[Federal Register Volume 64, Number 170 (Thursday, September 2, 1999)]
[Notices]
[Pages 48165-48175]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-22636]


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ENVIRONMENTAL PROTECTION AGENCY

[PF-883; FRL-6094-5]


Notice of Filing Pesticide Petitions to Establish a Tolerance for 
Certain Pesticide Chemicals in or on Food

AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.

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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 docket control number PF-883, must be 
received on or before October 4, 1999.
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'' section. To 
ensure proper receipt by EPA, it is imperative that you identify docket 
control number PF-883 in the subject line on the first page of your 
response.

FOR FURTHER INFORMATION CONTACT: The product manager listed in the 
table below:

----------------------------------------------------------------------------------------------------------------
                                      Office location/telephone
          Product Manager               number/e-mail address             Address           Petition number(s)
----------------------------------------------------------------------------------------------------------------
Dana Pilitt (PM 13)................  Rm. 202, CM #2, 703-305-     1921 Jefferson Davis    PP 9F6022
                                      7071, e-mail:                Hwy, Arlington, VA
                                      [email protected]
                                      v.
 
Shaja Brothers.....................  Rm. 284, CM #2, 703-308-     Do.                     PP 7E4862, 7E4866,
                                      3194, e-mail:                                        8E4939, 7E4877,
                                      [email protected]                           7E4861, and 4E4302
                                      .gov.
 
Mary Waller (PM 21)................  Rm. 249, CM #2, 703-308-     Do.                     PP 1F4030, 2F4155, and
                                      9354, e-mail:                                        9F3812
                                      [email protected]
                                      v.
 
Amelia M. Acierto..................  Rm. 707B, CM #2, 703-308-    Do.                     PP 9E6010
                                      8377, e-mail:
                                      [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:

[[Page 48166]]



 
------------------------------------------------------------------------
                                                          Examples of
           Categories                    NAICS            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 in the ``FOR FURTHER INFORMATION 
CONTACT'' section.

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-883 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-883 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, 401 M St., SW., 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 5.1/6.1 or ASCII file format. All comments in electronic 
form must be identified by docket control number PF-883. 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 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 in the ``FOR FURTHER INFORMATION 
CONTACT'' section.

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 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.

List of Subjects

    Environmental protection, Agricultural commodities, Feed additives, 
Food additives, Pesticides and pests, Reporting and recordkeeping 
requirements.

    Dated: August 25, 1999.

James Jones,

Director, Registration Division, Office of Pesticide Programs.

Summaries of Petitions

    Petitioner summaries of the pesticide petitions are printed below 
as required

[[Page 48167]]

by section 408(d)(3) of the FFDCA. The summaries of the petitions were 
prepared by the petitioners and represent the views of the petitioners. 
EPA is publishing the petition summaries verbatim without editing them 
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.

1. Centre Internationale d'Etudes du Lindane (C.I.E.L.) and its 
Member Company Inquinosa S.A.

PP 9F6022

    EPA has received a pesticide petition (9F6022) from Centre 
Internationale d'Etudes du Lindane (C.I.E.L.) and its member company 
Inquinosa S.A. , c/o Charles A. O'Conner III, Esq., McKenna & Cuneo, 
L.L.P., 1900 K St., NW., Washington, DC 20006-1108 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 time-
limited tolerance for residues of lindane in or on the raw agricultural 
commodities (RAC) canola seed at 0.01 parts per million (ppm). 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 supports granting of the petition. Additional data 
may be needed before EPA rules on the petition.

A. Residue Chemistry

    1. Plant metabolism. The metabolism of lindane in plants is 
adequately understood. Lindane is rapidly absorbed and eliminated by 
plants. Lindane translocates rapidly from treated seeds into the 
growing plant but concentrates primarily in the plant root. Both 
lindane and its metabolites appear to be readily lost to air and to 
soil. In almost all studies, the metabolites found in plants were 
identical to those found in animals although there may be variations in 
the conjugates detected. The same processes found in animals metabolize 
lindane in plants, i.e., dehydrogenation, dehydrochlorination, 
hydroxylation, and conjugation.
    2. Analytical method. There is a practical analytical method for 
detecting and measuring levels of lindane in or on food with a limit of 
quantitation (LOQ) that allows monitoring of food with residues at or 
above the levels set in the tolerances. The parent is analyzed by gas 
chromatography/electronic capture detector (GC/ECD).
    3. Magnitude of residues. Lindane was applied to seeds of canola. 
The RAC canola seed was harvested at the appropriate growth stage. A 
portion of harvested seed was processed into meal, which is an animal 
feed item, and edible canola oil, which is the only canola product that 
constitutes an appreciable portion of the human diet. Subsequent 
analyses determined that the residues of lindane will not exceed the 
proposed tolerance of 0.01 ppm for canola seed. Residues of canola in 
the processed commodities were < 0.005 ppm for meal and < 0.0005 ppm 
for edible oil. A cattle feeding study (20 ppm) was conducted to 
support foliar applications of lindane. Data was derived from 
extrapolation of this study to the 0.024 ppm maximum theoretical 
dietary burden in beef and diary cattle. Anticipated residues were 
0.008 ppm in milk, 0.013 ppm in beef fat, 0.0011 ppm in beef muscle, 
0.00038 ppm in beef kidney, and 0.00011 ppm in beef liver. Similarly, 
results of a poultry feeding study and the maximum anticipated dietary 
burden for poultry from lindane use as a seed treatment were used to 
derive anticipated residues of 0.0011 ppm in eggs, 0.00014 ppm in 
breast muscle, 0.00086 ppm in thigh muscle, and 0.00055 ppm in liver.

B. Toxicological Profile

    1. Acute toxicity. Lindane demonstrates moderate oral, dermal and 
inhalation toxicity. Reported acute oral LD50 values in the 
rat range from 90 to 250 milligrams/kilograms (mg/kg). The acute dermal 
LD50 value was 200 to 300 mg/kg for rabbits and 900 to 1,000 
mg/kg in rats. The acute inhalation LC50 value in the rat 
was 1,600 milligrams per liter (mg/L)/4h. Lindane is not irritating to 
rabbit skin and is slightly irritating to rabbit eyes. It did not cause 
skin sensitization in guinea pigs.
    2. Genotoxic. The mutagenicity of lindane has been adequately 
studied. Lindane has been extensively investigated for its ability to 
induce gene mutation in both bacteria and mammalian cells, and for its 
activation in the assay for sex-linked recessive lethal mutation in D. 
melanogaster. Negative results were obtained consistently. Lindane's 
ability to induce chromosomal damage and sister chromatid exchange has 
been investigated in mammalian cells both in vitro and in vivo, again 
with negative results. Both assays for DNA damage in bacteria and 
studies in vivo to investigate covalent binding to DNA in the liver of 
rats and mice following oral administration also gave negative results. 
The few studies in which positive results were obtained involved 
invalid study designs or lindane of unknown purity. Overall, lindane 
appears not to have mutagenic potential.
    3. Reproductive and developmental toxicity. Lindane is not 
considered to be a reproductive or a developmental toxin. In a 2-
generation reproduction study, the no observed adverse effect level 
(NOAEL) for reproductive and developmental toxicity was 2 mg/kg/day. In 
a developmental toxicity study, the rat maternal NOAEL was 5 mg/kg 
while the developmental NOAEL was 10 mg/kg. The developmental and 
parental (based on reduced food consumption, reduced weight gain, 
slight tachypnea and lethargy) NOAEL for the rabbit was greater than 20 
mg/kg/day. or a developmental toxin.
    4. Subchronic toxicity. 90-day feeding studies were conducted in 
mice and rats with lindane. The NOAEL for the mouse study was greater 
than 10 ppm highest dose tested (HDT). For the rat study, the NAOEL was 
10 ppm (0.75 mg/kg/bwt/day). Renal effects observed were related to 
2U-globulin and are not relevant to human safety. 
Hepatocellular hypertrophy and neurotoxicity were observed at the HDT. 
A 14-week inhalation study in mice had a NOAEL of 0.3 mg/cubic meter. 
In a 90-day inhalation study in rats, the NOAEL was 0.6 mg/cubic meter. 
90-day dermal toxicity studies have been conducted in rats and rabbits. 
In both species, the NOAELs were 10 mg/kg/bwt/day.
    5. Chronic toxicity. A 2-year feeding study was conducted in dogs 
with lindane. The NOAEL for this study was 50 ppm. A chronic study in 
rats found a NOAEL of 10 ppm (0.47 mg/kg/bwt/day) based upon liver 
toxicity at higher dose levels. Lindane is not carcinogenic to rats. A 
2-year combined chronic toxicity/oncogenicity study in the rat was 
negative for carcinogenicity. A total of 8 mouse oncogenicity studies 
have been conducted in several strains of mice. None of the mouse 
studies were considered by the Agency, however, to be adequate for a 
cancer risk assessment. Thus, a ninth study is in progress.
    6. Animal metabolism. The metabolism of lindane has been thoroughly 
investigated. Lindane does not appear to bioaccumulate in tissues. 
Lindane is rapidly absorbed and metabolized. The metabolism of lindane 
occurs via several different pathways. Major routes of metabolism 
include stepwise elimination of chlorines and conjuations with sulfates 
and glucuronides. Another pathway is via the formation of mercapurates.

[[Page 48168]]

    7. Metabolite toxicology. Dietary residues are comprised of lindane 
and a variety of metabolites. The dietary residues are qualitatively 
the same as those formed in the rat and have thus been bioassayed in 
the available toxicity studies. These metabolites are not considered to 
present a significant toxicological risk.
    8. Endocrine disruption. An evaluation of the potential effects on 
the endocrine systems of mammals has not been done. Reproductive 
effects of lindane are observed only at dose levels higher than those 
causing other forms of toxicity.

C. Aggregate Exposure

    1. Dietary exposure.--Food. Estimates dietary exposure from the 
proposed uses would account for approximately 1% or less of the 
reference dose (RfD). The available data do not indicate any evidence 
of significant toxicity from a 1-day or single event exposure by the 
oral route. The only crop use for lindane at this time is seed 
treatment which results in extremely low dietary exposure. Thus an 
acute dietary risk assessment is not necessary.
    2. Drinking water. Studies have shown that lindane will not move 
into ground water; therefore water has not been included in the dietary 
risk assessment.
    3. Non-dietary/non-occupational exposure. There are very few 
remaining registered uses of lindane and the potential for non-
occupational non-dietary exposure to the general population is 
negligible. As a seed treatment, lindane is limited to a small number 
of crops with extremely limited market share. The treated seed is 
either planted immediately, or stored in areas with limited access to 
the general public prior to sale and shipment to the user. Exposure is 
basically limited to occupational scenarios, i.e., application to seed 
and planting treated seed.

D. Cumulative Effects

    EPA is required to consider the potential for cumulative effects of 
lindane and other substances that have a common mechanism of toxicity. 
EPA consideration of a common mechanism of toxicity is not appropriate 
at this time since EPA does not have information to indicate that toxic 
effects produced by lindane would be cumulative with those of any other 
chemical compounds; thus only the potential risks of lindane are 
considered in this exposure assessment.

E. Safety Determination

    1. U.S. population. Using the conservative exposure assumptions 
described and based on the completeness and reliability of the toxicity 
data, the aggregate exposure to lindane will utilize less than 1% of 
the RfD for the U.S population. EPA generally has no concern for 
exposures below 100% of the RfD. Therefore, based on the completeness 
and reliability of the toxicity data and the conservative exposure 
assessment, there is a reasonable certainty that no harm will result 
from aggregate exposure to residues of lindane, including all 
anticipated dietary exposure and all other non-occupational exposures.
    2. Infants and children. In assessing the potential for additional 
sensitivity of infants and children to residues of lindane, EPA 
considers data from developmental toxicity studies in the rat and 
rabbit and the 2-generation reproduction study in the rat. The 
developmental toxicity studies are designed to evaluate adverse effects 
on the developing organism resulting from pesticide exposure during 
prenatal development. Reproduction studies provide information relating 
to effects on the reproductive capacity of males and females exposed to 
the pesticide. Developmental toxicity was not observed in toxicity 
studies using rats and rabbits. In these studies, the rat maternal 
NOAEL was 5 mg/kg/day and developmental NOAEL was 10 mg/kg/day. The 
parental and developmental NOAELs for the rabbit were greater than 20 
mg/kg/day. In a 2-generation reproduction study in rats, the NOAEL for 
reproductive and developmental toxicity was 2 mg/kg/day. Section 408 of 
the FFDCA provides that EPA may apply an additional safety factor for 
infants and children in the case of threshold effects to account for 
prenatal and postnatal toxicity and the completeness of the data base. 
Based on the current toxicological data requirements, the data base 
relative to prenatal and postnatal effects for children is complete and 
an additional uncertainty factor is not warranted. Therefore, at this 
time, the RfD of 0.0047 mg/kg/bwt/day is appropriate for assessing 
aggregate risk to infants and children.

F. International Tolerances

    Acceptable daily intake for lindane is 0.008 mg/kg/bwt. Codex 
Maximum Residue Levels (MRLs) have been set for several commodities for 
which tolerances have previously been proposed. In all cases, these 
MRLs are equal to or greater than the requested tolerances. The 
Canadian MRL for lindane in canola products is 0.1 ppm, i.e. 
negligible.

2. International Specialty Products

PP 9E6010

    EPA has received a pesticide petition [PP 9E6010] from 
International Specialty Products, 1361 Alps Road, Wayne, NJ 07470, 
proposing pursuant to section 408(d) of the FFDCA, 21 U.S.C. 346a(d), 
to amend 40 CFR part 180 to establish an exemption from the requirement 
of a tolerance for N-(n-octyl)-2-pyrrolidone (Agsolex 8 ) in or on the 
RACs soybeans, soybean forage, soybean fodder and soybean hay when used 
as an inert ingredient (solvent) in seed treatment applied at a maximum 
rate of 3 grams/acre. 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 
supports granting of the petition. Additional data may be needed before 
EPA rules on the petition.

A. Residue Chemistry

    The Agency does not generally require residue chemistry data or 
environmental fate data to rule on the exemption from the requirements 
of a tolerance for an inert ingredient. However, relevant dietary 
residue modeling has been completed on N-(n-octyl)-2-pyrrolidone and is 
discussed in the appropriate section below.

B. Toxicological Profile

    1. Acute toxicity. In a battery of acute studies, N-(n-octyl)-2-
pyrrolidone has a low order of mammalian toxicity by oral, dermal and 
inhalation exposure routes. It is a skin and eye irritant in rabbits 
and a dermal sensitizer in guinea pigs. However, these acute irritation 
and sensitization data are not relevant for oral exposures. Therefore, 
no special susceptibility is anticipated from minor dietary oral 
exposures to N-(n-octyl)-2-pyrrolidone.
    i. Acute oral toxicity in rats. N-(n-octyl)-2-pyrrolidone was 
administered by gavage to groups of five male and female rats (Wistar 
strain albino) at graded doses of 0.63-5.00 g/kg. Mortality and 
clinical observations, including signs of toxicity and pharmacological 
effects were conducted over a 14-day period. The acute oral 
LD50 for N-(n-octyl)-2-pyrrolidone was found to be 2.05 g/kg 
bodyweight, placing it in Category III for acute oral toxicity.
    ii. Primary ocular irritation in rabbits. Undiluted N-(n-octyl)-2-
pyrrolidone (i.e., as sold) was intra-ocularly applied once to each of 
nine New Zealand white rabbits at a volume of 0.1 milliliter (mL). An 
additional nine animals received a

[[Page 48169]]

single application of a 2% aqueous suspension of N-(n-octyl)-2-
pyrrolidone. In both assays, the eyes of six animals remained unwashed 
for 24 hours while the eyes of the remaining three animals were washed 
30 seconds after instillation of the test materials.
    Ocular irritations were evaluated at 24, 48, and 72 hours following 
instillation of test material. Additional readings were made at 4, 7, 
14, and 21 days in the assay with undiluted N-(n-octyl)-2-pyrrolidone. 
The eyes were scored for corneal opacity, iritis, conjunctivitis and 
other effects.
    The results indicate that N-(n-octyl)-2-pyrrolidone was extremely 
irritating when tested as sold (i.e., undiluted), with wash procedures 
reducing the severity of the irritation observed. The 2% aqueous 
suspension was nonirritating both with and without washout procedures. 
Undiluted N-(n-octyl)-2-pyrrolidone is considered extremely irritating, 
placing it in category I or II for eye irritation. However, the 2% 
aqueous suspension was nonirritating both with or without washout 
procedures, placing it in Category IV for eye irritation.
    iii. Primary dermal irritation in rabbits. The backs of six New 
Zealand white rabbits were closely clipped and the skin on the right 
side was abraded by making longitudinal epidermal incisions. The skin 
on the left side was left intact. A single application of 0.5 mL of N-
(n-octyl)-2-pyrrolidone, in commercially available form, was made to 
each test site. In a second assay, an additional six rabbits received 
single applications of a 2% aqueous suspension of N-(n-octyl)-2-
pyrrolidone.
    In both assays, the wrapping and compound were removed at 24 hours 
and the sites scored at 24 and 72 hours for erythema and edema using 
the Draize scale. The mean scores at 24 and 72 hours were averaged to 
yield a Primary Irritation Index of 7.45 for N-(n-octyl)-2-pyrrolidone, 
when tested as sold, and 0.50 when tested as a 2% gravimetric aqueous 
suspension. N-(n-octyl)-2-pyrrolidone, when tested as commercially 
available, is therefore, considered to be extremely irritating to 
rabbit skin, and is minimally irritating as a 2% suspension. N-(n-
octyl)-2-pyrrolidone, as sold, will therefore, be placed in Category I 
or II for skin irritation. However, the 2% aqueous suspension was only 
minimally irritating, placing it in Category II or III for skin 
irritation.
    iv. Acute dermal toxicity in rabbits. Six New Zealand white rabbits 
each received a single dermal application of undiluted N-(n-octyl)-2-
pyrrolidone at a dose level of 2 g/kg bodyweight. The skin of three 
animals was abraded, while the remaining animals' skin remained intact. 
Test sites were occluded for 24 hours at which time the occlusive wrap 
and any remaining test article were removed. Animals were observed for 
clinical signs and/or pharmacologic activity 1, 3, 6, and 24 hours 
after treatment and daily thereafter for a total of 14 days. On day 14, 
gross necropsy was performed on all animals. There was no mortality at 
the limit dose of 2 g/kg. The skin at the test sites showed crust 
formation, scaling and scarring. At necropsy, no gross internal changes 
and no deviations from normal were observed in any of the animals.
    The acute dermal LD50 for N-(n-octyl)-2-pyrrolidone when 
tested undiluted (i.e., as sold) is greater than 2 g/kg body weight, 
placing it in Category III for acute dermal toxicity.
    v. D.O.T. corrosivity. Six New Zealand white rabbits each received 
a single dermal application of 0.5 ml of undiluted N-(n-octyl)-2-
pyrrolidone on one intact test site. The test site was occluded for 4 
hours at which time the occlusive wrap and any remaining material were 
removed. Animals were observed for erythema, edema and other effects at 
4 and 48 hours and 7-days after application. Crust formation was 
observed in five of the six animals.
    Therefore, N-(n-octyl)-2-pyrrolidone when tested as sold, is 
corrosive to the skin of rabbits under conditions of this test.
    vi. Guinea pig sensitization study. Twenty female albino guinea 
pigs received intradermal injections of 0.05% v/v N-(n-octyl)-2-
pyrrolidone in both water and in freund's complete adjuvant (FCA) as 
well as FCA in water alone. One week after the injections the same 
interscapular area was covered occlusively for 48 hours with a patch 
saturated with 30%, v/v N-(n-octyl)-2-pyrrolidone in distilled water. 
During this induction phase, 10 control animals were treated similarly 
with the exception that the test material was omitted from the 
injections and topical applications.
    Two weeks after the induction period, both the test and control 
animals were challenged topically using a patch saturated in 0.2 mL N-
(n-octyl)-2-pyrrolidone, 10% v/v in distilled water applied to an 
anterior site on the flank and N-(n-octyl)-2-pyrrolidone, 5% v/v in 
distilled water applied in a similar manner to a posterior site. The 
patches were sealed to the flank covered for 24 hours. The challenge 
sites were evaluated at 24, 48, and 72 hours after patch removal. N-(n-
octyl)-2-pyrrolidone produced evidence of delayed contact 
hypersensitivity in 2 of the 20 test animals.
    vii. Clinical studies. Clinical exposure studies including 
phototoxicity, photoallergenicity and comedogenicity were conducted 
with N-(n-octyl)-2-pyrrolidone. N-(n-octyl)-2-pyrrolidone did not 
induce contact dermal phototoxic response, contact dermal photoallergy 
or contact dermal sensitization in human subjects under the exposure 
conditions of these tests.
    viii. Phototoxicity. Each of 10 human subjects, all female, 
received 0.2 mL of a 1% suspension of test material in tap water on 
both volar forearms. Following a 24-hour exposure period under 
occlusive wrapping, the patches were removed and the sites scored for 
erythema and edema. Immediately following scoring one arm was 
irradiated with UV-A light. Test sites were scored immediately after 
irradiation and again at 24 and 48 hours. The nonirradiated arm served 
as a control.
    No reactions were exhibited on either the irradiated or 
nonirradiated sites. N-(n-octyl)-2-pyrrolidone did not induce contact 
dermal phototoxic response in human subjects under the conditions of 
this test.
    ix. Photoallergy. Each of 25 human subjects, 6 male and 19 females, 
received 0.2 mL of a 1% suspension of test material in tap water on 
both volar forearms. Following a 24-hour exposure period under 
occlusive wrapping, the patches were removed and the sites scored for 
erythema and edema. Immediately after scoring one arm was irradiated 
with both ultraviolet (UV-A) and UV-B light. The UV-A exposure period 
was 15 minutes; the UV-B exposure period was adjusted based on each 
subject's skin type. Sites were scored immediately following 
irradiation. A series of six induction patches was applied twice a week 
for 3 weeks.
    Following a 2-week rest period, challenge patches were applied to 
virgin sites on each forearm. After a 24-hour exposure period, both 
sites were scored and the previously designated arm was irradiated. The 
sites were scored immediately after irradiation and again at 24 and 48 
hours.
    During the induction phase, 5 subjects exhibited a faint, minimal 
reaction on the irradiated contact site and one subject exhibited 
erythema and/or slight edema on the nonirradiated site. No reactions 
were exhibited at the challenge phase. N-(n-octyl)-2-pyrrolidone did 
not induce contact dermal photoallergy nor contact dermal sensitization 
in human subjects under the conditions of this test.

[[Page 48170]]

    x. Comedogenicity in rabbits. The comedogenicity potential of N-(n-
octyl)-2-pyrrolidone was assessed in New Zealand white rabbits. The 
external ear canal of six animals received dermal applications of 0.5 
ml of 2% N-(n-octyl)-2-pyrrolidone in distilled water for 5 days a 
week, over a 4-week period. This was followed by microscopic 
examinations of the treated tissues.
    Minimal to moderate local irritation was noted in all test animals 
characterized by redness, eschar, dryness and flaking. A mild to 
moderate comedogenic response was observed in 4 of the treated rabbits 
each receiving a comedogenic grade of 1.0 on a scale of 0 to 5. The 
remaining test animals received a grade of 0 (negative), yielding a 
mean comedogenic grade of 0.67. Under the conditions of this study, a 
mean comedogenic grade of > 2.0 in rabbits is considered to indicate a 
potential for comedogenesis in humans.
    Therefore, N-(n-octyl)-2-pyrrolidone is not expected to be 
comedogenic in humans. There were no neoplastic microscopic findings in 
this study.
    2. Genotoxicity-- Ames Salmonella/microsome/reverse mutation assay: 
N-(n-octyl)-2-pyrrolidone and potential metabolite(s) formed as a 
result of liver S9 fraction activation was tested, as sold, in the Ames 
Assay with Salmonella typhimurium tester strains TA 1,535, TA 1,537, TA 
1,538, TA 98 and TA 100. The entire 5-strain assay, with and without 
rat liver S9 fraction preparation, was performed twice.
    In both experiments, with and without metabolic activation, there 
was no increase in the incidence of histidine protrotrophic mutants, 
relative to the negative controls. Therefore, N-(n-octyl)-2-pyrrolidone 
when tested as sold, using the Ames Salmonella assay system, is not a 
mutagen.
    i. Mouse micronucleus test in vivo. N-(n-octyl)-2-pyrrolidone was 
tested for clastogenic (chromosome breaks) and aneugenic (numerical 
aberrations) effects on mouse bone marrow cells in vivo. Mice were 
administered N-(n-octyl)-2-pyrrolidone by intragastric gavage at a dose 
level of 1,720 mg/kg, based on results of a preliminary toxicity test. 
Negative controls receiving dosing vehicle alone and positive control 
(mitomycin C, 12 mg/kg) were also included. Bone marrow smears were 
obtained at 24, 48, and 72 hours post-dosing and examined for the 
presence of micronuclei in polychromatic and normochromatic 
erythrocytes. The ratio of polychromatic to normochromatic erythrocytes 
(P/N ratio) was also assessed.
    Mice treated with N-(n-octyl)-2-pyrrolidone showed no significant 
increase in frequency of micronucleated polychromatic erythrocytes, and 
no significant decrease in P/N ratio at any of the sampling times. N-
(n-octyl)-2-pyrrolidone is not mutagenic in this in vivo cytogenetic 
test system. There was no evidence of clastogenic or aneugenic effects 
in this test.
    ii. Mouse lymphoma mutagenesis assay. In this assay, N-(n-octyl)-2-
pyrrolidone was tested for its potential to induce mutations at the 
thymidine kinase (TK) locus of L5128Y TK+/- mouse lymphoma cells both 
in the presence and absence of exogenous metabolic activation. Based on 
the results of a range finding test N-(n-octyl)-2-pyrrolidone was 
tested at doses ranging 0.005 to 100 ul/ml which produced varying 
degrees of reduction in cell growth.
    The results of this assay indicate that N-(n-octyl)-2-pyrrolidone 
did not produce mutagenic response in cultures treated in both the 
absence and presence of exogenous activation with Aroclor-induced rat 
liver S-9 preparation.
    3. Reproductive and developmental toxicity. N-(n-octyl)-2-
pyrrolidone was administered orally by gavage, once daily, to pregnant 
female Wistar rats from day 6 through day 15 post coitum, at dosages of 
50, 200, or 800 mg/kg/body weight/day in order to assess the effects on 
embryonic and fetal development.
    At 800 mg/kg, one dam died after the 7th and one after the 10th 
test article administration. The females of this group had marked 
treatment-related clinical signs, reduced food consumption, slight body 
weight loss during the first day of dosing, and reduced corrected body 
weight gain. The mean fetal body weight was reduced at this dosage, 
combined with a delay in skeletal ossification.
    At 50 or 200 mg/kg, no treatment-related effects on maternal or 
fetal parameters were observed.
    Based on these findings, the NOAEL for the maternal and fetal 
parameters was determined to be 200 mg/kg/bwt/day. N-(n-octyl)-2-
pyrrolidone is not teratogenic to Wistar rats even at the maternally 
toxic dose of 800 mg/kg/bwt/day. Fetal body weight loss and delays in 
skeletal ossification at 800 mg/kg/day are not considered evidence of 
developmental toxicity since they occurred in the presence of severe 
maternal toxicity.
    4. Subchronic toxicity--i. Twenty-eight day oral toxicity in rats. 
N-(n-octyl)-2-pyrrolidone, formulated as a solution in corn oil, was 
administered daily to rats (5 male, 5 female per dosage level) by 
intragastric intubation at dose levels of 5, 55 or 320 mg/kg, for 28 
consecutive days. Similarly, control animals received corn oil (5 ml/
kg/day).
    At the high dose level (320 mg/kg/day), specific changes in general 
health, bwt gain, hematological and biochemical parameters were 
recorded. Statistically significant observations noted included:
    ii. Lower body weight gains - females (week 3).
    iii. Lower packed cell volume (PCV) and red blood cell counts - 
males.
    iv. Higher mean corpuscular hemoglobin concentration (MCHC)- males.
    v. Higher glutamic-pyruvic transaminase levels-females.
    In all other respects including food consumption, organ weights, 
macro and microscopic pathology, no treatment-related changes were 
noted at all the tested dose levels.
    In this 28-day study, the NOAEL of N-(n-octyl)-2-pyrrolidone was 
determined to be 55 mg/kg/day.
    5. 90-Day oral toxicity in dogs. Groups of 4 male and 4 female 
beagle dogs were given N-(n-octyl)-2-pyrrolidone orally via capsule at 
dose levels of 30, 90, and 240 mg/kg/day, for 90 days. All animals were 
observed daily for mortality and clinical signs of toxicity. At 
euthanatization, all surviving animals were subjected to histological 
examinations.
    Dose related neurological signs and bwt loss were observed at 90 
and 240 mg/kg levels. At 90 and 240 mg/kg treatment-related changes in 
clinical pathological parameters were also observed. In addition, dose-
related increases in both absolute and relative liver weights were 
observed in all dose groups but was statistically significant in only 
the 90 and 240 mg/kg/day groups. One female death occurred on day 42 in 
the 240 mg/kg group. No treatment-related toxicity or clinical signs 
were observed in the 30 mg/kg/day group. Thirty mg/kg/day was a clear 
NOAEL.
    6. 90-Day dietary toxicity in rats. Groups of 10 male and 10 female 
rats were given diets containing 0, 60, 600, or 10,000 ppm N-(n-octyl)-
2-pyrrolidone for 90 days. The approximate mean daily intakes of N-(n-
octyl)-2-pyrrolidone were calculated to be 0, 5.3, 53, or 686 mg/kg/
bwt.
    All animals were observed daily for clinical signs of toxicity. At 
euthanatization, all animals were necropsied and subjected to 
macroscopic and microscopic examinations.
    Reduced weight gain, increased absolute and relative liver weights 
and mild liver hypertrophy were observed at 10,000 ppm (686 mg/kg/bwt). 
No

[[Page 48171]]

treatment-related effects were observed at 60, (5.3 mg/kg bw/day), and 
600 (53 mg/kg/bwt/day) ppm.
    The liver was identified as a target organ and 600 ppm (53 mg/kg/
day) was a clear NOAEL.
    N-(n-octyl)-2-pyrrolidone is used mostly in household and 
institutional cleaners, especially as a constituent of hard-surface 
cleaners. Consistent with this public use, N-(n-octyl)-2-pyrrolidone is 
readily biodegradable in various microbially active matrices. It is 
freely soluble in water and has a relatively high polarity. For most 
compounds, there is a direct correlation between tissue uptake and 
bioaccumulation, and simple physical organic parameters such as log P, 
molecular mass and water solubility (Davies and Dobbs, 1984; Veith et 
al., 1979; Zitko and Hutzinger, 1976). The low bioaccumulation 
potential of N-(n-octyl)-2-pyrrolidone indicates that it is unlikely to 
accumulate in endocrine tissues, or disrupt endocrine functions. The 
safety, low uptake and low bioaccumulation potential of pyrrolidones in 
biological systems has also been experimentally demonstrated, even in 
active human sperms (Goldstein et al., 1998). These data strongly 
demonstrate that N-(n-octyl)-2-pyrrolidone is not an endocrine 
disrupter, and does not have any physiologically disruptive effects on 
endocrine processes. Additionally, it does not share any mechanistic or 
chemical similarity with currently known or suspected chemicals or 
chemical classes being studied for endocrine effects.
    Additionally, pyrrolidones are natural products of ornithine 
metabolism found in many edible plant tissues, including carrots and 
tobacco. No physiologically disruptive effects have been reported from 
dietary exposures to these plants.

C. Aggregate Exposure

    1. Dietary exposure. Residue data are generally not required for 
inert ingredient exemptions from a tolerance. Specific residue data for 
the inert ingredient N-(n-octyl)-2-pyrrolidone when used as a seed 
treatment are not available. Residue data are available to EPA for a 
number of pesticide products when applied as a seed treatment to 
soybeans at rates equal to or greater than 3 grams per acre. These data 
show that residues are non-detectable (< 0.01ppm) in soybeans, soybean 
forage, soybean fodder and soybean hay at harvest.
    For the purpose of determining the potential dietary exposure from 
the proposed use of N-(n-octyl)-2-pyrrolidone as an inert ingredient in 
pesticides applied as a soybean seed treatment, an ultra conservative 
assumption was made that residues in soybean products would be 0.66 
ppm. This assumption is based upon a maximum of 3 grams per acre of N-
(n-octyl)-2-pyrrolidone being applied per acre as a seed treatment and 
resulting crop yields of 35 bushels of soybeans per acre (2,100 pounds 
of soybeans yield per acre based on an average weight of 60 pounds per 
bushel). Further, the soybean seed yield per acre is equal to 
approximately 36% of the total weight of soybean products at harvest 
per acre (soybeans equal 36%; the remaining 64% is soybean fodder, 
stems and roots). It is further assumed that the 3 grams of N-(n-
octyl)-2-pyrrolidone is not degraded at all during the growth of the 
soybeans crop but instead at harvest is equally distributed in all 
plant parts at harvest.
    N-(n-octyl)-2-pyrrolidone has been exempted from the requirement of 
a tolerance when used as an inert ingredient in certain pesticide 
products applied to defoliate cotton. No specific residue data are 
available for N-(n-octyl)-2-pyrrolidone in cotton products. For the 
purpose of this dietary assessment, the ultra conservative assumption 
was made that residues of N-(n-octyl)-2-pyrrolidone in cotton products 
would be 2x the highest residue tolerance established by EPA for any 
pesticide in cotton products. This results in dietary calculations 
based upon 70 ppm in cotton seed and cotton seed products including 
cotton seed oil (based on a 35 ppm tolerance for dalapon in cotton 
seed) and 200 ppm in cotton gin byproducts (based on a 100 ppm 
tolerance for glyphosate in cotton gin byproducts). Also, for the 
purposes of this assessment, the ultra conservative assumption was made 
that eggs, milk, meat, fat and meat byproducts would contain 0.5 ppm 
residues of N-(n-octyl)-2-pyrrolidone.
    2. Chronic dietary exposure assessment for N-(n-octyl)-2-
pyrrolidone. Chronic dietary exposure was assessed for the U.S. 
population and population sub-groups utilizing the Dietary Exposure 
Evaluation Model (DEEMTM) from Novigen Sciences, Inc. Food 
consumption information (soybean food items only) was taken from USDA's 
1994-96 Continuing Survey of Food Intake by Individuals (CSFII).
    Exposure was compared to a chronic reference dose (RfD) of 0.03 mg/
kg/bwt/day which was based on a no observable adverse effect level 
(NOAEL) of 30 mg/kg/bwt obtained from a 90-day feeding study in dogs 
and a 1,000-fold safety factor.
    Results indicate that exposure for the overall U.S. population was 
21.4% the chronic RfD for the soybean proposed plus the current use on 
cotton. The most sensitive subpopulation (children 1-6 years old) 
results in a chronic that uses 68% of the chronic RfD. This assessment 
is extremely conservative since residue reduction probably occurs with 
exposure of the treated seed to the environment as well as processing 
(not taken into account in this assessment) and market shares for both 
crops were assumed to be 100%.
    3. Acute dietary exposure assessment for N-(n-octyl)-2-pyrrolidone. 
Using the same exposure estimates discussed above for soybean products 
results in an ultra conservative acute exposure for the overall U.S. 
population of 37.74% of the acute RfD for the proposed use on soybeans 
plus the current uses on cotton. The most sensitive subpopulation 
(children 1-6 years old) had an exposure of 52.85% of the acute RfD. 
These calculations were conducted at the 99.9% level.
    i. Food. See exposure estimate discussed above.
    ii. Drinking water. Based on its very low application rate, i.e., < 
3 grams/acre, as well as the environmental fate studies, N-(n-octyl)-2-
pyrrolidone would not be expected to persist in the environment, nor 
contaminate drinking water supplies.
    4. Non-dietary exposure. N-(n-octyl)-2-pyrrolidone may also be used 
in certain cleaners, specifically hard-surface cleaners. Annual volumes 
market volume for this use is modest and is not expected to 
significantly contribute to the exposure profile for N-(n-octyl)-2-
pyrrolidone.

D. Cumulative Effects

    While the Agency has some information in its files that may be 
helpful in determining whether chemicals share a common mechanism of 
toxicity with any other substances, EPA does not at this time have the 
methodology to resolve the scientific issues concerning common 
mechanism of toxicity in a meaningful way.

E. Safety Determination

    1. U.S. population. As per the details in the Dietary Residue 
Exposure System analysis, even the most sensitive population, children, 
1- 6 years old, would be exposed to considerably less than 100% of the 
RfD even using the ultra conservative assumptions discussed above.
    2. Infants and children. No developmental, embryotoxic, or 
teratogenic effects have been associated with N-(n-octyl)-2-
pyrrolidone.

[[Page 48172]]

F. International Tolerances

    The Applicant is not aware of any international tolerance or codes 
of Maximum Residue Limits (MRLs) for N-(n-octyl)-2-pyrrolidone on any 
crop or livestock commodities.

3. Interregional Research Project Number 4 and The Rohm and Haas 
Company

 PP 7E4862, 7E4866, 8E4939, 7E4877, 7E4861, 4E4302 PP 1F4030, 2F4155, 
and 9F3812

    EPA has received pesticide petitions [PP 7E4862, 7E4866, 8E4939, 
7E4877, 7E4861, and 4E4302] from the Interregional Research Project 
Number 4 (IR-4), New Jersey Agricultural Experiment Station, P. O. Box 
231 Rutgers University, New Brunswick, NJ 08903. EPA has also received 
pesticide petitions [PP 1F4030, 2F4155, and 9F3812] from the Rohm and 
Haas Company, 100 Independence Mall West, Philadelphia, PA 19106-2399. 
The petitions propose, pursuant to section 408(d) of the FFDCA, 21 
U.S.C. 346a(d), to amend 40 CFR part 180 by establishing tolerances for 
residues of the fungicide, myclobutanil [alpha-butyl-alpha-(4-
chlorophenyl)-1H-1,2,4-triazole)-1-propanenitrile], and it's 
metabolite, alpha -(3-hydroxybutyl)-alpha-(4-chloro-phenyl)-1H-1,2,4-
triazole-1-propanenitrile (free and bound) in or on the RAC commodity 
at the tolerance level ppm as follows:
    1. PP 7E4862. Proposes the establishment of a tolerance for 
asparagus at 0.02 ppm.
    2. PP 7E4866. Proposes the establishment of a tolerance for 
caneberry at 1.0 ppm.
    3. PP 8E4939. Proposes the establishment of tolerances for currant 
at 3.0 ppm and gooseberry at 2.0 ppm.
    4. PP 7E4877. Proposes the establishment of a tolerance for mint at 
3.0 ppm.
    5. PP 7E4861. Proposes the establishment of a tolerance for snap 
bean at 1.0 ppm.
    6. PP 4E4302. Proposes the establishment of a tolerance for 
strawberry at 0.5 ppm.
    7. PP 1F4030. Proposes the establishment of tolerances for tomato 
at 0.3 ppm and processed fractions for the following commodities: 
tomato pomace, wet at 3.0 ppm; tomato pomace, dry at 5.0 ppm; tomato 
juice at 0.3 ppm; tomato puree at 0.6 ppm; tomato paste at 1.2 ppm; 
tomato paste juice at 0.6 ppm; and tomato catsup at 0.6 ppm.
    8. PP 2F4155. Proposes the establishment of tolerances for 
cucurbits at 0.5 ppm and inadvertent residues at 0.03 ppm for the 
following rotational crop group: root and tuber vegetables, leaves of 
root and tuber vegetables, leafy vegetables (except brassica 
vegetables), brassica (cole) leafy vegetables, legume vegetables 
(except snapbeans), foliage of legume vegetable group, fruiting 
vegetables (except cucurbits), cereal grains-commodities; cereal 
grains-forage, fodder, and straw; and nongrass animal feeds (forage, 
fodder, straw, and hay).
    9. PP 9F3812. Proposes the establishment of a tolerance for pome 
fruit at 0.5 ppm.
    EPA has determined that the petitions contain 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 
petitions. Additional data may be needed before EPA rules on the 
petitions.

A. Residue Chemistry

    1. Metabolism in plants and animals--i. Plants. Based on the three 
metabolism studies in wheat, apples, and grapes, which indicate a 
similar metabolic route for crops in three different crop groups, Rohm 
and Haas Company (the registrant) concludes that the nature of the 
residue is adequately understood for the purpose of these tolerances.
    ii. Animals. The nature of the residue in animals is adequately 
understood. The residues of concern in animal commodities, except milk, 
are myclobutanil (RH-3866) and its metabolite RH-9090 (free). The 
residues of concern in milk are myclobutanil, and its metabolites RH-
9090 (free and bound) and alpha-(4-chlorophenyl)-alpha-(3,4-
dihydroxybutyl)-1H-1,2,4-triazole-1-propanenitrile; RH-80,294).
    2. Analytical method. An adequate enforcement method is available 
to enforce the established and proposed tolerances. Quantitation is by 
gas-liquid chromatography (GLC) using a nitrogen/phosphorous (NP) 
detector for RH-3866 and an electron capture (63Ni) for 
residues measured as the alcohol metabolite (RH-9090). Myclobutanil 
residues in animal commodities are measured in essentially the same 
manner with the additional diol metabolite in milk.
    3. Magnitude of residues. Field residue trials were conducted with 
wettable powder formulations of myclobutanil in geographically 
representative regions of the United States. The registrant concludes 
that the results from these studies support the proposed tolerances, 
and clearly indicate that the RH-9090 metabolite is a minor contributor 
to the total residue.

B. Toxicological Profile

    1. Acute toxicity. According to the Rohm and Haas Company, 
myclobutanil wettable powder formulations are essentially non-toxic 
after administration by the oral, dermal and respiratory routes 
moderately irritating to the eyes, and non-skin sensitizers. Of these 
test results, ocular irritation at Toxicity Category III (Caution) was 
shown to be the worst case acute toxicity.
    2. Genotoxicity. Myclobutanil was negative (non-mutagenic) in an 
Ames assay with and without hepatic enzyme activation. Myclobutanil was 
negative in a hypoxanthine guanine phosphoribosyl transferase (HGPRT) 
gene mutation assay using Chinese hamster ovary (CHO) cells in culture 
when tested with and without hepatic enzyme activation. In isolated rat 
hepatocytes, myclobutanil did not induce unscheduled DNA synthesis 
(UDS) or repair. Myclobutanil did not produce chromosome effects in 
vivo using mouse bone marrow cells or in vitro using CHO cells. On the 
basis of the results from this battery of tests, it is concluded that 
myclobutanil is not mutagenic or genotoxic.
    3. Reproductive and developmental toxicity. In the developmental 
study in rats, the maternal (systemic) no observed adverse effect level 
(NOAEL) was 93.8 mg/kg/day based on rough hair coat, and salivation at 
the lowest observed adverse effect level (LOAEL) of 312.6 mg/kg/day. 
The developmental (fetal) NOAEL was 93.8 mg/kg/day based on incidences 
of 14th rudimentary and 7th cervical ribs at the LOAEL of 312.6 mg/kg/
day.
    In the developmental study in rabbits, the maternal (systemic) 
NOAEL was 60 mg/kg/day based on reduced weight gain, clinical signs of 
toxicity, and abortions at the LOAEL of 200 mg/kg/day. The 
developmental (fetal) NOAEL was 60 mg/kg/day based on increases in 
number of resorptions, decreases in litter size, and a decrease in the 
viability index at the LOAEL of 200 mg/kg/day.
    In the 2-generation reproduction toxicity study in rats, the 
maternal (systemic) NOAEL was 2.5 mg/kg/day based on increased liver 
weights and liver cell hypertrophy at the LOAEL of 10 mg/kg/day. The 
developmental (pup) NOAEL was 10 mg/kg/day based on decreased pup body 
weight during lactation at the LOAEL of 50 mg/kg/day. The reproductive 
(parental) NOAEL was 10 mg/kg/day, based on an increased incidence of 
stillborns, and atrophy of

[[Page 48173]]

the testes, epididymides, and prostate at the LOAEL of 50 mg/kg/day.
    4. Subchronic toxicity--i. Subchronic feeding study in rats was 
conducted for 13 weeks. The NOAEL was determined to be 1,000 ppm (52 
and 66 mg/kg/day in males and females, respectively), and the LOAEL was 
3,000 ppm based on increased liver and kidney weights, hypertrophy and 
necrosis in the liver, pigmentation in convoluted kidney tubules, and 
vacuolated adrenal cortex.
    ii. A subchronic feeding study in mice was conducted for 13 weeks. 
The NOAEL was determined to be 300 ppm (43 and 66 mg/kg/day in males 
and females, respectively), and the LOAEL was 1,000 ppm based on 
increases in liver weight and clinical chemistry parameters, 
hypertrophy or necrosis and inflammation in the liver, and cytoplasmic 
eosinophilia and/or hypertrophy of the zona fasciculata cells of the 
adrenal gland.
    iii. A subchronic feeding study in dogs conducted for 13 weeks 
resulted in a NOAEL of 10 ppm (0.34 mg/kg/day) in males and 200 ppm (8 
mg/kg/day) in females. At the LOAEL of 200 ppm and above, 
hepatocellular centrilobular or midzonal hypertrophy was observed in 
males. At 800 ppm and above, the same effect was observed in females. 
In addition, increases in alkaline phosphatase, absolute liver weights 
in both sexes, and relative liver weights in males were observed. At 
1,600 ppm, all the previous effects plus increases in relative liver 
weights in females, a suggestion of mild red cell destruction or mild 
anemia, and decreases in body weight and food consumption (possibly 
related to palatability) were observed.
    iv. A 24.99% active ingredient (ai) emulsifiable concentrate (2EC) 
formulation was dermally applied to rats at 1, 10, or 100 mg/ai/kg/day 
and a 40% ai wettable powder (40 WP) formulation was dermally applied 
to rats at 100 mg/ ai/kg/day. Both formulations were applied once per 
day for a total of 19-20 treatments over a 4-week period. Application 
of the 2EC formulation resulted in a NOAEL for systemic effects of > 
100 mg/ai/kg/day, and a NOAEL and LOAEL for skin irritation of 10 and 
100 mg ai/kg/day, respectively. The 40 WP formulation at 100 mg/ai/kg/
day the highest dose tested (HDT) did not produce any systemic effects 
and only produced minor skin irritation.
    5. Chronic toxicity--i. A 1-year feeding study in dogs resulted in 
hepatocellular hypertrophy, increases in liver weights, ``ballooned'' 
hepatocytes, and increases in alkaline phosphatase, serum glutamic 
pyruvic transaminase (SGPT) and GGT, and possible slight hematological 
effects. The NOAEL and LOAEL were 100 ppm (3.1 and 3.8 mg/kg/day for 
males and females, respectively) and 400 ppm (14.3 and 15.7 mg/kg/day 
for males and females, respectively).
    ii. A 24-month chronic/carcinogenicity study in male and female 
mice was conducted at 0, 20, 100, and 500 ppm myclobutanil, and a 
second 24-month chronic/carcinogenicity study was conducted in female 
mice at 0 and 2,000 ppm (394 mg/kg/day). No carcinogenic effects were 
observed in either study. The NOAEL was 100 ppm (13.7 and 16.5 mg/kg/
day for males and females, respectively), and the LOAEL was 500 ppm (70 
and 85 mg/kg/day for males and females, respectively) based on 
increased hepatic mixed-function oxidase (MFO) activity, increased SGPT 
(males only), increased absolute and relative liver weights, increased 
incidences and severity of centrilobular hepatocytic hypertrophy, 
Kupffer cell pigmentation, periportal punctate vacuolation, individual 
hepatocellular necrosis (males only), and increased incidences of focal 
hepatocellular alterations and multifocal hepatocellular vacuolation. 
At 2,000 ppm, these effects, and decreased body weight and body weight 
gain, and cytoplasmic eosinophilia and hypertrophy of the cells of the 
zona fasciculata area of the adrenal cortex were observed.
    iii. A 24-month chronic/carcinogenicity study in male and female 
rats was conducted at 0, 25/35/50 (2 weeks/2 weeks/to termination), 
100/140/200, and 400/560/800 ppm myclobutanil, and a second 24-month 
chronic/carcinogenicity was conducted in male and female rats at 0 and 
2,500 ppm (125 mg/kg/day). No carcinogenic effects were observed in 
either study. The NOAEL and LOAEL were 50 ppm (2.5 mg/kg/day) and 200 
ppm (10 mg/kg/day), respectively, based on a decrease in testicular 
weight and increase in testicular atrophy. At 2,500 ppm, these effects, 
and increases in the incidences of centrilobular to midzonal 
hepatocellular enlargement and vacuolization in the liver of both 
sexes, increases in bilateral aspermatogenesis in the testes, increases 
in the incidence of hypospermia and cellular debris in the 
epididymides, and increased incidence of arteritis/periarteritis in the 
testes were observed. The chronic population adjusted dose (cPAD) of 
0.025 mg/kg/day was established based on the chronic feeding study in 
rats with a NOAEL of 2.5 mg/kg/day and an uncertainty factor of 100.
    6. Animal metabolism. The absorption, distribution, excretion, and 
metabolism of myclobutanil in rats was investigated. Following oral 
administration, myclobutanil was completely and rapidly absorbed, 
extensively metabolized to at least seven major metabolites, and 
rapidly excreted evenly distributed between urine and feces. 
Myclobutanil did not accumulate in tissues.
    7. Metabolite toxicology. Common metabolic pathways for 
myclobutanil have been identified in both plants (grapes, apples, 
wheat) and animals (rat, goat, hen). The metabolic pathway common to 
both plants and animals involves oxidation of the n-butyl alkyl side-
chain in the 3- and 4- positions, oxidation of the cyano- group, and 
subsequent conjugation. Extensive degradation and elimination of polar 
metabolites occurs in animals such that residues are unlikely to 
accumulate in humans or animals exposed to these residues through the 
diet.
    8. Endocrine disruption. The mammalian endocrine system includes 
estrogen and androgens as well as other hormonal systems. Myclobutanil 
is not known to interfere with reproductive hormones; thus, the 
registrant believes that myclobutanil should not be considered to be 
estrogenic or androgenic. The Rohm and Haas Company is not aware of any 
instances of proven or alleged adverse reproductive or developmental 
effects to people, domestic animals, or wildlife as a result of 
exposure to myclobutanil or its residues.

C. Aggregate Exposure

    1. Dietary (food) exposure. Permanent tolerances have been 
established (40 CFR 180.443) for the residues of myclobutanil in or on 
a variety of RAC including almond nutmeat at 0.1 ppm, almond hulls at 
2.0 ppm, apples at 0.5 ppm, apple pomace, wet/dry at 5.0 ppm, banana 
whole (Post-H) at 4.0 ppm, stone fruits except cherry at 2.0 ppm, 
cherries, sweet/sour at 5.0 ppm, plums, dried (prunes) at 8.0 ppm, 
cotton seed at 0.02 ppm, grapes at 1.0 ppm, grape pomace, wet/dry at 
10.0 ppm, raisins at 10.0 ppm, and raisin waste at 25.0 ppm. In 
addition, permanent tolerances have been established for meat and meat 
byproducts including cattle, fat at 0.05 ppm, cattle, liver at 1.0 ppm, 
cattle, meat at 0.1 ppm, cattle, meat byproducts at 0.2 ppm, poultry, 
fat at 0.02 ppm, poultry, meat at 0.02 ppm, poultry, meat byproducts at 
0.02 ppm, eggs at 0.02 ppm, and milk at 0.2 ppm.
    Risk assessments were conducted by Rohm and Haas Company to assess

[[Page 48174]]

dietary exposures and risks from myclobutanil as follows:
    i. Acute exposure and risk. No acute endpoint was identified for 
myclobutanil, and no acute risk assessment is required.
    ii. Chronic exposure and risk. Risk associated with chronic dietary 
exposure from myclobutanil was assessed on two levels using two dietary 
exposure models. In the first assessment, tolerance level residues were 
assumed (except bananas in which 0.8 ppm was used in the dietary risk 
assessment rather than the tolerance of 4.0 ppm on whole fruit, since 
residues in the pulp will not exceed 0.8 ppm), and, in the second 
assessment average field trial residues were used. Both assessments 
utilized percent of crop treated refinements. The Anticipated Residue 
Contribution (ARC) from all proposed and existing food uses of 
myclobutanil was assessed. Additional proposed food uses of 
myclobutanil not previously mentioned in this document include peppers, 
hops, and artichokes (IR-4 petitions for these crops will likely be 
submitted in 1999). The percent of crop values used in these 
assessments were 79% for grapes, 60% for apples, 47% for cherries, 40% 
for bananas, 22% for peaches, 8% for pears, 3% for plums, 1% for 
apricots, 1% for almonds, and 1% for cottonseed. Percent crop treated 
data were used for the above commodities in the chronic exposure 
assessment, but were not considered when calculating the dietary burden 
from which secondary residue tolerances in meat, milk and poultry were 
derived or for the proposed uses on tomatoes and tomato processed 
fractions, cucurbit vegetables, and all of the subject minor crops of 
this petition. For rotational crops, the assessments conservatively 
assumed the extreme worse-case that 100% of all plantable United States 
acreage contained crops with residues at the 0.03 ppm proposed 
tolerance level.
    The cPAD used for the chronic dietary analysis is 0.025 mg/kg/day. 
Potential chronic exposure was estimated using NOVIGEN'S Dietary 
Exposure Evaluation Model (DEEM Version 5.31), which uses United States 
Department of Agricultural (USDA) food consumption data from the 1989-
1992 survey. The existing and proposed myclobutanil tolerances, and 
average myclobutanil residues result in ARCs that are equivalent to the 
following percentages of the cPAD (assumes residues are present at 
tolerance levels and includes percent crop treated refinements): For 
the U.S. Population (48 contiguous states) subgroup, the percent cPAD 
utilized is 19.1%. For the most highly exposed population subgroup, 
children (1 to 6 years old), the percent cPAD utilized is 57.7%.
    iii. Drinking water. There is no established Maximum Concentration 
Level (MCL) for residues of myclobutanil in drinking water. No drinking 
water health advisory levels have been established for myclobutanil. 
There is no entry for myclobutanil in the ``Pesticides in Groundwater 
Database.'' Submitted environmental fate studies suggest that 
myclobutanil has low to moderate mobility potential in soil. 
Myclobutanil is stable to hydrolysis and soil photolysis, but does 
degrade photolytically in natural waters and soil. Field-trial soil 
dissipation studies had half-lives in the range of 50 to 400 days and 
indicated no significant downward movement of residues. Field trials 
showed myclobutanil degrades much more rapidly outdoors on foliage; the 
foliar decline on turf has a half-life of approximately 7 days.
    The registrant believes that myclobutanil will not contaminate 
ground water or drinking water because of its adsorptive properties on 
soil, solubility in water, and degradation rate. Data from laboratory 
studies and field dissipation studies have been used in the PRZM/EXAMS 
computer model to predict the movement of myclobutanil. The model 
predicts that myclobutanil will not leach into ground water, even if 
heavy rainfall is simulated. The modeling predictions are consistent 
with the data from environmental studies in the laboratory and the 
results of actual field dissipation studies. Review of terrestrial 
field dissipation data indicates that myclobutanil did not leach into 
ground water in either sandy loam or coastal soil. Based on conducted 
studies to assess environmental risk, the registrant believes that 
significant exposure to residues of myclobutanil in drinking water is 
not anticipated.
    2. Non-dietary exposure. Myclobutanil has no veterinary 
applications and is not approved for use in swimming pools. It is 
labeled for application to golf courses or other recreational areas, 
for use on ornamentals, and myclobutanil may be applied to residential 
lawns. However, this latter application represents less than 5% of 
myclobutanil's total non-dietary applications and is almost exclusively 
done by professional lawn care service companies. There are no indoor 
residential uses of myclobutanil; therefore, there is no indoor 
exposure to myclobutanil. Based on reasonable assumptions of exposure, 
the registrant does not anticipate significant exposure to residues of 
myclobutanil via non-dietary routes.

D. Cumulative Effects

    The potential for cumulative effects of myclobutanil with other 
substances that have a common mechanism of toxicity was considered. The 
primary toxicological target organs for myclobutanil exposures are the 
rodent testes and liver. Myclobutanil can also produce phytotoxicity at 
high application rates. Myclobutanil belongs to the class of fungicide 
chemicals known as triazoles having demethylase inhibition capability. 
There are data available which suggest that there is a biochemical 
target site in fungal cell wall synthesis for myclobutanil and other 
fungicides in this class. However, there are no data which demonstrate 
that fungicides of this class have a common mode of action for 
exaggerated-dose phytotoxicity in plants, nor is there evidence that 
the toxicological effects produced by fungicides of this class in 
animals have a common mode of action.
    EPA does not have, at this time, available data to determine 
whether myclobutanil has a common mechanism of toxicity with other 
substances or how to include this pesticide in a cumulative risk 
assessment

E. Safety Determination

    1. U.S. population. Using the conservative exposure assumptions 
described above and taking into account the completeness and 
reliability of the toxicity data, the percentage of the cPAD that will 
be utilized by dietary (food only) exposure to residues of myclobutanil 
from existing, pending, and proposed tolerances is 19.1% and 3.2% for 
the U.S. population assuming residues are present at their tolerance 
levels and average levels, respectively. The registrant believes that 
aggregate exposure (food, water, residential) is not expected to exceed 
100% of the cPAD. EPA generally has no concern for exposures below 100% 
of the cPAD because the cPAD represents the level at or below which 
daily aggregate dietary exposure over a lifetime will not pose 
appreciable risks to human health. The Rohm and Haas Company concludes 
that there is a reasonable certainty that no harm will result from 
aggregate exposure to myclobutanil residues to the U.S. population.
    2. Infants and children--In general. In assessing the potential for 
additional sensitivity of infants and children to residues of 
myclobutanil, data from developmental toxicity studies in the rat and 
rabbit, and 2-generation reproduction studies in the rat are 
considered. The developmental toxicity

[[Page 48175]]

studies are designed to evaluate adverse effects on the developing 
organism resulting from maternal pesticide exposure during gestation. 
Reproduction studies provide information relating to effects from 
exposure to the pesticide on the reproductive capability of mating 
animals and data on systemic toxicity.
    3. Developmental toxicity studies--i. Rat. In the developmental 
study in rats, the maternal (systemic) NOAEL was 93.8 mg/kg/day based 
on rough hair coat, and salivation at the LOAEL of 312.6 mg/kg/day. The 
developmental (fetal) NOAEL was 93.8 mg/kg/day based on incidences of 
14th rudimentary and 7th cervical ribs at the LOAEL of 312.6 mg/kg/day.
    ii. Rabbit. In the developmental toxicity study in rabbits, the 
maternal (systemic) NOAEL was 60 mg/kg/day, based on reduced weight 
gain, clinical signs of toxicity and abortions at the LOAEL of 200 mg/
kg/day. The developmental (fetal) NOAEL was 60 mg/kg/day, based on 
increases in number of resorptions, decreases in litter size, and a 
decrease in the viability index at the LOAEL of 200 mg/kg/day.
    iii. Reproductive toxicity study. In the 2-generation reproductive 
toxicity study in rats, the parental (systemic) NOAEL was 2.5 mg/kg/
day, based on increased liver weights and liver cell hypertrophy at the 
LOAEL of 10 mg/kg/day. The developmental (pup) NOAEL was 10 mg/kg/day, 
based on decreased pup body weight during lactation at the LOAEL of 50 
mg/kg/day. The reproductive NOAEL was 10 mg/kg/day, based on the 
increased incidences of stillborns, and atrophy of the testes, 
epididymides, and prostate at the LOAEL of 50 mg/kg/day.
    iv. Prenatal and postnatal sensitivity. The prenatal and postnatal 
toxicology data base for myclobutanil is complete with respect to 
current toxicological data requirements. There is approximately a 25-
fold difference between the developmental NOAEL of 60 mg/kg/day from 
the rabbit developmental toxicity study and the NOAEL of 2.5 mg/kg/day 
from the chronic rat feeding study which was the basis of the cPAD. It 
is further noted that in both the rabbit and rat developmental toxicity 
studies, the developmental NOAEL and maternal NOAEL are comparable (60 
mg/kg/day for the rabbit and 93.8 mg/kg/day for the rat). In the rat 
reproduction study, the maternal NOAEL (2.5 mg/kg/day) was four times 
lower than the developmental (pup) and reproductive NOAELs (10 mg/kg/
day). According to the registrant, these studies indicate that there is 
no additional sensitivity for infants and children in the absence of 
maternal toxicity for myclobutanil.
    v. Acute risk. No acute dietary risk has been identified for 
myclobutanil.
    vi. Chronic risk. Using the exposure assumptions described above, 
the exposure to myclobutanil from food will utilize 14.4% (nursing 
infants < 1-year old), and 40.9% (non-nursing infants < 1-year old) of 
the cPAD assuming residues are present at tolerance levels, and will 
utilize 3.0% (nursing infants < 1-year old), and 7.3% (non-nursing 
infants < 1-year old) of the cPAD assuming residues are present at 
their average field residue levels. The percent of the cPAD that will 
be used by the food exposure for children 1 to 6 years old is 57.7% and 
8.0% assuming residues are present at tolerance levels and average 
field residue levels, respectively. The percent of the cPAD that will 
be used by the food exposure for children 7 to 12 years old is 28.5% 
and 4.5% assuming residues are present at tolerance levels and average 
field residue levels, respectively. EPA generally has no concern for 
exposures below 100% of the cPAD because the cPAD represents the level 
at or below which daily aggregate dietary exposure over a lifetime will 
not pose appreciable risks to human health.
    2. Non-dietary exposure. Given the limited potential for exposure 
to myclobutanil from residential exposure, it is not expected that the 
aggregate exposure will exceed 100% of the cPAD. The registrant 
believes that there is a reasonable certainty that no harm will result 
from aggregate exposure to myclobutanil residues.
    3. Conclusion. The Rohm and Haas Company concludes that reliable 
and complete data support the use of the 100-fold uncertainty factor, 
and that an additional 10-fold factor is not needed to ensure the 
safety of infants and children from dietary exposure.

F. International Tolerances

    There are Codex Maximum Residue Limits (MRLs) for myclobutanil. The 
myclobutanil data base was evaluated by the World Health Organization 
(WHO) and the Food and Agricultural Organization (FAO) Expert Panels at 
the Joint Meeting on Pesticide Residues (JMPR) in September 1992, and 
an additional evaluation by the FAO Expert Panels was conducted in 
September 1997 and September 1998. An Acceptable Daily Intake (ADI; 
cPAD) of 0.025 mg/kg/day was established by the WHO panel and a total 
of 13 Codex MRLs are approved, including 0.01 ppm for both meat and 
milk. An additional nine Codex MRLs were proposed in the 1997 data 
submission including tomatoes (0.3 ppm), tomato paste (2.0 ppm), pome 
fruit (0.5 ppm), and strawberries (0.5 ppm).
    The EPA has established the residue definition as the total of 
parent plus RH-9090, but the Codex has decided residues of parent alone 
are sufficient.

[FR Doc. 99-22636 Filed 9-1-99; 8:45 am]
BILLING CODE 6560-50-F