[Federal Register Volume 65, Number 169 (Wednesday, August 30, 2000)]
[Notices]
[Pages 52735-52740]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-22013]


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ENVIRONMENTAL PROTECTION AGENCY

[PF-956; FRL-6595-5]


Notice of Filing a Pesticide Petition to Establish a Tolerance 
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-956, must be 
received on or before September 29, 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-956 in the subject line on the first page of your 
response.

FOR FURTHER INFORMATION CONTACT:  By mail: Indira Gairola, Registration 
Division (7505C), Office of Pesticide Programs, Environmental 
Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460; 
telephone number: (703) 308-6379; 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-956. 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-956 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, 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

[[Page 52736]]

number PF-956. 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 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 support 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 15, 2000.
Peter Caulkins, Acting
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. 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.

International Specialty Products

6E4728

    EPA has received a pesticide petition PP 6E4728 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) and N-(n-dodecyl)-2-
pyrrolidone (Agsolex 12 ) when used as an inert ingredient in 
or on growing crops, when applied to raw agricultural commodities, or 
to animals (40 CFR 180.1001(c) and (e)). 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

    Plant metabolism. The Agency does not generally require residue 
chemistry data or environmental fate data to rule on the exemption from 
the requirement of a tolerance for an inert ingredient. However, 
relevant dietary residue modeling as well as extensive environmental 
fate data has been completed.

B. Toxicological Profile

    1. Acute toxicity--i. N-(n-octyl)-2-pyrrolidone. The acute oral 
LD50 for N-(n-octyl)-2-pyrrolidone when tested as sold, was 
found to be 2.05 grams/kilograms bodyweight (g/kg bwt). Graded dose 
levels (0.63-5.00 g/kg) of N-(n-octyl)-2-pyrrolidone were administered 
to five groups of fasted Wistar-strain albino rats (5 male, 5 female 
per group). The animals were observed for pharmacological effects, 
external signs of toxicity, and mortality over a 14-day period.
    ii. N-(n-dodecyl)-2-pyrrolidone. The acute oral LD50 for 
N-(n-dodecyl)-2-pyrrolidone, when tested as supplied, was found to be 
greater than 5 g/kg bwt. A single dose level of N-(n-dodecyl)-2-
pyrrolidone was administered to 10 fasted Wistar-strain albino rats (5 
male, 5 female). The animals were observed for external signs of 
toxicity or pharmacological effects and mortality over a 14-day period.
    2. Primary ocular irritation--i. N-(n-octyl)-2-pyrrolidone. N-(n-
octyl)-2-pyrrolidone was found to be extremely irritating when tested 
as sold, with wash procedures reducing the severity of the irritation 
observed. The 2% aqueous suspension was nonirritating both with and 
without washout procedures. Nine New Zealand white rabbits each 
received a single intra-ocular application of 0.1 mL of N-(n-octyl)-2-
pyrrolidone tested as sold. An additional 9 animals received a single 
application of a 2% aqueous suspension of N-(n-octyl)-2-pyrrolidone. In 
both assays, the eyes of 6 animals remained unwashed for 24 hours while 
the eyes of the remaining 3 animals were washed 30 seconds after 
instillation of the test materials. Observations of ocular irritation 
were recorded 24, 48, and 72 hours following instillation of test 
materials. Additional readings were made at 4, 7, 14, and 21 days in 
the assay where N-(n-octyl)-2-pyrrolidone was tested as sold. The eyes 
were scored for corneal opacity, iritis, conjunctivitis and other 
effects.
    ii. N-(n-dodecyl)-2-pyrrolidone. N-(n-dodecyl)-2-pyrrolidone when 
tested as sold was considered moderately irritating to rabbit eyes, 
with wash procedures reducing both the severity and duration of the 
irritation observed. The 2% aqueous suspension was nonirritating both 
with and without washout procedures. Nine New Zealand white rabbits 
each received a single intraocular application of 0.1 mL of N-(n-
dodecyl)-2-pyrrolidone tested as sold. An additional 9 animals received 
a

[[Page 52737]]

single application of a 2% aqueous suspension of N-(n-dodecyl)-2-
pyrrolidone. In both assays, the eyes of 6 animals remained unwashed 
for 24 hours while the eyes of the remaining 3 animals were washed 30 
seconds after instillation of the test materials. Observations for 
ocular irritation were recorded 24, 48, and 72 hours following 
instillation of test materials. Additional readings were made at 4, 7, 
14, and 21 days in the assay where N-(n-dodecyl)-2-pyrrolidone was 
tested as sold. The eyes were scored for corneal opacity, iritis, 
conjunctivitis and other effects.
    3. Primary dermal irritation--i. N-(n-octyl)-2-pyrrolidone. N-(n-
octyl)-2-pyrrolidone was extremely irritating to rabbit skin when 
tested as sold, and minimally irritating as a 2% suspension. The backs 
of 6 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, tested as sold, was made to each test 
site. In a second assay, an additional 6 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.
    ii. N-(n-dodecyl)-2-pyrrolidone. N-(n-dodecyl)-2-pyrrolidone was 
severely irritating to rabbit skin when tested as sold, and mildly 
irritating as a 2% suspension. The backs of 6 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-dodecyl)-2-
pyrrolidone, tested as sold, was made to each test site. In a second 
assay, an additional 6 rabbits received single applications of a 2% 
aqueous suspension of N-(n-dodecyl)-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 6.5 for N-(n-dodecyl)-2-pyrrolidone, when tested as sold, and 
1.28 when tested as a 2% gravimetric aqueous suspension.
    4. Acute dermal toxicity--i. N-(n-octyl)-2-pyrrolidone. The acute 
dermal LD50 for N-(n-octyl)-2-pyrrolidone when tested 
undiluted was determined to be greater than 2 g/kg bwt. 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 bwt. The skin of 3 
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 
pharmacologic activity 1, 3, 6, and 24 hours after treatment and daily 
thereafter for a total of 14 days. A gross necropsy was performed on 
all animals. The skin at the test sites showed crust formation, scaling 
and scarring. No gross internal changes were observed in any of the 
animals.
    ii. N-(n-dodecyl)-2-pyrrolidone. The acute dermal LD50 
for N-(n-dodecyl)-2-pyrrolidone, when tested undiluted, was determined 
to be greater than 2 g/kg bwt. Six New Zealand white rabbits each 
received a single dermal application of N-(n-dodecyl)-2-pyrrolidone at 
a dose level of 2 g/kg bwt. The skin of 3 animals was abraded, while 
the remaining animals' skin remained intact. Test sites were occluded 
for 24 hours at which time the wrap and any remaining test article were 
removed. Animals were observed for pharmacologic activity 1, 3, 6, and 
24 hours after treatment and daily thereafter for a total of 14 days. A 
gross necropsy was performed on all animals. The skin at the test sites 
was moderately to severely reddened, with crust formation, scarring, 
and scaling observed. No gross internal changes were observed in 5 of 
the 6 animals. One female animal died on day 5 of the observation 
period.
    5. Department of Transportation corrosivity--i. N-(n-octyl)-2-
pyrrolidone. N-(n-octyl)-2-pyrrolidone when tested as sold, was found 
to be corrosive to the skin of rabbits under conditions of this test. 
Six New Zealand white rabbits each received a single dermal application 
of 0.5 mL of undiluted N-(n-octyl)-2-pyrrolidone on 1 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, 48, hours, and 7 days after 
application. Crust formation was observed in 5 of the 6 animals.
    ii. N-(n-dodecyl)-2-pyrrolidone. N-(n-dodecyl)-2-pyrrolidone, when 
tested undiluted, was found to be corrosive to rabbit skin under the 
conditions of this test. Six New Zealand white rabbits each received a 
single dermal application of 0.5 mL N-(n-dodecyl)-2-pyrrolidone on 1 
intact test site. The test site was occluded for 4 hours at which time 
the occlusive wrap and any remaining test material were removed. The 
animals were observed for erythema, edema, and other effects at 4, 48, 
hours, and 7 days after application. Crust formation was seen in 5 of 6 
animals at day 7.
    6. Guinea pig sensitization study--i. N-(n-octyl)-2-pyrrolidone. In 
the screening test described below, N-(n-octyl)-2-pyrrolidone produced 
evidence of delayed contact hypersensitivity in 2 of the 20 test 
animals. 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 N-(n-octyl)-2-
pyrrolidone 30% v/v 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.
    ii. N-(n-dodecyl)-2-pyrrolidone. In the screening test described 
below, N-(n-dodecyl)-2-pyrrolidone produced evidence of delayed contact 
hypersensitivity. Twenty female albino guinea pigs received intradermal 
injections of 0.05% v/v N-(n-dodecyl)-2-pyrrolidone in both water and 
in 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 N-(n-dodecyl)-2-pyrrolidone, 2.5% v/v in distilled 
water. During this induction phase, 10 control animals were similarly 
treated 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-dodecyl)-2-pyrrolidone, 1% v/v 
in distilled water applied to an anterior site on the flank and N-(n-
dodecyl)-2-pyrrolidone, 0.5% v/v in distilled water applied in a 
similar

[[Page 52738]]

manner to a posterior site. The patches were sealed to the flank and 
covered for 24 hours. The challenge sites were evaluated at 24, 48, and 
72 hours after patch removal. Evidence of delayed contact sensitivity 
was produced by N-(n-dodecyl)-2-pyrrolidone in 5 animals. An 
inconclusive response was seen in 2 animals.
    7. Clinical studies--i. 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 conditions of the following tests.
    ii. N-(n-dodecyl)-2-pyrrolidone. N-(n-dodecyl)-2-pyrrolidone did 
not induce contact dermal phototoxic response, contact dermal 
photoallergy or contact dermal sensitization in human subjects under 
conditions of the following tests.
    8. Phototoxicity--i. N-(n-octyl)-2-pyrrolidone. Each of 10 human 
subjects, all 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 following scoring, 
1 arm was irradiated with ultraviolet (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 conditions of this test.
    ii. N-(n-dodecyl)-2-pyrrolidone. Each of 10 human subjects, all 
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 following scoring, 1 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. One subject exhibited a faint, minimal reaction to the test 
material before and after irradiation. N-(n-dodecyl)-2-pyrrolidone did 
not induce contact dermal phototoxic response under conditions of this 
test.
    9. Photoallergy--i. N-(n-octyl)-2-pyrrolidone. Each of 25 human 
subjects, 6 males 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, 1 
arm was irradiated with both 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 minimal erythema dose. Sites were scored 
immediately following irradiation. A series of 6 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 under conditions of this test.
    ii. N-(n-dodecyl)-2-pyrrolidone. Each of 25 human subjects, 6 males 
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, 1 arm was irradiated 
with 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 
minimal erythema dose. Sites were scored immediately following 
irradiation. A series of 6 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 24 and 48 hours. During the induction phase, 9 subjects exhibited 
a faint, minimal reaction at the irradiated contact site and 4 subjects 
exhibited a similar reaction at the non-irradiated contact site. No 
reactions were exhibited at the challenge phase. N-(n-dodecyl)-2-
pyrrolidone induced neither contact dermal photoallergy nor contact 
dermal sensitization under conditions described.
    10. Repeated insult patch test--i. N-(n-octyl)-2-pyrrolidone. Each 
of 100 human subjects, 26 males and 74 females, received 0.2 mL of a 1% 
suspension of test material in tap water on the left upper back area. 
Following a 24-hour exposure period under occlusive wrapping, the 
patches were removed and scored for erythema and edema. A series of 9 
induction phases was applied 3 times a week for 3 weeks. Following a 2-
week rest period, challenge patches were applied to a virgin site on 
the right upper back area and allowed to remain in skin contact for 24 
hours. Challenge sites were scored for erythema and edema at 24, 48, 
and 72 hours post-patching. During the induction phase, 61 subjects 
exhibited slight reactions; several subjects exhibited 
hyperpigmentation and/or dryness. The induction patch sites exhibited 
no reactions during the rest period or at the challenge. During the 
challenge phase, 3 subjects exhibited a faint, minimal reaction at the 
challenge site. After repeated applications under conditions of this 
test, N-(n-octyl)-2-pyrrolidone did not induce contact dermal 
sensitization.
    ii. N-(n-dodecyl)-2-pyrrolidone. Each of 100 human subjects, 26 
males and 74 females, received 0.2 mL of a 1% suspension of test 
material in tap water on the left upper back area. Following a 24-hour 
exposure period under occlusive wrapping, the patches were removed and 
scored for erythema and edema. A series of 9 induction patches was 
applied 3 times a week for 3 weeks. Following a 2-week rest period, 
challenge patches were applied to a virgin site on the right upper back 
area and allowed to remain in skin contact for 24 hours. Challenge 
sites were scored for erythema and edema at 24, 48, and 72 hours post-
patching. During the induction phase, 50 subjects exhibited slight 
reactions, several subjects exhibited hyperpigmentation and/or dryness. 
The induction patch sites exhibited no reactions during the rest period 
or at the challenge. During the challenge phase, 12 subjects exhibited 
faint, minimal reactions at the challenge site, 1 exhibited dryness. 
After repeated applications under conditions of this test, N-(n-
dodecyl)-2-pyrrolidone did not induce contact dermal sensitization.
    11. Comodogenicity--i. N-(n-octyl)-2-pyrrolidone. Under conditions 
of this study, in which a mean comedogenic grade of 2.0 in 
rabbits is considered to indicate potential comedogenesis in humans, N-
(n-octyl)-2-pyrrolidone is not expected to be comedogenic in humans. 
The comedogenicity potential of N-(n-octyl)-2-pyrrolidone was assessed 
in New Zealand white rabbits. The external ear canal of 6 animals 
received dermal application of 0.5 mL of 2% N-(n-octyl)-2-pyrrolidone 
in distilled water, 5 days a week over a 4-week period. Microscopic 
examination of the treated tissues was then

[[Page 52739]]

performed. 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. There were no neoplastic microscopic 
findings in this study.
    ii. N-(n-dodecyl)-2-pyrrolidone. Under conditions of this study, in 
which a mean comedogenic grade of 2.0 in rabbits is 
considered to indicate potential comedogenesis in humans, N-(n-
dodecyl)-2-pyrrolidone is not expected to be comedogenic in humans. The 
comedogenicity potential of N-(n-dodecyl)-2-pyrrolidone was assessed in 
New Zealand white rabbits. The external ear canal of 6 animals received 
dermal applications of 0.5 mL of 2% N-(n-dodecyl)-2-pyrrolidone in 
distilled water, 5 days a week over a 4-week period. Microscopic 
examination of the treated tissue was then performed. 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 1 of the treated rabbits receiving 
a comedogenic grade of 3 on a scale of 0 to 5. The remaining test 
animals received a grade of 0 (negative), yielding a mean comedogenic 
grade of 0.5. There were no neoplastic microscopic findings.
    12. Ames Salmonella/microsome reverse mutation assay--i. N-(n-
octyl)-2-pyrrolidone. No mutagenic activity was demonstrated by N-(n-
octyl)-2-pyrrolidone when tested as sold in the Ames assay. N-(n-
octyl)-2-pyrrolidone was tested, as sold, in the Ames assay with 
Salmonella typhimurium tester strains TA 1535, TA 1537, TA 1538, TA 98, 
and TA 100. Tests were conducted in all 5 strains both with and without 
metabolic activation (induced S-9 rat liver preparation). The entire 
assay was performed twice.
    ii. N-(n-dodecyl)-2-pyrrolidone. No mutagenic activity was 
demonstrated for N-(n-dodecyl)-2-pyrrolidone in the Ames Salmonella/
microsome reverse mutation assay. N-(n-dodecyl)-2-pyrrolidone was 
tested, as sold, in the Ames assay with Salmonella typhimurium tester 
strains TA-1535, TA-1537, TA-1538, TA-98, and TA-100. Tests were 
conducted in all 5 strains both with and without metabolic activation 
(induced S-9 rat liver preparation). The results from the initial assay 
were confirmed in an independent assay.
    13. Mouse micronucleas test--i. N-(n-octyl)-2-pyrrolidone. N-(n-
octyl)-2-pyrrolidone was found to be non-mutagenic at a dose level of 
1,720 mg/kg in this in vivo cytogenetic test. 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. Controls were 
dosed in the same manner. 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. At sampling times mice treated with N-(n- octyl)-2-
pyrrolidone showed no significant increase in frequency of 
micronucleated polychromatic erythrocytes, nor was there a significant 
decrease in P/N ratio at any of the sampling times.
    ii. N-(n-dodecyl)-2-pyrrolidone. N-(n-dodecyl)-2-pyrrolidone was 
found to be non-mutagenic at a dose level of 5,000 mg/kg in this in 
vivo cytogenetic test. Mice were administered N-(n-dodecyl)-2-
pyrrolidone by intragastric gavage at a dose level of 5,000 mg/kg, 
based on results of a preliminary toxicity test. Vehicle controls were 
dosed with corn oil in the same manner. 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. At sampling times, mice treated with N-
(n-dodecyl)-2-pyrrolidone showed no significant increase in frequency 
of micronucleated polychromatic erythrocytes. There was, however, a 
statistically significant decrease in P/N ratio at 24 and 72 hour 
sampling times which may be indicative of bone marrow cell depression/
toxicity.
    14. Mouse lymphoma mutagenesis assay. The results of this assay 
indicate that N-(n-octyl)-2-pyrrolidone produced a negative response in 
cultures treated in either the absence of exogenous activation or the 
presence of Aroclor-induced rat liver S-9 mix. In this assay, N-(n-
octyl)-2-pyrrolidone was tested for its potential to induce mutations 
at the thymidine Kinase 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 the test article was tested in the 
assay at doses ranging 0.005 to 100 uL/mL which produced varying 
degrees of reduction in cell growth.
    15. 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 bwt/day in order to assess the effects on 
embryonic and fetal development. At 800 mg/kg/day, 1 dam died after the 
7th and 1 after the 10th test article administration. The females of 
this group had marked clinical signs of reaction to treatment, 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 of skeletal 
ossification. At 50 or 200 mg/kg/day, no effects of treatment with the 
test article on maternal or fetal parameters were evident. Based on the 
results of this study, the no observed adverse effect level (NOAEL) for 
the maternal and fetal parameters was considered to be 200 mg/kg bwt/
day. N-(n-octyl)-2-pyrrolidone did not reveal any teratogenic potential 
up to and including the highest dose tested (HDT) level of 800 mg/kg 
bwt/day when administered to pregnant Wistar rats under the conditions 
described for this study.
    16. 28-Day oral toxicity--i. N-(n-octyl)-2-pyrrolidone. In a 28-day 
oral toxicity study in rats, the no-effect level of N-(n-octyl)-2-
pyrrolidone was determined to be 55 mg/kg/day. At 320 mg/kg/day 
specific changes in general health, body weight gain, hematological and 
biochemical parameters were recorded. N-(n-octyl)-2-pyrrolidone, 
formulated as a solution in corn oil, was administered to rats (5 
males, 5 females per dosage level) by intragastric intubation at dosage 
levels of 5, 55, or 320 mg/kg/day. Treatment was carried out once daily 
for 28 consecutive days. Similarly, control animals received corn oil 
(5 mL/kg/day) included: Statistically significant observations noted at 
the high dose level of 320 mg/kg day included: Lower body weight gains 
in females (week 3); lower packed cell volume (PCV) and red blood cell 
counts in males, corpuscular hemoglobin concentration (MCHC) in males; 
and higher glutamic-pyruvic transaminase levels in females. In all 
other respects including food consumption, organ weights, macroscopic 
and microscopic pathology, no changes were noted that were considered 
to be treatment-related.
    ii. N-(n-dodecyl)-2-pyrrolidone. In a 28-day oral toxicity study in 
rats, the no-effect level of N-(n-dodecyl)-2-pyrrolidone was determined 
to be 100 mg/kg/day. N-(n-dodecyl)-2-pyrrolidone, formulated as a 
solution in corn oil, was administered to rats (5 males, 5 females per 
dosage level) by

[[Page 52740]]

intragastric intubation at dosage levels of 10, 100, or 1,000 mg/kg/
day. Treatment was carried out once daily for 28 consecutive days. 
Similarly, control animals received corn oil (5 mL/kg/day). At 1,000 
mg/kg/day specific changes in general health, body weight gains, food 
consumption, biochemical parameters, organ weights, macroscopic and 
microscopic pathology were recorded. Statistically significant 
observations noted at the high dose level of 1,000 mg/kg/day included: 
Lower food consumption and bodyweight gains in males; higher glutamic-
pyruvic transaminase levels in males and females; higher blood urea 
nitrogen levels in females; and higher adjusted liver weights in 
females, and minimal centrilobular hepatocyte enlargement in males and 
females.
    17. 90-Day oral toxicity in dogs. In a 90-day oral toxicity study 
in dogs, a dose level of 30 mg/kg/day was determined to be the NOAEL. 
N-(n-octyl)-2-pyrrolidone was administered orally via capsule at dosage 
levels of 30, 90, and 240 mg/kg/day. All animals were observed daily 
for clinical signs of toxicity. After treatment, all surviving animals 
were subjected to complete necropsy with histological examination. Dose 
related neurological signs and body weight loss were observed at 90 and 
240 mg/kg/day levels. Also at 90 and 240 mg/kg/day, changes in clinical 
pathological parameters were observed and were dose-related. In 
addition, dose-related increases in both absolute and relative liver 
weights were observed in all groups but was significant in only 90 and 
240 mg/kg/day groups. One female death occurred on day 42 in the 240 
mg/kg/day group.
    18. 90-Day dietary toxicity in rats. Based on the results of a 90-
day feeding study in rats, 600 parts per million (ppm) was considered a 
NOAEL following dietary administration of N-(n-octyl)-2-pyrrolidone for 
90 days. N-(n-octyl)-2-pyrrolidone was administered orally via diet to 
rats at dosage levels of 60, 600, and 10,000 ppm. All animals were 
observed daily for clinical signs of toxicity. After treatment, all 
surviving animals were subjected to complete necropsy with histological 
examination. Reduced weight gain, increased absolute and relative liver 
weights and mild hepatocyte hypertrophy were observed at 10,000 ppm. No 
treatment-related effects were observed at 60 and 600 ppm.
    19. Endocrine disruption. N-(n-octyl)-2-pyrrolidone and N-(n-
dodecyl)-2-pyrrolidone are not expected to be endocrine disrupters. 
They do not share structural similarity with currently known or 
suspected chemicals or chemical classes being studied for this effect.

C. Aggregate Exposure

    1. Dietary exposure--i. Food. Residue data are generally not 
required for inert ingredient exemptions from a tolerance. 
International Specialty Products has exposure data on 4 representative 
crops to support the listing of N-(n-octyl)-2-pyrroidone and N-(n-
dodecyl)-2-pyrrolidone as an inert ingredient exempted from the 
requirements of a tolerance when used in accordance with good 
agricultural practices at levels not to exceed 1% in the final solution 
for preharvest and postharvest application, and application to animals. 
A dietary residue exposure system (DRES) analysis was run using a model 
based on Kenaga and Hoerger's ``Maximum Expected Residues on 
Vegetation.'' The four representative crops chosen for the analysis 
were: Wheat, lettuce, apples, and sugar beets. The reference dose used 
by EPA, was derived from the NOAEL obtained from an animal study in 
dogs, the most sensitive species in chronic studies with these 
materials. For N-(n-octyl)-2-pyrrolidone the NOAEL was 30 mg/kg bwt/day 
in the 90-day dog study. A 250-fold safety factor results in a 
reference dose of 0.12 mg/kg bwt/day. This reference dose (RfD) can 
then be compared to the dietary exposure yielding a ``percent of dose 
utilized'' estimate. An application rate of 0.25 lb (113 grams) N-(n-
octyl)-2-pyrrolidone and N-(n-dodecyl)-2-pyrrolidone/acre of crop was 
used for the analysis. Apples, under the category of ``fruit-cherries, 
peaches'' results in an estimated residue of 1.75 ppm. Lettuce (head 
and leaf), under the category ``leaves and leafy crops'' results in an 
estimated residue of 31 ppm. Wheat, under the category of ``forage-
alfalfa, clover'' results in an estimated residue of 14 ppm. Sugar 
beets (root crop) is not estimated in the model, but a default value of 
5 ppm is assumed. This is a conservative estimate given that the 
pesticide formulation does not physically touch the crop.
    Using these input parameters, a residue file was assembled which 
lists the chronic reference dose and all of the relevant commodities 
that are included in the consumption data base. The exposure analysis 
shows that, for the U.S. population (general population, 48 contiguous 
states, all seasons), the listed crops utilize only 25% of the 
reference dose. This analysis shows there is a substantial margin of 
safety for the use of N-(n-octyl)-2-pyrrolidone and N-(n-dodecyl)-2-
pyrrolidone on these crops at 0.25 lb/acre.
    ii. Drinking water. Based on its very low application rate, as well 
as the environmental fate studies, N-(n-octyl)-2-pyrrolidone and N-(n-
dodecyl)-2-pyrrolidone would not be expected to persist in the 
environment, nor contaminate drinking water supplies.
    2. Non-dietary exposure. N-(n-octyl)-2-pyrrolidone and N-(n-
dodecyl)-2-pyrrolidone are used in household and institutional 
cleaners, specifically hard-surface cleaners. Annual volumes to this 
market segment approach 150,000 pounds each.

D. Cumulative Effects

    There are no cumulative effects expected since N-(n-octyl)-2-
pyrrolidone and N-(n-dodecyl)-2-pyrrolidone rapidly degrade and the 
very low use rate is not conducive to build-up in the environment.

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 to 6 years old, still would be expected to consume slightly more than 
1% of the RfD, for the 4 representative crops analyzed.
    2. Infants and children. No developmental, embryotoxic, or 
teratogenic effects have been associated with N-(n-octyl)-2-pyrrolidone 
and N-(n-dodecyl)-2-pyrrolidone.

F. International Tolerances

    The applicant is not aware of any international tolerance or CODEX 
of maximum residue limits (MRLs) for N-(n-octyl)-2-pyrrolidone and N-
(n-dodecyl)-2-pyrrolidone on any crop or livestock commodities.
[FR Doc. 00-22013 Filed 8-29-00; 8:45 am]
BILLING CODE 6560-50-F