[Federal Register Volume 65, Number 78 (Friday, April 21, 2000)]
[Notices]
[Pages 21427-21432]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-9928]


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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.

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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: [email protected].

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:

 
------------------------------------------------------------------------
                                                          Examples of
           Categories                 NAICS codes         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: ``[email protected],'' 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

[[Page 21428]]

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.

[[Page 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

[[Page 21430]]

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 flow-through 
diffusion cells. The test substance was applied at two dose levels, 200 
g/cm22 (high) and 2 g/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  deg.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 alpha-reductase 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 anti-androgen 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 anti-androgenic 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 long-term 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 anti-androgenic 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:

[[Page 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 hormone-related 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 hormone-related 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 non-occupational 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 golf-courses (tees, 
greens and collars only) and turf. The turf use is limited to non-
residential 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

[[Page 21432]]

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