48848 Federal Register / Vol. 62, No. 180 / Wednesday, September 17, 1997 / Notices

tumorigenic in animals even at

maximally tolerated doses and has a

different spectrum of toxicological

effects.

E. Safety Determination

1. US population. The Rohm and Haas

Company estimates the risk to the U.S.

adult population from use of

fenbuconazole on wheat as utilizing

approximately 0.36% of the RfD. Using

the EPA low dose extrapolation model

and the risk factor based on the mouse

data (0.36 x 10-6 (mg/kg/day)-1) the

excess cancer risk from dietary sources

for fenbuconazole use on wheat and the

associated animal commodities is

estimated at 0.3 x 10-6. The upper bound

estimate on excess cancer risk for all

uses including wheat is 0.7 x 10-6.

This assumes that all of the wheat

consumed in the U.S. will contain

residues of fenbuconazole (in actuality a

small fraction of the total crop is likely

to be treated). The combined risk for

wheat plus registered uses will not

exceed either the dietary risk standard

established by the Food Quality

Protection Act (FQPA) for the US

population, (one x 10-6), or the RfD.

The sole acute risk would be for

women of childbearing age. The EPA/

OREB calculated that the worst-case

Margin of Exposure (MOE) for

fenbuconazole measured against the

developmental LOEL would be greater

than 30,000. This is clearly adequate.

The MOE would be even higher for

consumer dietary exposure from any

source. Thus, there is adequate safety

for this group and there is a reasonable

certainty that no harm will result from

fenbuconazole use on wheat.

2. Infants and children. The

reproductive and developmental

toxicity data base for fenbuconazole is

complete. There is no selective increase

in toxicity to developing animals. Thus,

there is no evidence that prenatal and

postnatal exposure would present

unusual or disproportionate hazard to

infants or children. Therefore, there is

no need to impose an additional

uncertainty factor to protect infants and

children.

The EPA calculated the dietary risk to

infants and children for existing

tolerances. The estimated dietary

exposure (TMRC) for this subpopulation

is 0.00522 mg/kg/day which represents

only 17% of the RfD; no other subgroup

used in excess of 17% of the RfD. The

EPA estimated lifetime oncogenic risk

in the range of one in a million at 0.9

x 10-6, using (Q1* = 1.06x10-2 (mg/kg/

day)-1). (60 FR 27420; May 24,1995).

For the wheat use the most sensitive

subgroup is children 1 to 6 years old

and the estimated risk to this subgroup

is less than 18% of the RfD. Utilizing

the risk factor (Q1* = 0.36x10-2 (mg/kg/

day)-1), the estimated excess cancer risk

for the U.S. population is less than 1 x

10-6. Therefore the wheat use is safe

within the meaning of the FQPA and

there is a reasonable certainty that no

harm will result to infants or children

from the approval of fenbuconazole use

on wheat.

F. International Tolerances

There are no Codex Maximum

Residue Levels (MRLs) for

fenbuconazole, but the fenbuconazole

database will be evaluated by the WHO

and the FAO Expert Panels at the Joint

Meeting on Pesticide Residues (JMPR)

in September 1997. An Allowable Daily

Intake (ADI (RfD)) of 0.03 mg/kg/day is

proposed and a total of 36 Codex MRLs

are proposed in the data submission.

G. Environmental Fate Summary

Fenbuconazole has little to no

mobility in soil (Koc = 4425). It is stable

to hydrolysis and aqueous photolysis in

buffered solutions, but does degrade

photolytically in natural waters and soil

(half–life 87 and 79 days, respectively).

Laboratory soil metabolism half–lives or

DT50 values for fenbuconazole range

from 29 to 532 days under terrestrial

conditions and from 442 to 906 in soil

exposed to aquatic conditions. Fieldtrial soil dissipation studies had half–

lives ranging from 157 to 407 days and

indicated no significant downward

movement of residues. These field trials

show fenbuconazole degrades more

rapidly outdoors than in laboratory

metabolism studies. When material was

applied in a single application,

fenbuconazole degraded to about 50%

of the applied material in less than 60

days. In wheat the DT50 in green heads

was measured as 18 days and in green

wheat stalks the DT50 was 84.4 days.

These results only reflect foliar

dissipation in wheat at the particular

growth stage(s) during the study and not

at all stages of wheat. The results of

residue decline analyses in a number of

environmental media support the EPA

conclusion that there is no

environmental hazard associated with

the proposed agricultural use of this

chemical.

[FR Doc. 97–24693 Filed 9–16–97; 8:45 am]

BILLING CODE 6560–50–F

ENVIRONMENTAL PROTECTION

AGENCY

[PF–754; FRL–5735–8]

Notice of Filing of Pesticide Petitions

AGENCY: Environmental Protection

Agency (EPA).

ACTION: Notice.

SUMMARY: This notice announces the

initial filing of pesticide petitions

proposing the establishment 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.
Federal Register / Vol. 62, No. 180 / Wednesday, September 17, 1997 / Notices 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 (LD)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 multigeneration 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
48850 Federal Register / Vol. 62, No. 180 / Wednesday, September 17, 1997 / Notices

(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 pnitroanisole 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, nondietary 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
Federal Register / Vol. 62, No. 180 / Wednesday, September 17, 1997 / Notices 48851

relevant to humans was established

based on the NOEL from the multigeneration 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-trichloroisophthalonitrile 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 fourhour 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 14Cchlorothalonil, 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.
48852 Federal Register / Vol. 62, No. 180 / Wednesday, September 17, 1997 / Notices

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 CD1 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. SpragueDawley 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 SDS3701 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.
Federal Register / Vol. 62, No. 180 / Wednesday, September 17, 1997 / Notices 48853

e. Reproductive toxicity. In a 1-

generation reproduction study, SDS3701 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(μg/l) and limit of

quantitation of 0.12 μg/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
48854 Federal Register / Vol. 62, No. 180 / Wednesday, September 17, 1997 / Notices

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 10–10. 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––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 10–7 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 GAMRM-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 postemergence, 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, prebloom 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
Federal Register / Vol. 62, No. 180 / Wednesday, September 17, 1997 / Notices 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 upperbound 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
48856 Federal Register / Vol. 62, No. 180 / Wednesday, September 17, 1997 / Notices

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 threegeneration 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

ENVIRONMENTAL PROTECTION

AGENCY

[PF–763; FRL–5742–9]

Notice of Filing of Pesticide Petitions

AGENCY: Environmental Protection

Agency (EPA).

ACTION: Notice.

SUMMARY: This notice announces the

initial filing of pesticide petitions

proposing the establishment of

regulations for residues of certain

pesticide chemicals in or on various

food commodities.

DATES: Comments, identified by the

docket control number PF–763, must be

received on or before October 17, 1997.

ADDRESSES: By mail submit written

comments to: Public Information and

Records Integrity Branch (7506C),

Information Resources and Services

Division, Office of Pesticides Programs,

Environmental Protection Agency, 401

M St., SW., Washington, DC 20460. In

person bring comments to: Rm. 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: Beth Edwards, Registration

Division (7505C), Office of Pesticide

Programs, Environmental Protection

Agency, 401 M St., SW., Washington,

DC 20460. Office location and telephone

number: Rm. 206, CM #2, 1921 Jefferson

Davis Highway, Arlington, VA 22202,

(703) 305–5400; e-mail:

edwards.beth@epamail.epa.gov.

SUPPLEMENTARY INFORMATION: EPA has

received pesticide petitions as follows

proposing the establishment and/or

amendment of regulations for residues

of certain pesticide chemicals in or on

various food commodities under section

408 of the Federal Food, Drug, and

Comestic Act (FFDCA), 21 U.S.C. 346a.

EPA has determined that these petitions

contain data or information regarding

the elements set forth in section

408(d)(2); however, EPA has not fully

evaluated the sufficiency of the

submitted data at this time or whether

the data supports granting of the

petition. Additional data may be needed

before EPA rules on the petition.

The official record for this notice of

filing, as well as the public version, has

been established for this notice of filing

under docket control number [PF–763]

(including comments and data

submitted electronically as described

below). A public version of this record,

including printed, paper versions of

electronic comments, which does not

include any information claimed as CBI,

is available for inspection from 8:30

a.m. to 4 p.m., Monday through Friday,

excluding legal holidays. The official

record is located at the address in

‘‘ADDRESSES’’ at the beginning of this

document.

Electronic comments can be sent

directly to EPA at:

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 number [pf–763] and

appropriate petition number. Electronic

comments on this notice may be filed