Federal Register / Vol. 65, No. 78 / Friday, April 21, 2000 / Notices 21427

List of Subjects

Environmental protection, Chemicals,

Premanufacturer notices.

Dated: April 14, 2000.

Deborah A. Williams,

Acting Director, Information Management

Division, Office of Pollution Prevention and

Toxics.

[FR Doc. 00–10040 Filed 4–20–00; 8:45 am]

BILLING CODE 6560–50–F

ENVIRONMENTAL PROTECTION

AGENCY

[PF–937; FRL–6555–6]

Notice of Filing a Pesticide Petition to

Establish Tolerances for a Certain

Pesticide Chemical in or on Food

AGENCY: Environmental Protection

Agency (EPA).

ACTION: Notice.

SUMMARY: This notice announces the

initial filing of a pesticide petition

proposing the establishment of

regulations for residues of a certain

pesticide chemical in or on various food

commodities.

DATES: Comments, identified by docket

control number PF–937, must be

received on or before May 22, 2000.

ADDRESSES: Comments may be

submitted by mail, electronically, or in

person. Please follow the detailed

instructions for each method as

provided in Unit I.C. of the

‘‘SUPPLEMENTARY INFORMATION.’’

To ensure proper receipt by EPA, it is

imperative that you identify docket

control number PF–937 in the subject

line on the first page of your response.

FOR FURTHER INFORMATION CONTACT: By

mail: Mary L. Waller, EPA, Registration

Division (7505C), Office of Pesticide

Programs, Environmental Protection

Agency, Ariel Rios Bldg., 1200

Pennsylvania Ave., NW., Washington,

DC 20460; telephone number: (703)

308–9354; e-mail address:

waller.mary@epamail.epa.gov.

SUPPLEMENTARY INFORMATION:

I. General Information

A. Does this Action Apply to Me?

You may be affected by this action if

you are an agricultural producer, food

manufacturer or pesticide manufacturer.

Potentially affected categories and

entities may include, but are not limited

to:

CategoriesNAICS

codes

Examples of potentially affected entities

Industry 111 Crop production

112 Animal production

311 Food manufacturing

32532 Pesticide manufacturing

This listing is not intended to be

exhaustive, but rather provides a guide

for readers regarding entities likely to be

affected by this action. Other types of

entities not listed in the table could also

be affected. The North American

Industrial Classification System

(NAICS) codes have been provided to

assist you and others in determining

whether or not this action might apply

to certain entities. If you have questions

regarding the applicability of this action

to a particular entity, consult the person

listed under ‘‘FOR FURTHER

INFORMATION CONTACT.’’

B. How Can I Get Additional

Information, Including Copies of this

Document and Other Related

Documents?

1. Electronically. You may obtain

electronic copies of this document, and

certain other related documents that

might be available electronically, from

the EPA Internet Home Page at http://

www.epa.gov/. To access this

document, on the Home Page select

‘‘Laws and Regulations’’ and then look

up the entry for this document under

the ‘‘Federal Register—Environmental

Documents.’’ You can also go directly to

the Federal Register listings at http://

www.epa.gov/fedrgstr/.

2. In person. The Agency has

established an official record for this

action under docket control number PF–

937. The official record consists of the

documents specifically referenced in

this action, any public comments

received during an applicable comment

period, and other information related to

this action, including any information

claimed as confidential business

information (CBI). This official record

includes the documents that are

physically located in the docket, as well

as the documents that are referenced in

those documents. The public version of

the official record does not include any

information claimed as CBI. The public

version of the official record, which

includes printed, paper versions of any

electronic comments submitted during

an applicable comment period, is

available for inspection in the Public

Information and Records Integrity

Branch (PIRIB), Rm. 119, Crystal Mall

#2, 1921 Jefferson Davis Highway,

Arlington, VA, from 8:30 a.m. to 4 p.m.,

Monday through Friday, excluding legal

holidays. The PIRIB telephone number

is (703) 305–5805.

C. How and to Whom Do I Submit

Comments?

You may submit comments through

the mail, in person, or electronically. To

ensure proper receipt by EPA, it is

imperative that you identify docket

control number PF–937 in the subject

line on the first page of your response.

1. By mail. Submit your comments to:

Public Information and Records

Integrity Branch (PIRIB), Information

Resources and Services Division

(7502C), Office of Pesticide Programs

(OPP), Environmental Protection

Agency, Ariel Rios Bldg., 1200

Pennsylvania Ave., NW., Washington,

DC 20460.

2. In person or by courier. Deliver

your comments to: Public Information

and Records Integrity Branch (PIRIB),

Information Resources and Services

Division (7502C), Office of Pesticide

Programs (OPP), Environmental

Protection Agency, Rm. 119, Crystal

Mall #2, 1921 Jefferson Davis Highway,

Arlington, VA. The PIRIB is open from

8:30 a.m. to 4 p.m., Monday through

Friday, excluding legal holidays. The

PIRIB telephone number is (703) 305–

5805.

3.Electronically. You may submit your

comments electronically by e-mail to:

‘‘opp-docket@epa.gov,’’ or you can

submit a computer disk as described

above. Do not submit any information

electronically that you consider to be

CBI. Avoid the use of special characters

and any form of encryption. Electronic

submissions will be accepted in

Wordperfect 6.1/8.0 or ASCII file

format. All comments in electronic form

must be identified by docket control

number PF–937. Electronic comments

may also be filed online at many Federal

Depository Libraries.

D. How Should I Handle CBI That I

Want to Submit to the Agency?

Do not submit any information

electronically that you consider to be

CBI. You may claim information that

you submit to EPA in response to this

document as CBI by marking any part or

all of that information as CBI.

Information so marked will not be

disclosed except in accordance with

procedures set forth in 40 CFR part 2.

In addition to one complete version of

the comment that includes any

information claimed as CBI, a copy of

the comment that does not contain the

information claimed as CBI must be

submitted for inclusion in the public

version of the official record.

Information not marked confidential

21428 Federal Register / Vol. 65, No. 78 / Friday, April 21, 2000 / Notices

will be included in the public version

of the official record without prior

notice. If you have any questions about

CBI or the procedures for claiming CBI,

please consult the person identified

under ‘‘FOR FURTHER INFORMATION

CONTACT.’’

E. What Should I Consider as I Prepare

My Comments for EPA?

You may find the following

suggestions helpful for preparing your

comments:

1. Explain your views as clearly as

possible.

2. Describe any assumptions that you

used.

3. Provide copies of any technical

information and/or data you used that

support your views.

4. If you estimate potential burden or

costs, explain how you arrived at the

estimate that you provide.

5. Provide specific examples to

illustrate your concerns.

6. Make sure to submit your

comments by the deadline in this

notice.

7. To ensure proper receipt by EPA,

be sure to identify the docket control

number assigned to this action in the

subject line on the first page of your

response. You may also provide the

name, date, and Federal Register

citation.

II. What Action is the Agency Taking?

EPA has received a pesticide petition

as follows proposing the establishment

and/or amendment of regulations for

residues of a certain pesticide chemical

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

this petition contains 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.

List of Subjects

Environmental protection,

Agricultural commodities, Feed

additives, Food additives, Pesticides

and pests, Reporting and recordkeeping

requirements.

Dated: April 12, 2000.

James Jones,

Director, Registration Division, Office of

Pesticide Programs.

Summary of Petition

The petitioner summary of the

pesticide petition is printed below as

required by section 408(d)(3) of the

FFDCA. The summary of the petition

was prepared by the petitioner and

represents the view of the petitioner.

EPA is publishing the petition summary

verbatim without editing it in any way.

The petition summary announces the

availability of a description of the

analytical methods available to EPA for

the detection and measurement of the

pesticide chemical residues or an

explanation of why no such method is

needed.

BASF Corporation

0F6079

EPA has received a pesticide petition

0F6079 from BASF Corporation,

Agricultural Products, PO Box 13528,

Research Triangle Park, NC 27709

proposing, pursuant to section 408(d) of

the Federal Food, Drug, and Cosmetic

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

amend 40 CFR part 180 by establishing

a tolerance for residues of vinclozolin

[3-(3,5-dichlorophenyl)-5-methyl-5-

vinyl-1,3-oxazolidine-2,4-dione] and

metabolites containing the 3,5-

dichloroanaline moiety in or on the raw

agricultural commodities succulent

beans and canola at 2.0, and 1.0 parts

per million (ppm) respectively. EPA has

determined that the petition contains

data or information regarding the

elements set forth in section 408(d)(2) of

the FFDCA; however, EPA has not fully

evaluated the sufficiency of the

submitted data at this time or whether

the data support granting of the petition.

Additional data may be needed before

EPA rules on the petition.

A. Residue Chemistry

1. Plant metabolism. BASF

Corporation notes that metabolism in

plants is understood, the residues of

concern are vinclozolin [3-(3,5-

dichlorophenyl)-5-methyl-5-vinyl-1,3-

oxazolidine-2,4-dione] and metabolites

containing the 3,5-dichloroanaline

moiety.

2. Analytical method. The proposed

analytical method involves extraction,

hydrolysis, distillation, partition, and

deriviatization followed by detection of

residues by gas chromatography/

electron capture detector (gc/ecd). An

enforcement method has been published

in FDA’s Pesticide Analytical Methods,

Volume II pg. 876–887.

3. Magnitude of residues. Sixteen

residue trials were carried out in several

major succulent bean producing states;

CA, FL, MI, NY, NC, OR, and WI.

Residue in the succulent beans ranged

from 0.38 ppm to 2.40 ppm and

averaged 0.83 ppm.

Four residues trials were carried out

in three canola producing provinces of

Canada (Alberta, Manitoba, and

Saskatchewan) which accounts for 98%

of the canola production in Canada.

Residues in the canola seeds ranged

from 0.044 ppm to 0.360 ppm and

averaged 0.17 ppm.

B. Toxicological Profile

1. Acute toxicity. The acute toxicity

studies place technical vinclozolin in

acute toxicity category IV for acute oral

(LD50 of greater 15,000 milligrams

kilograms (mg/kg), acute inhalation LD50

of greater than 29.1 mg/L and dermal

irritation (slight), and in category III for

acute dermal LD50 of greater than 2,500

mg/kg and eye irritation (slight). The

technical material is a positive skin

sensitizer.

2. Genotoxicty. A modified Ames test

(three studies; point mutation):

Negative; Host-Mediated Assay (point

mutation): Negative; Mouse Lymphoma

Test (point mutation): Negative; In Vitro

CHO cells (point mutation): Negative; In

Vitro Cytogenetics-CHO cells

(Chromosome Aberrations): Negative; In

Vivo Dominant Lethal Test-Male NMRI

Mouse (Chromosome Aberrations):

Negative; Rec Assay (two test; DNA

damage and repair): Negative; In Vitro

unscheduled DNA synthesis (UDS) test

using Hepatocyte (DNA damage and

repair): Negative; In Vivo SCE using

Chinese Hamster (DNA damage and

repair): Negative. Based on the data

present and weight of evidence, BASF

concludes that vinclozolin does not

pose a mutagenic hazard to humans.

3. Developmental toxicity—i. A

combination of four developmental

studies in rats via oral gavage resulted

in dosages of 0, 15, 50, 100, 150, 200,

400, 600, and 1,000 highest dose tested

(HDT) mg/kg/day with a developmental

toxicity no observed adverse effect level

(NOAEL) of 15 mg/kg/day and a

maternal toxicity NOAEL equal to or

greater than 400 mg/kg/day based on the

following:

a. No obvious signs of maternal

toxicity were observed at dose levels

less than or equal to 400 mg/kg/day.

b. An increased number of fetuses

with retarded ossification of thoracic

vertebral bodies at dose levels greater

than or equal to 200 mg/kg/day and

increased number of fetuses with soft

tissue variations at dose levels greater

than or equal to 400 mg/kg/day, both

findings are regarded as unspecific

embryo/fetotoxic effects indicating

transient delays in development but not

indicative of a teratogenic effect.

c. A statistically significant decrease

or reduction of the anogenital index

(AGI) in males was observed at levels

greater than or equal to 50 mg/kg/day.

Federal Register / Vol. 65, No. 78 / Friday, April 21, 2000 / Notices 21429

In a developmental study in rats via

dermal exposure for 6 hours/day on

intact skin with dosages of 0, 60, 180,

and 360 mg/kg/day HDT with a

developmental toxicity NOAEL of 60

mg/kg/day and a maternal toxicity

NOAEL of 60 mg/kg/day based on the

following: Increased absolute liver

weights at dose levels greater than 180

mg/kg/day, and decreased anogenital

distance and index at dose levels greater

than 180 mg/kg/day.

ii. A developmental study in rabbits

via oral gavage was conducted with

dosages of 0, 20, 80, and 300 mg/kg/day

HDT with a developmental toxicity

NOAEL of 300 mg/kg/day and a

maternal toxicity NOAEL of 300 mg/kg/

day based on no signs of maternal or

meaningful fetal toxicity at any of the

dose levels mentioned.

A second developmental study in

rabbits via oral gavage resulted in

dosages of 0, 50, 200, and 800 mg/kg/

day highest dose tested (HDT) with a

developmental toxicity NOAEL of 200

mg/kg/day and a maternal toxicity

NOAEL of 50 mg/kg/day based on the

following: Severe maternal toxicity with

simultaneous change in hematological

values changes and high number of

abortions at the HDT, and increased

absolute and/or relative weights for

adrenals in the mid and high dose

groups.

4. Reproductive toxicity. Two 2–

generation reproduction studies in rats

were conducted: Study A-dose levels of

0, 2.0, and 4.1 mg/kg/day: Study B-dose

levels of 0, 4.9, 30, 96, and 290 mg/kg/

day (males) and 0, 5.3, 31, 101, and 290

mg/kg/day (females). The results

demonstrated a reproductive NOAEL of

4.9 mg/kg/day based on feminization of

males and the ability not to mate at dose

levels greater than 100 mg/kg/day and

pup effects at 29 mg/kg/day; and with

a parental NOAEL of 4.9 mg/kg/day

based on general toxicity consistent

with previous rat studies at levels

greater than 29 mg/kg/day. Study A was

performed to clarify an equivocal

finding of decreased absolute and

relative weight of the epididymides

without any morphological correlation

in the male FY and FZ generations in

Study B. However, EPA stated ‘‘the

effects at the 4.9 mg/kg/day dose level

was minimal and considered

sufficiently close to a NOAEL. The

study is acceptable and 4.9 mg/kg/day

dose level was considered to be the

NOAEL.

5. Chronic toxicity—i. A 1–year

feeding study in dogs fed dosages of 0,

1.1 , 2.4, 4.9, and 48.7 mg/kg/day with

a NOAEL of 2.4 mg/kg/day based on the

following effects:

a. Slight anemia and increased serum

bilirubin in the 48.7 mg/kg/day dose

group HDT.

b. Increased absolute and/or relative

weights for the testes, adrenals, liver,

spleen, and thyroids in either the 4.9 or

48.7 mg/kg/day dose groups.

c. A dose-related atrophy of the

prostate in the 4.9 and 48.7 mg/kg/day

dose groups.

d. Microscopic findings in the adrenal

and testes in the 48.7 mg/kg/day dose

group and liver findings for both male

and female dogs in the 48.7 mg/kg/day

dose groups and in the females in the

4.9 mg/kg/day dose group, only.

ii. A combination of two chronic

feeding and one carcinogenicity study

that were performed separately, resulted

in rats being fed combined dosages of 0,

1.2, 2.4, 7.0, 23, 71, 143, and 221 mg/

kg/day (males) and 0, 1.6, 3.1, 9.0, 29,

88, 180, and 257 mg/kg/day (females)

with a NOAEL of 1.2 mg/kg/day (males)

and 1.6 mg/kg/day (females) based on

the following effects:

a. Decreased body weights in both

males and females at dose levels greater

than or equal to 23 mg/kg/day with a

progression of severity to the upper dose

levels.

b. Cataracts with associative

histopathology at dose levels greater

than or equal 23 mg/kg/day and

lenticular changes at dose levels greater

than or equal 7.0 mg/kg/day for male

and female rats.

c. Hematological and clinical

chemistry value changes at dose levels

greater than or equal to 71 mg/kg/day

with an increase of severity at the higher

doses tested.

d. Increased absolute and/or relative

weights for adrenals at dose levels

greater than or equal 143 mg/kg/day, for

the liver at dose levels greater than or

equal 71 mg/kg/day, for the testes at

dose levels greater than or equal 23 mg/

kg/day, and for the ovaries at dose levels

greater than or equal 143 mg/kg/day.

e. Microscopic findings were observed

in the liver, adrenal, pancreas, testes,

ovaries and uterus at dose levels of

greater than or equal to 7.0 mg/kg/day

with a progression of severity of

histological effects in the upper dose

levels.

f. An increased incidence of

neoplasms occurred at dose levels

greater than or equal to the maximum

tolerated dose (MTD) of 23 mg/kg/day in

the liver, adrenals, pituitary, prostate,

uterus, and ovaries. In the testes (males),

neoplasms were seen slightly below the

MTD at dose levels greater than or equal

23.0 mg/kg/day due the antiandrogenic

nature of vinclozolin.

6. Oncogenicity. An oncogenicity

study in mice fed dosages of 0, 2.1, 20.6,

432, and 1,225 (HDT) mg/kg/day (males)

and 0, 2.8, 28.5, 557, and 1,411 (HDT)

mg/kg/day (females) with a NOAEL of

2.1 mg/kg/day (males) and 2.8 mg/kg/

day (females) based on the following

effects:

i. Increased mortality in the highest

dose tested (HTD) as compared to

controls.

ii. Decreased body weights and

significant signs of clinical toxicity were

observed in both males and female mice

at the upper two dose levels with a

progression of severity, and an

equivocal body weight gain decrease at

the next lower dose.

iii. Hematological and clinical

chemistry value changes were observed

at the highest dose tested.

iv. Increased absolute and/or relative

weights for adrenals and liver were

observed at the upper two dose levels,

atrophic seminal vesicles and

coagulation glands with reduced size of

the prostate and atrophic uteri were

observed at the upper two dose levels.

v. Microscopic findings were

observed in the liver, adrenal, testes,

ovaries and uterus, and related sexual

organs were seen in the upper two dose

levels.

vi. An increased incidence of

neoplasms occurred at dose levels

greater than the maximum tolerated

dose (28.5 mg/kg/day) in the liver of

female mice.

7. Animal metabolism—i. Oral

studies. BASF has submitted results

from a number of metabolism studies

using Wistar rats. The results of these

studies can be summarized as follows:

vinclozolin is well absorbed (ca. 85%)

and intensively metabolized, the liver

playing an important role (ca. 65%) of

the radioactivity administered was

found in the bile and no unchanged

active ingredient was excreted in the

urine). Excretion is rapid by both

urinary and biliary routes.

ii. Dermal study. In an in vivo dermal

absorption study, male Wistar rats were

dosed with 14C vinclozolin. Dose levels

of 0.002, 0.02, 0.2, and 2.0 mg/cm were

administered to 24 rats per dose level,

applied to a shaved area of

approximately 13 cm2 on the back of the

rat. Groups of 4 rats were sacrificed at

0.5, 1, 2, 4, 10, or 72 hours following

application of the dose. Urine and feces

were collected during this period. At the

end of the exposure period (10 hours in

the case of the 72 hour treatment group),

the skin site was washed with cotton

swabs moistened with water. A blood

sample was taken prior to sacrifice. The

treated skin along with the

gastrointestinal tract, liver, kidneys,

adrenals, testes, eyes, brain and carcass

were subjected to radioactive mass

21430 Federal Register / Vol. 65, No. 78 / Friday, April 21, 2000 / Notices

balance analysis. Urine from the bladder

was added to the voided samples.

Results of this analysis showed

recoveries of between 81.6% to 104%.

The lowest dose of 0.002 mg/cm2 from

the 10–hour exposure period is

considered to be the most appropriate

dose for use in the occupational risk

assessment, as this dose most closely

approximates the dermal deposition

results obtained in the worker exposure

studies. After the 10–hour exposure, the

total percent absorbed at this dose level

was 29.1%.

Percutaneous absorption of 14C–

vinclozolin was also assessed in vitro

using rat and human epidermis in flowthrough diffusion cells. The test

substance was applied at two dose

levels, 200 μg/cm22 (high) and 2 μg/cm2

(low), and assessed over 24 hours. A

total of 32 samples (16 rat and 16

human) were used at the high dose

level, and 34 (17 rat and 17 human) at

the low dose level. Samples of human

skin were obtained at postmortem.

Human epidermis was prepared from

full thickness skin by immersion in

water at 60 °C for 1 minute. Rat

epidermis was prepared by soaking the

skin in 2M sodium bromide for

approximately 24 hours. With respect to

the worker exposure relevant time of 8

hours, penetration through human skin

was 16.7 times less at the high dose

tested and 4.2 times less at the low dose

tested than through rat skin.

8. Endocrine disruption. A series of

mechanistic studies were performed to

elucidate and define the anti-androgenic

properties of vinclozolin. The following

conclusions can be drawn from the in

vivo data: The anti-androgenic effects

observed are not related to an inhibition

of androgen-steroid hormone synthesis.

The anti-androgenic effects are not

related to an inhibition of 5 alphareductase activity. The anti-androgenic

effects are a result of a competitive

binding to the androgen receptor

resulting in an inactivation of this

receptor. The anti-androgenic effects are

mediated by the hydrolysis metabolites

M1 and/or M2 and probably not by

vinclozolin or the main metabolite, R8.

M2 is a slightly more potent antiandrogen than M1; however, M2

concentrations are very low and the

compound may not contribute much to

the in vivo effects.

Vinclozolin is known to be an antiandrogenic agent; thus, the consequence

of hormonal imbalance are two-fold; the

primary anti-androgenic effect is a

suppression in androgen target organs

such as epidymides, prostate or seminal

vesicle, whereas stimulation is seen in

organs involved in steroid hormone

synthesis (testes, adrenals, ovaries).

Target organs for hormones must be able

to respond to changes in physiological

levels of hormones, which can fluctuate

significantly as evidenced by the

hormone changes during the female

estrus cycle. It was indeed demonstrated

that changes induced in these organs

were reversible when hormone levels

return to normal concentrations. It is

only when hormone imbalance

continues over a long time that

irreversible changes occur.

In the case of suppression the affected

organ is forced into a hypofunctional

state. Progressively, the organ becomes

hypotrophic and hypoplastic. With

stimulation on the other hand the initial

changes can be described as

hyperfunction, hypertrophy and

hyperplasia. As mentioned before, it is

only when the hormonal imbalance

continues over a long time that the

ultimate reversible adaptation of the

affected organ (hypoplasia or

hyperplasia) is still not sufficient to

handle the situation and only then an

irreversible transition takes place. In the

case of hormonal suppression, atrophy

is the ultimate consequence, in the case

of stimulation, the ultimate

consequence are tumors in the affected

organs. It is thus plausible that at dose

levels which do not result in

hypertrophy/hyperplasia or

hypotrophy/hypoplasia, the ultimate

consequence of these adaptive changes,

i.e. tumors or-atrophy, respectively,

cannot occur. For risk assessment

purposes this mode of action offers the

possibility to determine a threshold for

both tumor formation and atrophy by

histopathological examination of the

hyper-or hypo-functional organ. Thus,

at dose levels which do not affect these

organs, a mechanistic NOAEL can be

defined and risk assessment can be

carried out using assessment or safety

factors.

The increase in neoplasia observed in

the adrenals, ovaries and uterus were

only seen in female rats at the highest

dose levels. As determined by BASF

and EPA, the 71 mg/kg/day dose level

of the rat chronic/oncogenicity toxicity

study exceeded the criteria for a MTD.

Therefore, the physiological status of

the animals may be deteriorated in such

a way that low dose extrapolation of

results obtained at this dose level is not

possible. Similarly, the liver tumors

arising in the mouse oncogenicity study

were observed only at the 1,411 mg/kg/

day dose level (in which severe body

weight losses and significant mortality

were observed) which clearly exceeded

the MTD (as determined by BASF and

EPA - Cancer Peer Review Document,

September 1996) and therefore are not

relevant for risk assessment purposes.

Additionally, vinclozolin is not a

genotoxic agent and mechanistic studies

have shown the increased incidence of

liver tumors in male rat and female mice

is a result of liver tumor promoting

properties of the test substance.

Vinclozolin is not an initiator of the

carcinogenic event. Based on the

available data, the mechanism of

promotion is the induction of liver cell

proliferation of the test substance. The

data available also indicate that dose

levels which do not induce liver toxicity

also do not induce cell proliferation nor

enhance the carcinogenic process.

Therefore, BASF concludes that a

threshold for liver carcinogenicity can

be defined to be at least 143 mg/kg/day

in the rat and at least 557 mg/kg/day in

the mouse.

Concerning the testicular tumors

(Leydig cell tumors), results of the longterm studies with vinclozolin

demonstrate that hormone-related

carcinogenesis was only observed in

rats, and with the exception of Leydig

cell tumors only at dose levels which

exceeded the MTD criteria. The

relevance of Leydig cell tumors to men

should be seen in the light that this is

a very rare human tumor and that the

precursor change (i.e. Leydig cell

hyperplasia) has not been observed in

patients treated with flutamide. In

addition, the toxicology of cimitidine,

an H2–receptor antagonist with antiandrogenic properties results in a size

reduction and atrophy of the prostate

and seminal vesicles in chronic rat

studies. Moreover, an increase in benign

Leydig cell tumors, and a decrease in

pituitary and mammary tumor

incidence were noted; hence a toxicity

potential not unlike that of vinclozolin

is evident. Despite the fact that over 30

million patients have been treated with

cimitidine, this therapeutic agent has

been demonstrated to be extremely safe,

clearly indicating that the rat Leydig cell

tumors have very little relevance for

humans. A similar conclusion is drawn

by other investigators ‘‘Leydig cell

tumors of the rat have limited

significance because of the fundamental

differences in testicular control

mechanisms.’’ It is therefore concluded

that the observed neoplastic changes do

not pose a relevant hazard to humans.

EPA in the September 1996, Cancer Peer

Review Document, came to the same

basic conclusion that the Leydig cell

tumors are a very uncommon tumor

type in humans which implies the

threshold dose for humans would be

greater than for rats. EPA based this

conclusion on the work performed by

Dr. Charles C. Capen (Professor Charles

C. Capen, Leydig Cell Tumors:

Federal Register / Vol. 65, No. 78 / Friday, April 21, 2000 / Notices 21431

Pathology, Physiology, and Mechanistic

Considerations in Rats, The Toxicology

Forum, 1994 Annual Summer Meeting,

p. 110).

Consistent with the data and the

advice of the OPP Scientific Advisory

Panel and using its Guidelines for

Carcinogen Risk Assessment published

September 24, 1986 (51 FR 33992), EPA

has classified vinclozolin as a Group C

chemical-possible human carcinogen.

The Agency Cancer Peer Review

Committee (CPRC) chose a non-linear

approach margin (MOE) based on a

NOAEL of 4.9 mg/kg/day for hormonerelated effects decreased epididymal

weight at 30 mg/kg/day in the 2–

generation oral rat reproductive toxicity

study to quantify human risk. The MOE

approach was chosen because the

remaining tumors (Leydig cell) were

benign at dose levels which were not

considered to be excessive.

C. Aggregate Exposure

1. Dietary exposure. The established

reference dose (RfD) for vinclozolin is

based on a 2–year feeding study in rats

with a threshold NOAEL of 1.2 mg/kg/

day. Using an uncertainty factor of 100,

the RfD is calculated to be 0.012 mg/kg/

day.

i. Food—a. Acute risk. EPA has

expressed concern for acute dietary risk

in the draft RED for the subgroup

population-women of childbearing age

(13 years and older) due to the

hormonal effects of vinclozolin. In

response to this concern, BASF

requested that ENVIRON, conduct an

acute dietary analysis for vinclozolin

that used the current consumption data

and exposure models capable of

calculating a real world estimates of

potential exposure to residues in food.

The acute exposure analysis, utilized

the principles of Tier 1 and Tier 3

analyzes presented to the FIFRA

Science Advisory Panel in September

1995, and subsequently implemented by

OPP/EPA. Using appropriate

methodology, available residue

distribution data, and percent crop

treated information it was determined

the margin of exposure to the most

sensitive sub-population exceeded 1,000

(the value currently being used by the

Agency for this compound) at the very

conservative 99.9th percentile of the

population; when all crops having

tolerances; plus succulent beans, and

canola, and cranberries were included

in the analysis. The margin of exposure

at the 99.9th percentile was determined

to be approximately 1,100 for women of

childbearing age.

b. Chronic. In its review granting a

temporary tolerance for vinclozolin in

succulent beans in October 1997, for

purposes of assessing the potential

chronic dietary exposure (food only)

from the use of vinclozolin, EPA used

the percent of crop treated/percent

imported data to refine the risk

estimates for selected commodities

(apricots, beans, raspberries, cherries,

cucumbers, lettuce, nectarines, onions,

peaches, peppers, and strawberries),

while other commodities were assumed

to be 100% treated/imported

(caneberries (other than raspberries),

cranberries, endive, garlic, wine/sherry,

kiwifruit, and shallots). No chronic

anticipated residue refinement has been

performed. Therefore, the resulting

exposure (food only) estimates should

be viewed as partially refined; further

refinement using anticipated residues

and additional percent of crop treated/

percent imported data would result in

lower chronic dietary exposure

estimates. The Anticipated Residue

Contribution (ARC) for chronic dietary

exposure estimates is equivalent to 12%

of the RfD for the U.S. population (48

states). The ARC for infants and

children and other subgroups ranged

from 7 to 15% of the RfD. The

incremental risk associated with canola

will not significantly change this

assessment.

In addition, BASF has performed a

more refined analysis of chronic dietary

risk and finds that when market share

and average residues are considered, no

sub-population in the United States is

exposed to over 1% of the RfD.

BASF concurs with the SAP and

believes vinclozolin should be regulated

under the margin of safety (MOS)

approach for non-threshold effects.

BASF has calculated the MOS for food

and water using the Agency’s

conservative assessments discussed

above. The MOS was calculated against

a NOAEL of 4.9 mg/kg/day for hormonerelated effects (decreased epididymal

weight at 30 mg/kg/day) in the 2–

generation oral rat reproductive toxicity

study to quantify human risk. The

resulting MOS for food is over 900,000.

ii. Drinking water. Exposure to

vinclozolin for the general population to

residues of vinclozolin are residues in

drinking water and exposure from nonoccupational sources. For drinking

water, based on the available

environmental fate data, BASF does not

anticipate routine exposure to residues

of vinclozolin in drinking water. There

is no established maximum

concentration level (MCL) or health

advisory level (HAL) for vinclozolin

under the Safe Drinking Water Act

(SDWA).

In its 1997 assessment, EPA

calculated drinking water exposure from

extremely conservative models. For

chronic exposure, EPA calculated a

level of 1 parts per billion (ppb). Using

standard EPA assumptions consumption

of water containing 1 ppb would

consume less than 2% of the RfD in the

most exposed subgroup (children 1 to

6). BASF believes this estimate to be

very conservative and is currently

analyzing the available data to

determine a more realistic value for

drinking water exposure.

2. Non-dietary exposure. Vinclozolin

is included in a number of formulations

used for professional treatment of golfcourses (tees, greens and collars only)

and turf. The turf use is limited to nonresidential uses. BASF believes that

these uses do not contribute

significantly to the aggregates risk.

D. Cumulative Effects

BASF has considered the potential for

cumulative effects of vinclozolin and

other substances that have a common

mechanism of toxicity. BASF is aware of

two other substance active ingredients

which are structurally similar,

iprodione and procymidone. However,

BASF believes that consideration of a

common mechanism of toxicity is not

appropriate at this time. This

conclusion was similarly drawn by

Rhone-Poulenc the manufacturer of

iprodione in a recent Notice of Filing for

that compound.

The Agency has previously noted

both structural and toxicological

similarities between iprodione,

procymidone, and vinclozolin. BASF

believes that there are clear differences

in both the type and magnitude of

effects observed after exposure to

vinclozolin when contrasted with

iprodione. BASF believes that there is

no reliable data to indicate cumulative

effects should be considered in

reference to iprodione. As to

procymidone, BASF is unaware of any

conclusive data that would indicate a

common mode of action with

procymidone. It should also be noted

that procymidone’s tolerances are

limited to grapes grown for wine

production outside the United States.

EPA has expressed concern regarding

a common metabolite of these three

compounds, 3,5–dichloroaniline (3,5–

DCA). Under FQPA, EPA is also

required to estimate the risk for

consumption of food and water

containing 3,5–DCA across vinclozolin,

iprodione, and procymidone. There is

no toxicological data base; thus no RfD

or Q1* for 3,5–DCA. However, EPA has

used the Q1* for p-chloroaniline (PCA)

to assess the carcinogenic risk for other

structurally-related chloroanilines

because EPA does not have any

evidence that 3,5–DCA is not

21432 Federal Register / Vol. 65, No. 78 / Friday, April 21, 2000 / Notices

carcinogenic. In 1988, the Q1* for PCA

was estimated to be 0.039 (mg/kg/day)-1.

However, a revised Q1* of 0.059 (mg/

kg/day)-1 for PCA has been used for this

assessment based on more recent data

on male and female tumors.

At the time of the risk assessment

done for vinclozolin time-limited

tolerances, EPA concluded that the risk

associated with 3,5–DCA was negligible.

Since that time, BASF has cancelled

uses in strawberries and stone fruit

which will further reduce the

theoretical risk. BASF does not believe

it is appropriate to assume that 3,5–DCA

should be regulated as an oncogen. The

Agency has relied on the simple fact

that PCA and DCA are structurally

similar and are likely to behave

similarly in animal systems for that

reason alone. While both compounds

are anilines and both have chlorine

moieties they differ significantly in

terms of electron density distribution,

which is the single most important

factor in the determination of how a

molecule behaves in chemical and

biochemical systems. BASF has

presented this and other information to

the Agency and awaits their response.

E. Safety Determination

1. U.S. population. Using the

exposure assumptions described above

and the completeness and the reliability

of the toxicity data, BASF has estimated

that aggregate exposure to vinclozolin

will utilize less than 1% of the RfD for

the US population. EPA generally has

no concern for exposure below 100% of

the RfD. Therefore, based on the

completeness and reliability of the

toxicity data, and the exposure

assessment discussed above, BASF

concludes that there is a reasonable

certainty that no harm will result from

aggregate exposure to residues of

vinclozolin.

2. Infants and children. Based on the

completeness of vinclozolin’s

toxicological data base and the risk

assessment information cited above

BASF believes the RfD used to assess

safety to children should be the same as

that for the general population, 0.012

mg/kg/day. BASF concluded that the

most sensitive child population group is

that of children ages 1 to 6. BASF has

calculated that the exposure (food and

water) to this group to be less than 1%

of the RfD for all uses including those

proposed in this document. Therefore,

based on the completeness and

reliability of the toxicity data, and the

exposure assessment discussed above,

BASF concludes that there is a

reasonable certainty that no harm will

result to infants and children from

aggregate exposure to residues of

vinclozolin.

F. International Tolerances

A maximum residue level for

succulent beans has not been

established for vinclozolin by the Codex

Alimentarius Commission.

[FR Doc. 00–9928 Filed 4–20–00; 8:45 am]

BILLING CODE 6560–50–F

ENVIRONMENTAL PROTECTION

AGENCY

[FRL–6483–5]

Draft General NPDES Permit for

Seafood Processors in Alaska in

Waters of the United States; General

NPDES Permit No. AK–G52–0000

AGENCY: Environmental Protection

Agency, Region 10.

ACTION: Notice of Draft General NPDES

Permit.

SUMMARY: The Director, Office of Water,

EPA Region 10, is proposing to reissue

general National Pollutant Discharge

Elimination System (NPDES) permit no.

AK–G52–0000 for seafood processors in

Alaska pursuant to the provisions of the

Clean Water Act (CWA) 33 U.S.C. 1251

et seq. The proposed general NPDES

permit will authorize discharges from

off-shore and near-shore vessels and

shore-based facilities engaged in the

processing of fresh, frozen, canned,

smoked, salted and pickled seafoods.

The proposed permit will also authorize

discharges from off-shore vessels

(operating more than one nautical mile

from shore at MLLW) that are engaged

in the processing of seafood paste,

mince or meal, as well as fresh, frozen,

canned, smoked, salted and pickled

seafoods. The proposed permit will

authorize discharges of processing

wastes, process disinfectants, sanitary

wastewater and other wastewaters,

including domestic wastewater, gray

water, cooling water, boiler water, fresh

water pressure relief water, refrigeration

condensate, water used to transfer

seafood to a facility, and live tank water.

The proposed permit will authorize

discharges to waters of the United States

in and contiguous to the State of Alaska,

except for receiving waters excluded

from coverage as protected, special, atrisk, degraded waters, or as waters

adjacent to the City of Kodiak or the

Pribilof Islands (and covered by general

permits specific to each of these areas).

The proposed general NPDES permit

for seafood processors in Alaska will not

authorize discharges from near-shore or

shore-based seafood processors of

mince, paste or meal (operating one

nautical mile or less from shore at

MLLW). The proposed permit will not

authorize discharges of petroleum

hydrocarbons, toxic pollutants, or other

pollutants not specified in the permit.

This is the fourth reissuance of a

general permit for seafood processors in

Alaska. While the general permit for

seafood processors issued in 1995

contained numerous substantial

changes, the proposed 2000 permit

contains one major change. The major

new provision in the proposed general

permit is a limit on the total annual load

of settleable solid seafood processing

waste. The total allowable residues of

offal for permittees covered under the

proposed permit must not exceed eight

million pounds per year (based on

deposition modeling using EPA’s Water

Quality Analysis Simulation Program).

Other minor changes in the proposed

permit clarify requirements of the

Notice of Intent to be covered and give

specific schedules for submitting

seafloor monitoring surveys. EPA

anticipates that the State of Alaska

Department of Environmental

Conservation will certify a 100 foot

mixing zone for all discharges and zone

of deposit of one acre for near-shore and

shore-based dischargers.

A draft NPDES permit, fact sheet and

other documents of the administrative

records are available upon request.

Public Notice Issuance Date: April 28,

2000

Public Notice Expiration Date: June 12,

2000

Public Comments

Persons wishing to comment on the

tentative requirements and conditions

contained in the proposed general

permit may do so before the expiration

date of the public notice. EPA

appreciates both supportive and critical

comments in this public review and

comment period. All persons, including

applicants, who believe any condition

of a draft permit is inappropriate or that

the Director’s tentative decision to

prepare this draft permit is

inappropriate, must raise all reasonably

ascertainable issues and submit all

reasonably available arguments

supporting their position by the close of

the public comment period. Any

supporting materials which are

submitted shall be included in full and

may not be incorporated by reference,

unless they are already part of the

administrative record or are a generally

available document or reference. All

written comments must include the

name, address, and telephone number of

the commenter and must be submitted

to EPA to the attention of Burney Hill