[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:
jackson.sidney@epamail.epa.gov.
[[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:
opp-docket@epamail.epa.gov
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="">50 in
the rat is 2,500 milligrams (mg)/kilogram (kg) and the acute dermal
LD50 in the rabbit is >2,000 mg/kg. The inhalation lethal
concentration (LC)50 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)50 >10,000
milligrams(mg)/kilogram(kg) (Toxicity Category IV) in rats; a dermal
LD50 >10,000 mg/kg (Toxicity Category IV) in rabbits; a
four-hour inhalation lethal concentration (LC)50 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 14C-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)-1 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 LD50 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="">g/l) and limit of quantitation of 0.12 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
10-10.
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. 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. 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="">-7 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
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)50 > 2,000 milligram (mg)/
kilogram (kg), acute dermal in the rabbit LD50 > 2,000 mg/
kg, acute inhalation in the rat LD50 > 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)-1 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 10-6 for the U.S. Population. The
upper-bound carcinogenic risk from the proposed use on snap beans is
calculated at 1.4 x 10-6. 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 10-6 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 10-6. 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
