in guinea pigs, or primates (including humans). 
A NOEL of 35 mg/kg/day for reproductive effects

[[Page 48851]]

relevant to humans was established based on the NOEL from the multi-
generation reproduction study in guinea pigs. In addition, a NOEL of 13 
mg/kg/day for developmental effects was established based upon the NOEL 
from the teratology study in rats. Therefore, DowElanco concludes that 
an additional uncertainty factor is not needed and that the RfD at 
0.065 mg/kg/day is appropriate for assessing risk to infants and 
children.
    Using the exposure assumptions previously described, the percent 
RfD utilized by the aggregate exposure to residues of fenarimol from 
previously established tolerance and the proposed tolerance on filberts 
is less than 2% for children 1 to 6 years of age, the population 
subgroup most highly exposed to dietary residues of fenarimol. Thus, 
based on the completeness and reliability of the toxicity data and the 
conservative exposure assessment, DowElanco concludes that there is a 
reasonable certainty that no harm will result to infants and children 
from aggregate exposure to fenarimol on filberts.

F. International Tolerances

    A temporary tolerance of 0.02 ppm for fenarimol on pecans; and a 
0.1 ppm Mexican limit for fenarimol on walnuts exist. Since there are 
not Codex, Mexican or Canadian limits for fenarimol on filberts, 
international compatibility is not considered to be at issue.

2. ISK Biosciences Corporation

PP 2E4042, 2E4018 and 6E4672

    EPA has received pesticide petitions (PP 2E4042, 2E4018 and 6E4672) 
from the Interregional Research Project Number 4 (IR-4), 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 tolerances 
for residues of Chlorothalonil (tetrachloroisophthalonitrile) and its 
metabolite 4-hydroxy-2,5,6-trichloro-isophthalonitrile in or on the raw 
agricultural commodities at levels of 0.1 parts per million(ppm) for 
asparagus, 1.0 ppm for mangoes, and 0.2 ppm for pistachios.

A. Residue Chemistry

    1. Plant metabolism. The nature of the residue of chlorothalonil in 
asparagus, mangoes and pistachios is adequately understood. The parent 
compound and its metabolite (4-hydroxy-2,5,6-trichloro-
isophthalonitrile) are the regulated residues. Chlorothalonil is not 
systemic in plants.
    2. Analytical method. An adequate analytical method (gas 
chromatography) is available for enforcement purposes. The method is 
listed in the Pesticide Analytical Manual, Vol. II (PAM II).
    3. Magnitude of residues. Residue data from studies conducted with 
asparagus, mangoes and pistachios support the proposed tolerances for 
combined residues of chlorothalonil and its metabolite, 4-hydroxy-
2,5,6-trichloro-isophthalonitrile in/on these raw agricultural 
commodities.

B. Toxicological Profile

    1. Acute toxicity. Acute toxicity studies on technical grade 
chlorothalonil show: an oral lethal dose (LD)<INF>50</INF> >10,000 
milligrams(mg)/kilogram(kg) (Toxicity Category IV) in rats; a dermal 
LD<INF>50</INF> >10,000 mg/kg (Toxicity Category IV) in rabbits; a 
four-hour inhalation lethal concentration (LC)<INF>50</INF> of 0.092 
mg/L in female rats and 0.094 mg/L in male rats (Toxicity Category II); 
and a primary eye irritation study showing chlorothalonil as corrosive 
causing irreversible eye effects (Toxicity Category I) in the rabbit at 
21 days. Chlorothalonil was shown not to be a dermal irritant (Toxicity 
Category IV) in a primary dermal irritation study in rabbits and not a 
skin sensitizer in a dermal sensitization study in guinea pigs.
    2. Genotoxicity. Mutagenicity studies with chlorothalonil include 
gene mutation assays in bacterial and mammalian cells; in vitro and in 
vivo chromosomal aberration assays; DNA repair assays in bacterial 
systems; and cell transformation assays. All were negative with the 
following two exceptions:
    Chlorothalonil was positive in an in vitro chromosomal aberration 
assay in chinese hamster ovary (CHO) cells without metabolic activation 
but was negative with metabolic activation. In vivo chromosomal 
aberration studies in rats and mice were negative and one study in the 
Chinese hamster was equivocal. These results suggest that 
chlorothalonil is not mutagenic and does not have clastogenic potential 
in intact mammalian systems.
    In bacterial DNA repair tests, chlorothalonil was negative in 
Bacillus subtilis, but was positive in Salmonella typhimurium. In an in 
vivo DNA binding study in rats with <SUP>14</SUP>C-chlorothalonil, 
there was no covalent binding of the radiolabel to the DNA of the 
kidney, the target organ for chlorothalonil toxicity in rodents.
    3. Reproductive and developmental toxicity. A developmental 
toxicity study with rats fed doses of 0, 25, 100, and 400 mg/kg body 
weight/day from days 6 through 15 of gestation resulted in a no 
observed effect level (NOEL) for maternal toxicity of 100 mg/kg/day 
based on increased mortality, reduced body weight, and a slight 
increase in early resorptions at the highest dose. There were no 
developmental effects observed at any dose in this study.
    A developmental toxicity study in rabbits fed doses of 0, 5, 10, or 
20 mg/kg/day on days 7 through 19 of gestation resulted in a maternal 
NOEL of 10 mg/kg/day. Effects observed in the dams in the high-dose 
group were decreased body weight gain and reduced food consumption. 
There were no developmental effects observed in this study.
    A two-generation reproduction study in rats fed diets containing 0, 
500, 1,500 and 3,000 ppm resulted in a reproductive NOEL of 1500 ppm 
(equivalent to 115 mg/kg/day) based on lower neonatal body weights by 
day 21. There were no effects seen on any other reproductive parameter 
at any dose level in this study.
    4. Subchronic toxicity. A subchronic toxicity study was conducted 
in rats at doses of 0, 1.5, 3.0, 10 and 40 mg/kg/day for 13 weeks. 
Treatment related hyperplasia and hyperkeratosis of the forestomach was 
observed at the two highest dose levels. Initial histopathological 
evaluation did not demonstrate any nephrotoxicity, however, a 
subsequent evaluation observed a treatment-related increase in 
hyperplasia of the proximal tubule epithelium at 40 mg/kg/day. Based on 
these findings, the NOEL was 3.0 mg/kg/day and the lowest observed 
effect level (LOEL) in rats was 10.0 mg/kg/day.
    A 90-day oral toxicity study was conducted in dogs with dose levels 
of technical chlorothalonil of 15, 150 and 750 mg/kg/day. The two 
highest dosages resulted in lower body weight gain in male dogs. The 
NOEL was 15 mg/kg/day, and the LOEL was 150 mg/kg/day based on 
decreased body weight gain in males.
    Two 21-day dermal toxicity studies were conducted with technical 
chlorothalonil. In the initial study, rabbits were dosed at 50, 2.5 and 
0.1 mg/kg/day. The NOEL and LOEL for systemic effects and dermal 
effects were both greater than 50 mg/kg/day. The NOEL for dermal 
irritation was 0.1 mg/kg/day. A subsequent 21-day dermal study was 
conducted in male rats, to specifically evaluate the potential for 
nephrotoxicity in this laboratory species following dermal dosing. In 
this study the doses were 60, 100, 250 and 600 mg/kg/day. The NOEL for 
nephrotoxicity was greater than 600 mg/kg/day.

[[Page 48852]]

    Estrogenic effects. ISK Biosciences concludes that based upon all 
of the chronic toxicity, developmental toxicity, mutagenicity and 
reproductive studies conducted with chlorothalonil and its metabolites, 
results did not indicate any potential to cause estrogenic effects, or 
endocrine disruption.
    5. Chronic toxicity. A 12-month chronic oral toxicity study in 
Beagle dogs was conducted with technical chlorothalonil at dose levels 
of 15, 150 and 500 mg/kg/day. The no observed adverse effect level 
(NOAEL) was 150 mg/kg/day based on lower blood albumin levels at the 
highest dose. There was no nephrotoxicity observed at any dose in this 
study.
    A chronic feeding/carcinogenicity study with Fischer 344 rats fed 
diets containing 0, 800, 1,600 or 3,500 ppm (equivalent to 0, 40, 80 or 
175 mg/kg body weight (body weight (bwt))/day) for 116 weeks in males 
or 129 weeks in females, resulted in a statistically higher incidence 
of combined renal adenomas and carcinomas. At the high dose, which was 
above the maximum tolerated dose (MTD), there was also a statistically 
significant higher incidence of tumors of the forestomach in female 
rats.
    In a second chronic feeding/carcinogenicity study with Fischer 344 
rats, designed to define the NOEL for tumors and the preneoplastic 
hyperplasia, animals were fed diets containing 0, 2, 4, 15 or 175 mg/
kg/day. The NOEL in this study, based on renal tubular hyperplasia, was 
a nominal dose of 2 mg/kg body weight (bwt)/day. Because of the 
potential for chlorothalonil to bind to diet, the 2 mg/kg bwt/day dose, 
expressed as unbound chlorothalonil is 1.8 mg/kg body weight(bwt)/day. 
The NOEL for hyperplasia and hyperkeratosis of the forestomach was 4 
mg/kg body weight(bwt)/day or a dose of 3.8 mg/kg bwt/day based on 
unbound chlorothalonil.
    A 2-year carcinogenicity study in CD-1 mice at dietary levels of 0, 
750 and 1,500 or 3,000 ppm (equivalent to 0, 107, 214 or 428 mg/kg/
day), resulted in a statistically higher incidence of squamous cell 
carcinomas of the forestomach in both sexes, and a statistically higher 
incidence of combined renal adenomas/carcinomas in only the male mice 
receiving the low dose. There were no renal tumors in any female mouse 
in this study.
    A 2-year carcinogenicity study in male CD-1 mice for the purpose of 
establishing the no effect level for renal and forestomach effects, was 
conducted at dietary levels of 0, 10/15, 40, 175, or 750 ppm 
(equivalent to 0, 1.4/2.1, 5.7, 25 or 107 mg/kg/day). The NOEL level 
for renal effects was 40 ppm and the NOEL for forestomach effects was 
15 ppm.
    The Agency classifies and regulates chlorothalonil as a B2 
(probable human carcinogen). This classification was based on 
statistically significant increases in the incidence of renal adenomas 
and carcinomas in male and female Fisher 344 rats, a statistically 
significant increase in combined renal adenoma/carcinoma of the 
forestomach in male and female Osborne-Mendel rats, and statistically 
significant increases in carcinoma of the forestomach in male and 
female CD-1 mice, as well as positive dose-related trend for combined 
renal adenoma/carcinoma in male mice.
    A carcinogenic potency factor, Q1*, of 0.00766 (mg/kg/
day)<SUP>-1</SUP> is used by the Agency when conducting mathematical 
modeling to estimate carcinogenic risk to humans. The carcinogenic 
potency factor was calculated based upon female rat renal (adenoma and/
or carcinoma) tumor rates.
    The Agency is currently evaluating recently submitted mechanistic 
data in connection with the registrants' assertions regarding the 
carcinogenicity of chlorothalonil. No conclusions are available at this 
time.
    Reference Dose (RfD): A RfD of 0.02 mg/kg/day was determined based 
on the NOEL of 2 mg/kg/day established in a 2-year dietary study in 
rats and using an uncertainty factor of 100.
    The no effect level (NOEL) for chlorothalonil is based on the 
nephrotoxicity observed in the chronic rat study. The Agency considers 
the NOEL to be 2.0 mg/kg/bwt, which is the nominal dose.
    No effect levels for maternal toxicity from developmental studies 
are 10 mg/kg body weight (bwt) in rabbits and 100 mg/kg body weight 
(bwt) in the rat. The no effect level for pup growth in the 
reproduction study was 1,500 mg/kg body weight(bwt) which would be most 
conservatively estimated as equating to approximately 75 mg/kg/bwt.
    6. Animal metabolism. Approximately 33% of chlorothalonil at dose 
levels at or below 50 mg/kg was orally absorbed. Of this amount, 80 to 
90% was eliminated in the feces and 15-20% of the dose was excreted 
into the bile. No significant levels of chlorothalonil were found in 
any tissues. The compound was metabolized primarily via glutathione 
conjugation (mono, di and triglutathione conjugates; possibly tetra). 
These conjugates were excreted directly into bile; some were shown to 
have been transported to the kidneys where they were cleaved to thio 
metabolites, the excretion of which was rate-limited, and therefore, 
could lead to nephrotoxicity.
    7. Metabolite toxicology. The primary metabolite of chlorothalonil 
is 4-Hydroxy-2,5,6-Trichloroisophthalonitrile ( 4-OH or SDS-3701). The 
toxicity data base for SDA-3701 is adequate. Two data gaps currently 
exist for a 1-year chronic toxicity study in dogs and a developmental 
toxicity study in rats. SDS-3701 has been show to be a minor residue in 
soil and rotated crops. The existing toxicity data base can be 
summarized as follows:
    a. Acute toxicity. The acute oral LD<INF>50</INF> for male rats was 
422 mg/kg and for female rats was 242 mg/kg, with the combined sexes 
value being 332 mg/kg.
    b. Subchronic toxicity. Sprague-Dawley rats dosed with SDS-3701 at 
0, 0.5, 2.5, 5 or 10 mg/kg/day in a 4-month feeding study resulted in a 
NOEL at 5 mg/kg/day and the LOEL at 10 mg/kg/day based on depressed 
body weight and an increase in liver weight. Sprague-Dawley rats of 
both sexes dosed for 61-69 days at doses of 0, 10, 20, 40, 75, 125, 
250, 500 or 750 mg/kg/day. The NOEL was 20 mg/kg/day and the LOEL was 
40 mg/kg/day based on decreased body weights, anemia and renal cortical 
atrophy. In a 3-month feeding study in beagle dogs with SDS-3701 fed at 
0, 1.25, 2.5 or 5.0 mg/kg/day, the NOEL was 2.5 mg/kg/day and the LOEL 
was 5.0 mg/kg/day based on renal tubular degeneration and vacuolation 
in males.
    c. Chronic toxicity and carcinogenicity. In a 2-year study SDS-3701 
was fed to Sprague-Dawley rats at 0, 0.5, 3.0, 15 (reduced to 10 at 
week 30) or 30 (reduced to 20 at week 30) mg/kg/day. The NOEL was 3.0 
mg/kg/day. The LOEL was 10 mg/kg/day based on reduced body weight, 
microcyticanemia, hemosiderin and decreased serum potassium. In a 2-
year study with CD-mice and SDS-3701 were fed at 0, 54, 107 or 214 mg/
kg/day, the NOEL was not established; the LOEL was <54 mg/kg/day based 
on increased liver-to-body weight ratios in males. In both the above 
studies, there was no evidence of carcinogenicity in either sex.
    d. Developmental toxicity. SDS-3701 was fed to pregnant Dutch 
Belted rabbits at dose levels of 1, 2.5, or 5 mg/kg/day on gestation 
days six through fifteen. For maternal toxicity the NOEL was 1 mg/kg/
day and the LOEL was 2.5 mg/kg/day based on a dose dependent increase 
in maternal death and abortion. The developmental toxicity NOEL was 5 
mg/kg/day. No LOEL was established.

[[Page 48853]]

    e. Reproductive toxicity. In a 1-generation reproduction study, 
SDS-3701 was fed to Sprague-Dawley CD rats at 0, 0.5, 1.0, 1.5, 3.0 or 
6.0 mg/kg/day. For paternal systemic toxicity, the NOEL was 1.5 mg/kg/
day. In a 3-generation reproduction study with the same rat species fed 
SDS-3701 at 0, 0.5, 3.0, or 6.25 mg/kg/day the parental systemic NOEL 
was 0.5 mg/kg/day. In both the 1 and 3-generation studies the LOEL was 
the same, 3.0 mg/kg/day based on reduced weaning body weight and the 
reproductive toxicity NOEL was similar at 6.0 and 6.25 mg/kg/day.
    f. Mutagenicity. SDS-3701 did not cause DNA damage in S. 
Typhimurium or induce a mutagenic response when tested in this species 
or in tests with cultured Chinese hamster V 79 cells or BALB/3T3 mouse 
fibroblasts. No evidence of mutagenesis was found in host mediated 
assay using S. typhimurium tester strains and mice exposed daily for 5 
days to 6.5 mg/kg/day of the compound.

C. Aggregate Exposure

    1. Dietary exposure. Available information on anticipated residues 
was incorporated into the analysis to estimate the Anticipated Residue 
Contribution (ARC) from each existing use. Potential dietary exposure 
determinations were based on estimates of anticipated residues of 
chlorothalonil in food and drinking water.
    a. Food. Chlorothalonil would be applied to asparagus ferns which 
regrow after harvest of the spears to protect the ferns from diseases. 
There is no harvest until the following crop season and little chance 
of chemical residues of chlorothalonil or its major metabolite on the 
spears. ISK Biosciences determined that anticipated actual residues of 
chlorothalonil on asparagus spears would be 0.0000000891 mg/kg body 
weight(bwt)/day to the U.S. population and 0.0000000719 mg/kg body 
weight(bwt)/day to children ages 1-6.
    Chlorothalonil would be applied to mango trees during the growing 
season for control of diseases. ISK Biosciences determined that 
anticipated actual residues of chlorothalonil on mangoes would be 
0.0000000633 mg/kg body weight(bwt)/day to the U.S. population and 
0.000000129 mg/kg body weight(bwt)/day to children ages 7-12.
    Chlorothalonil would be applied to pistachio trees during the 
growing season for control of diseases. The nuts used for human 
consumption are not directly exposed to the sprays. Thus, there is 
little chance of significant levels of residues of chlorothalonil or 
its major metabolite on pistachio nutmeats. ISK Biosciences determined 
that anticipated actual residues of chlorothalonil on pistachios would 
be 0.0000000167 mg/kg body weight(bwt)/day to the U.S. population and 
0.0000000304 mg/kg body weight(bwt)/day to children ages 1-6.
    There is no reasonable expectation that secondary residues will 
occur in milk, eggs, or meat, fat, or meat byproducts of livestock or 
poultry as a result of this action; there are no livestock feed items 
associated with asparagus, mangoes or pistachios.
    ISK Biosciences believes that exposure, based on the current 
registered uses for chlorothalonil, is 0.0000642 mg/kg body 
weight(bwt)/day for the general U.S. population and 0.000105 mg/kg body 
weight(bwt)/day for infants and children 1-6 years of age. For all 
published and pending tolerances, the respective exposures are 
0.0000651 mg/kg body weight(bwt)/day and 0.000106 mg/kg body 
weight(bwt)/day.
    b. Drinking water. Results of monitoring studies in the National 
Survey of Pesticides in Drinking Water Wells conducted by EPA showed 
that no chlorothalonil residues were detected in any of the 1,300 
community water systems and domestic wells (using methodology for 
chlorothalonil having a limit of detection (LOD) of 0.06 micro 
grams(<greek-m>g/l) and limit of quantitation of 0.12 <greek-m>g/l). 
The absence of chlorothalonil detections in the National Survey 
suggests that chlorothalonil is not a contaminant in drinking water 
wells and that the population is not exposed to chlorothalonil in these 
water sources. These findings are consistent with the physical and 
chemical properties of chlorothalonil, including low water solubility 
(0.9 ppm) and high affinity for organic matter including soil. It has 
also been demonstrated that chlorothalonil does not leach into 
groundwater from applications made to growing crops.
    Aerobic aquatic metabolism studies with chlorothalonil establish a 
half-life in natural aquatic habitats of less than 10 hours, depending 
on environmental conditions. The short half-life of chlorothalonil in 
natural water/sediment systems and practiced water treatment techniques 
prior to consumption, suggest that chlorothalonil is not likely to be 
present in drinking water obtained from natural surface water systems.
    An exposure estimate, based on surface water concentration recently 
cited by EPA, would conclude that the average concentration in surface 
water would be less than 0.002 parts per billion (ppb). Assuming that 
everyone in the US consumed untreated surface water, the exposure to 
chlorothalonil of the general population would be less than 0.00000058 
mg/kg body weight(bwt)/day. This would be a worst case scenario, which 
would greatly overestimate exposure.
    2. Non-dietary exposure. Potential non-dietary exposures to 
chlorothalonil may result from the following uses of chlorothalonil. In 
each case, the exposure would be from the dermal route and only for an 
intermittent duration. The two 21-day dermal studies that have been 
conducted in the rabbit and rat indicate that there is no 
nephrotoxicity associated with the dermal exposure to chlorothalonil at 
dose levels up to 600 mg/kg/day. Therefore, ISK Biosciences concludes 
the exposures from the uses of chlorothalonil listed below, would not 
be expected to add to the carcinogenic risk associated with 
chlorothalonil.
    a. Residential owner uses. ISK Biosciences contends that 
application of chlorothalonil to home lawns and gardens represents 
minor uses and would be expected to present very little potential for 
homeowner exposure.
    b. Paint. Chlorothalonil is used in paints and stains for control 
of mildew and molds on exterior surfaces of buildings and occasionally 
for interior paints. The company estimates that only about 2% of the 
chlorothalonil used in paint is used in interior paint and only 0.2% or 
less of interior paints in the United States contains chlorothalonil. 
In paints chlorothalonil is tightly bound within the paint matrices; 
thus, effective control of mildew may last for several years and the 
potential for exposure is very limited.
    c. Grouts. Chlorothalonil is used in cement tile grouts, also for 
control of mildew and molds. Chlorothalonil is bound within the grout 
matrices and presents little exposure opportunity. This is a minor use 
of chlorothalonil and non-occupational dermal exposure of humans to 
chlorothalonil from this source is extremely low.
    d. Wood treatment. Chlorothalonil is used for control of sapstain 
as a surface treatment on rough-cut, newly-sawn lumber to protect it 
from molds and mildews while drying. Chlorothalonil does not occur in 
structural wood used for residential or occupational scenarios.

D. Cumulative Effects

    ISK Biosciences has considered the potential for cumulative effects 
of chlorothalonil and other substances that have a common mechanism of 
toxicity. Chlorothalonil is a halogenated benzonitrile fungicide which 
readily undergoes displacement of chlorine in

[[Page 48854]]

the 2, 4 and 6 positions by glutathione and other thiol containing 
amino acids and proteins. In the rat, the glutathione conjugates are 
sufficiently absorbed from the gut and subsequently metabolized to form 
di- and tri-thiol metabolites which may produce a nephrotoxic effect. 
In dogs where this absorption and subsequent metabolism to di- and tri-
thiol metabolites does not occur, nephrotoxicity does not occur. ISK 
Biosciences does not have any information to indicate that toxic 
effects observed in rats occur through a mechanism which is common to 
any other agricultural chemical. Thus, it appears inappropriate to 
group chlorothalonil with any other pesticide at this time.

E. Safety Determination

    1. U.S. population.Exposure to anticipated actual residues of 
chlorothalonil on asparagus, as discussed above, would represent only 
0.0005% of the RfD (0.018 mg/kg/day) in the diets of the U.S. 
population with a corresponding carcinogenic risk of 6.8 X 
10<SUP>-10</SUP>.
    Exposure to anticipated actual residues of chlorothalonil on 
mangoes, as discussed above, would represent only <0.0004% of the RfD 
(0.018 mg/kg/day) in the diets of the U.S. population with a 
corresponding oncogenic risk of 4.8 X 10<SUP>-10</SUP>. For infants and 
children ages 1-6, residues on mangoes would represent <0.0008% of the 
RfD. Exposure to anticipated actual residues of chlorothalonil on 
pistachios, as discussed above, would represent only <0.0001% of the 
RfD (0.018 mg/kg/day) in the diets of the U.S. population with a 
corresponding oncogenic risk of 6.8 X 10-<SUP>-10</SUP>. For infants 
and children ages 1-6, residues on pistachios would represent <0.0002% 
of the RfD.
    All published and pending tolerances for chlorothalonil utilize 
less than 1% of the RfD for all segments of the U.S. population with 
corresponding oncogenic risks of 5.0 X 10<SUP>-7</SUP> for the general 
U.S. population.
    Because the worst case assumptions for human exposure from drinking 
water indicate that exposure would be only 1% of the dietary exposure, 
the risk assessment is not significantly altered by considering the 
exposure from drinking water.
    2. Infants and children. There is a complete database for 
chlorothalonil which includes pre- and post-natal developmental 
toxicity data as well as mechanistic data related to the rodent 
specific nephrotoxicity observed in subchronic and chronic studies. The 
toxicological effects of chlorothalonil in rodents are well understood. 
Chlorothalonil has a low level of toxicity in dogs.
    In a two-generation reproduction study in rats, all reproductive 
parameters investigated showed no treatment-related effects except pup 
weight gain. Specifically, the weights of pups exposed to 
chlorothalonil were comparable to controls at parturition through day 
four of lactation. It was only after day four of lactation, when the 
pups begin to consume the test diet, that body weight gain lags behind 
controls. This only occurred at the highest dose tested; 3,000 ppm. The 
dose of chlorothalonil the pups would receive would be far in excess of 
the estimated adult dose of 150 mg/kg body weight(bwt)/day (3,000 ppm 
<divide> 20). The doses for the pups could have easily exceeded 500 mg/
kg body weight (bwt)/day. Dose levels of 375 mg/kg body weight (bwt) 
and above have been shown to significantly affect body weight in the 
rat. Therefore, the reduction of body weight gain observed in the 
reproduction study is considered to be comparable to the effects that 
have been observed in older rats. The NOEL for this effect was 1,500 
ppm.
    In developmental toxicity studies conducted in the rat and the 
rabbit, chlorothalonil did not cause any developmental effects even at 
dose levels that produced significant maternal toxicity. In the rabbit 
a dose level of 20 mg/kg body weight (bwt) caused maternal toxicity, 
but there were no developmental effects and in the rat, a dose level of 
400 mg/kg body weight (bwt) caused maternal toxicity without 
developmental toxicity.
    The extensive data base that is available for chlorothalonil is 
devoid of any indication that chlorothalonil would represent any 
unusual or disproportionate hazard to infants or children. Therefore, 
ISK Biosciences believes that there is no need to impose an additional 
10X safety factor for infants or children and argues that the standard 
uncertainty factor of 100X should be used for all segments of the human 
population when calculating risks associated with chlorothalonil.

F. International Tolerances

    A maximum residue level has not been set for chlorothalonil on 
pistachios by the Codex Alimentarius Commission.

3. Zeneca Ag Products

PP 6E4653

    EPA has received a pesticide petition (PP 6E4653) from the 
Interregional Research Project No. 4 (IR-4), New Jersey Agricultural 
Experiment Station, P.O. Box 231, Rutgers University, New Brunswick, NJ 
08903, 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 sodium salt of 
fomesafen (also referred to in this document as fomesafen, 5-[2-chloro-
4- (trifluoromethyl)phenoxy]-N-(methylsulfonyl)-2-nitrobenzamide, in or 
on the raw agricultural commodity snap beans at 0.05 parts per million 
(ppm).

A. Residue Chemistry

    1. Plant metabolism. Fomesafen metabolism has been extensively 
studied in soybeans. Once in the plant, fomesafen shows very rapid 
metabolism with either cleavage or conjugation of the intermediate 
degradation products to a complex mixture of low level degradation 
products. There is no significant translocation. For purposes of 
regulation, the parent compound fomesafen is the residue of concern on 
harvested bean crops.
    2. Analytical method. The method of analysis uses High Pressure 
Liquid Chromatography. It is method GAM-RM-001/86, which was developed 
for analytical work on soybeans and adapted for use on snap beans. The 
limit of detection of the analytical method is 0.025 ppm.
    3. Magnitude of residues. Residue data are available for fomesafen 
applied post-emergence on snap beans at the maximum label rate of 0.375 
pounds active ingredient/acre (lb ai/A). The residue field trials were 
conducted by the IR-4 project in the States of Florida, North Carolina, 
New York, Oregon, and Wisconsin, representing approximately 50% of the 
national snap bean acreage. Each treated plot received a single post-
emergence, prebloom application at either 0.25 or 0.375 lb ai/A. Four 
snap bean samples per treatment were collected from each trial. Samples 
were harvested 22 to 31 days after treatment, a normal range for snap 
beans. There are no detectable residues in snap beans when fomesafen is 
applied up to 0.375 lb ai/A prior to pod development, pre-bloom 
application.
    Based on the results of the poultry and ruminant metabolism 
studies, fomesafen is rapidly metabolized and excreted. There are no 
expected residues of fomesafen in meat, milk, or eggs. Snap beans are 
not a significant livestock feed commodity.

B. Toxicological Profile

    1. Acute toxicity. The acute toxicity profile of technical 
fomesafen is low by oral, dermal and inhalation routes. Similarly the 
formulated fomesafen

[[Page 48855]]

product (REFLEX) is of low oral, dermal and inhalation toxicity but is 
classed as Category I toxicity based on the highest hazard, severe eye 
irritancy. Fomesafen is not a skin sensitizer and only a slight 
irritant to the skin.
    Results of the acute toxicity testing with REFLEX show acute oral 
in the rat lethal dose (LD)<INF>50</INF> > 2,000 milligram (mg)/
kilogram (kg), acute dermal in the rabbit LD<INF>50</INF> > 2,000 mg/
kg, acute inhalation in the rat LD<INF>50</INF> > 5.48 mg/liter (L), 
eye irritation in the rabbit showed severe irritancy, and skin 
irritation in the rabbit showed a slight irritancy. REFLEX is not a 
skin sensitizer.
    2. Genotoxicity. Fomesafen tested negative in assay systems for 
gene mutation, structural chromosome aberration and other genotoxic 
effects. However fomesafen did produce a weak clastogenic response in 
the rat bone marrow when the analysis of the data was undertaken with 
gap-type aberrations both included and excluded.
    In the registrant's view, gap-type aberrations (small 
discontinuities in the staining of the chromosomes, as distinct from 
breaks), do not indicate significant chromosomal damage and should be 
excluded from the evaluation of such assays. Their conclusion therefore 
is that these data should be considered to indicate no clastogenic 
effect of fomesafen with no biologically significant genotoxic effects.
    3. Reproductive and developmental toxicity. In a 2-generation 
reproduction study in rats fed diets containing 0, 50, 250 or 1,000 ppm 
fomesafen (equivalent to 2.5, 12.5 or 50 mg/kg/day) no reproductive 
effects were observed. The no observed effects level (NOEL) for 
systemic toxicity (reduction in body weight gain and liver necrosis) is 
established at 250 ppm for this study.
    In a developmental toxicity study in rats given oral doses of 
fomesafen at 0, 50, 100, or 200 mg/kg/day on gestation days 6 to 15 
there was no developmental toxicity and the NOEL was established at 50 
mg/kg/day, following evaluation of a second study at lower doses.
    A developmental toxicity study in rabbits given oral doses of 0, 
2.5, 10, or 40 mg/kg/day on gestation days 6 to 18 with no 
developmental toxicity.
    4. Subchronic toxicity. Subchronic oral toxicity studies in the rat 
(90-day) and dog (26 weeks) show that the liver is the primary target 
of toxicity in both sexes. Rats were dosed at 1, 5, 100, and 1,000 ppm 
in the diet. The lowest observed effect level (LOEL) in this study was 
100 ppm (5 mg/kg/day) and the NOEL was 5 ppm (0.25 mg/kg/day). The dogs 
were dosed at 0.1, 1 and 25 mg/kg/day. The LOEL in this study was 25 
mg/kg/day and the NOEL was 1 mg/kg/day.
    A 21-day dermal toxicity study in the rabbit at doses of 10, 100, 
and 1,000 mg/kg/day showed moderate to severe skin irritation at the 
application site but no systemic effects at doses up to 1,000 mg/kg/
day. The LOEL for skin irritation was 100 mg/kg/day and the NOEL was 10 
mg/kg/day.
    5. Chronic toxicity. Beagle dogs were administered fomesafen in 
gelatin capsules at dose levels of 0, 0.1, 1.0 or 25 mg/kg body weight 
(bwt)/day for 26 weeks with a NOEL of 1.0 mg/kg/day. There were no 
deaths, no clinical signs of toxicity and no treatment related effects 
on bodyweight or food consumption. Evidence of toxicity was observed at 
25 mg/kg/day. Hypolipidemia was present in dogs of both sexes. At 
autopsy liver weight was increased at 25 mg/kg/day; microscopic 
examination revealed eosinophilic damage and peroxisome proliferation 
in both sexes.
    A 2-year feeding/carcinogenicity study with rats fed diets 
containing 0, 5, 100, or 1,000 ppm of fomesafen gave a NOEL for 
systemic effects of 5 ppm (0.25 mg/kg/day). At the lowest-effect level 
(LEL) 100 ppm (5 mg/kg/day) there were minor changes associated with 
liver toxicity. There were no carcinogenic effects observed under the 
conditions of the study.
    A carcinogenicity study was conducted in CD-1 mice fed diets 
containing 0, 1, 10, 100 or 1,000 ppm fomesafen (equivalent to 0.15, 
1.5, 15 or 150 mg/kg/day) for up to 89 weeks. Increased mortality was 
seen at 1,000 ppm in both males and females and liver weights were 
increased at 100 and 1,000 ppm. A dose-related increase in the 
incidence of benign and malignant hepatocellular tumors was observed. 
Both tumor types were statistically significant in males and females at 
1,000 ppm. At the 100 ppm feeding level (male and female), the 
increased incidence was confined to benign tumors. The increase in 
benign liver tumors at 1 ppm in males only was not considered related 
to fomesafen, due to the lack of any increase at 10 ppm.
    The Agency has classified fomesafen as a Group C carcinogen 
(possible human carcinogen) with a potency factor (Q1*) of 0.0019 mg/
kg/day.
    6. Animal metabolism. Fomesafen is well absorbed and completely 
metabolized in the rat. Excretion is rapid with 90% of the compound 
excreted within 7 days of ingestion. There is no accumulation of 
fomesafen.
    7. Metabolite toxicology. Toxicity testing results for the 
fomesafen parent compound is indicative of any metabolites, either in 
the plant or animal.

C. Aggregate Exposure

    1. Dietary exposure. For purposes of assessing the potential 
dietary exposure, ZENECA estimated aggregate exposure based on the 
tolerance for fomesafen on soybeans and snap beans at 0.05 ppm. Dietary 
exposure to residues of fomesafen in or on food will be limited to 
residues on soybean and snap beans. Based on the animal metabolism 
data, and because there are no residues on the crops at time of 
harvest, the company has concluded that there is reasonable expectation 
that no measurable residues of fomesafen will occur in meat, milk, 
poultry, or eggs from this use. There are no other established U.S. 
tolerances for fomesafen.
    2. Food. On the bases of the Group C carcinogen classification of 
fomesafen the upper-bound carcinogenic risk from dietary exposure to 
fomesafen was calculated using a potency factor (Q*) of 0.19 (mg/kg/
day)<SUP>-1</SUP> and dietary exposure as estimated by the Anticipated 
Residue Contribution (ARC) for existing tolerances and the proposed 
tolerance for snap beans. The upper-bound carcinogenic risk from 
established tolerances and the proposed tolerance for snap beans is 
calculated at 1.56 x 10<SUP>-6</SUP> for the U.S. Population. The 
upper-bound carcinogenic risk from the proposed use on snap beans is 
calculated at 1.4 x 10<SUP>-6</SUP>. Therefore, the potential cancer 
risk from residues of fomesafen resulting from the combined established 
tolerance on soybeans and the proposed tolerance for snap beans is 
negligible.
    3. Drinking water. Other potential sources of exposure of the 
general population to residues of pesticides are residues in drinking 
water and exposure from non-occupational sources. Field dissipation 
data and a prospective groundwater study indicate that fomesafen is 
persistent and has the potential to leach to groundwater. There is no 
established Maximum Concentration Level (MCL) for residues in drinking 
water. No drinking water health advisory has been established.
    Risk of contaminating surface water. Zeneca contends that fomesafen 
is unlikely to enter surface water bodies to any significant degree 
except by direct accidental over-spray. Should this arise, fomesafen 
will be readily degraded by a number of contributory processes. 
Fomesafen is not persistent in water in sunlit aquatic conditions. All 
these processes will ensure that any fomesafen entering surface water 
bodies will be short-lived and will not result in

[[Page 48856]]

any significant contamination of potential drinking water sources.
    Therefore, Zeneca concludes that potential exposures from residues 
of fomesafen in drinking water added to the current dietary exposure 
will not present significant risk to the U.S. population.
    4. Non-dietary exposure. Since fomesafen is not registered for 
residential or turf uses, exposures from other than dietary or 
occupational sources are extremely unlikely. At this time there are no 
reliable data to assess the potential risk from non-dietary sources.

D. Cumulative Effects

    Fomesafen is a diphenyl ether class of chemicals. At this time, EPA 
has not made a determination that fomesafen and other compounds have a 
common mechanism of toxicity resulting in cumulative effects. 
Therefore, aggregate exposure is evaluated on the uses of fomesafen 
only.

E. Safety Determination

    1. U.S. population. The Reference Dose (RfD) for fomesafen has not 
been established by the Agency's. For purposes of this action, the RfD 
is calculated at 0.0025 mg/kg of body weight/day. The RfD is based on a 
NOEL of 0.25 mg/kg/day from the rat feeding/carcinogenicity study and 
an uncertainty factor of 100. The ARC for the overall U.S. population 
from established tolerances and the proposed tolerance for snap beans 
utilizes 1.4% of the RfD. EPA generally has no concern for exposures 
below 100% of the RfD.
    The upper-bound carcinogenic risk from established tolerance on 
soybeans and the proposed tolerance for snap beans is calculated at 
1.56 x 10<SUP>-6</SUP> for the U.S. population, based on the available 
market share data. The upper-bound carcinogenic risk from the proposed 
use on snap beans is calculated at 1.4 x 10<SUP>-6</SUP>. Therefore, 
Zeneca believes that the potential cancer risk from residues of 
fomesafen resulting from the combined established tolerance on soybeans 
and the proposed tolerance for snap beans is negligible.
    2. Infants and children. Zeneca noted that the potential for 
additional sensitivity for infants and children to residues of 
fomesafen have been considered based on the three-generation 
reproductive study in rats and the developmental toxicity studies in 
rat and rabbit. Zeneca concluded that fomesafen showed no evidence of 
reproductive toxicity and caused no developmental toxicity in the 
rabbit or in the rat.
    FFDCA section 408 provides that EPA may apply an additional safety 
factor for infants and children in the case of threshold effects to 
account for pre- and post-natal toxicity and the completeness of the 
database. Based on the current toxicological data requirements, the 
database relative to pre- and post-natal effects for children is 
complete for fomesafen. Zeneca AG Products concludes that there is 
reasonable certainty that no harm will result to infants and children 
from aggregate exposure to fomesafen.

F. International Tolerances

    There are no Codex Maximum Residue Levels established for fomesafen 
residues.

[FR Doc. 97-24692 Filed 9-16-97; 8:45 am]
BILLING CODE 6560-50-F


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