[Federal Register Volume 70, Number 12 (Wednesday, January 19, 2005)]
[Notices]
[Pages 3026-3032]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 05-824]


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ENVIRONMENTAL PROTECTION AGENCY

[OPP-2004-0297; FRL-7690-5]


[S,S]-Ethylene diamine disuccinic acid; Notice of Filing a 
Pesticide Petition to Establish a Tolerance for a Certain Pesticide 
Chemical in or on Food

AGENCY:  Environmental Protection Agency (EPA).

[[Page 3027]]


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 identification (ID) number OPP-
2004-0297, must be received on or before February 18, 2005.

ADDRESSES:  Comments may be submitted electronically, by mail, or 
through hand delivery/courier. Follow the detailed instructions as 
provided in Unit I. of the SUPPLEMENTARY INFORMATION.

FOR FURTHER INFORMATION CONTACT:  Bipin Gandhi, Registration Division 
(7505C), Office of Pesticide Programs, Environmental Protection Agency, 
1200 Pennsylvania Ave., NW., Washington, DC 20460-0001; telephone 
number: (703) 308-8380; e-mail address: [email protected].

SUPPLEMENTARY INFORMATION:

I. General Information

A. Does this Action Apply to Me?

    You may be potentially affected by this action if you are an 
agricultural producer, food manufacturer, or pesticide manufacturer. 
Potentially affected entities may include, but are not limited to:
     Crop production (NAICS 111)
     Animal production (NAICS 112)
     Food manufacturing (NAICS 311)
     Pesticide manufacturing (NAICS 32532)
    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 this unit could also be 
affected. The North American Industrial Classification System (NAICS) 
codes have been provided to assist you and others in determining 
whether this action might apply to certain entities. If you have any 
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 Copies of this Document and Other Related Information?

    1. Docket. EPA has established an official public docket for this 
action under docket ID number OPP-2004-0297. The official public docket 
consists of the documents specifically referenced in this action, any 
public comments received, and other information related to this action. 
Although a part of the official docket, the public docket does not 
include Confidential Business Information (CBI) or other information 
whose disclosure is restricted by statute. The official public docket 
is the collection of materials that is available for public viewing at 
the Public Information and Records Integrity Branch (PIRIB), Rm. 119, 
Crystal Mall 2, 1801 S. Bell St., Arlington, VA. This docket 
facility is open from 8:30 a.m. to 4 p.m., Monday through Friday, 
excluding legal holidays. The docket telephone number is (703) 305-
5805.
    2. Electronic access. You may access this Federal Register document 
electronically through the EPA Internet under the ``Federal Register'' 
listings at http://www.epa.gov/fedrgstr/.
    An electronic version of the public docket is available through 
EPA's electronic public docket and comment system, EPA Dockets. You may 
use EPA Dockets at http://www.epa.gov/edocket/ to submit or view public 
comments, access the index listing of the contents of the official 
public docket, and to access those documents in the public docket that 
are available electronically. Although not all docket materials may be 
available electronically, you may still access any of the publicly 
available docket materials through the docket facility identified in 
Unit I.B.1. Once in the system, select ``search,'' then key in the 
appropriate docket ID number.
    Certain types of information will not be placed in the EPA Dockets. 
Information claimed as CBI and other information whose disclosure is 
restricted by statute, which is not included in the official public 
docket, will not be available for public viewing in EPA's electronic 
public docket. EPA's policy is that copyrighted material will not be 
placed in EPA's electronic public docket but will be available only in 
printed, paper form in the official public docket. To the extent 
feasible, publicly available docket materials will be made available in 
EPA's electronic public docket. When a document is selected from the 
index list in EPA Dockets, the system will identify whether the 
document is available for viewing in EPA's electronic public docket. 
Although not all docket materials may be available electronically, you 
may still access any of the publicly available docket materials through 
the docket facility identified in Unit I.B. EPA intends to work towards 
providing electronic access to all of the publicly available docket 
materials through EPA's electronic public docket.
    For public commenters, it is important to note that EPA's policy is 
that public comments, whether submitted electronically or in paper, 
will be made available for public viewing in EPA's electronic public 
docket as EPA receives them and without change, unless the comment 
contains copyrighted material, CBI, or other information whose 
disclosure is restricted by statute. When EPA identifies a comment 
containing copyrighted material, EPA will provide a reference to that 
material in the version of the comment that is placed in EPA's 
electronic public docket. The entire printed comment, including the 
copyrighted material, will be available in the public docket.
    Public comments submitted on computer disks that are mailed or 
delivered to the docket will be transferred to EPA's electronic public 
docket. Public comments that are mailed or delivered to the docket will 
be scanned and placed in EPA's electronic public docket. Where 
practical, physical objects will be photographed, and the photograph 
will be placed in EPA's electronic public docket along with a brief 
description written by the docket staff.

C. How and to Whom Do I Submit Comments?

    You may submit comments electronically, by mail, or through hand 
delivery/courier. To ensure proper receipt by EPA, identify the 
appropriate docket ID number in the subject line on the first page of 
your comment. Please ensure that your comments are submitted within the 
specified comment period. Comments received after the close of the 
comment period will be marked ``late.'' EPA is not required to consider 
these late comments. If you wish to submit CBI or information that is 
otherwise protected by statute, please follow the instructions in Unit 
I.D. Do not use EPA Dockets or e-mail to submit CBI or information 
protected by statute.
    1. Electronically. If you submit an electronic comment as 
prescribed in this unit, EPA recommends that you include your name, 
mailing address, and an e-mail address or other contact information in 
the body of your comment. Also include this contact information on the 
outside of any disk or CD ROM you submit, and in any cover letter 
accompanying the disk or CD ROM. This ensures that you can be 
identified as the submitter of the comment and allows EPA to contact 
you in case EPA cannot read your comment due to technical difficulties 
or needs further information on the substance of your comment. EPA's 
policy is that EPA will not edit your comment, and any identifying or 
contact information provided in the body of a comment will

[[Page 3028]]

be included as part of the comment that is placed in the official 
public docket, and made available in EPA's electronic public docket. If 
EPA cannot read your comment due to technical difficulties and cannot 
contact you for clarification, EPA may not be able to consider your 
comment.
    i. EPA Dockets. Your use of EPA's electronic public docket to 
submit comments to EPA electronically is EPA's preferred method for 
receiving comments. Go directly to EPA Dockets at http://www.epa.gov/edocket/, and follow the online instructions for submitting comments. 
Once in the system, select ``search,'' and then key in docket ID number 
OPP-2004-0297. The system is an ``anonymous access'' system, which 
means EPA will not know your identity, e-mail address, or other contact 
information unless you provide it in the body of your comment.
    ii. E-mail. Comments may be sent by e-mail to [email protected], 
Attention: Docket ID Number OPP-2004-0297. In contrast to EPA's 
electronic public docket, EPA's e-mail system is not an ``anonymous 
access'' system. If you send an e-mail comment directly to the docket 
without going through EPA's electronic public docket, EPA's e-mail 
system automatically captures your e-mail address. E-mail addresses 
that are automatically captured by EPA's e-mail system are included as 
part of the comment that is placed in the official public docket, and 
made available in EPA's electronic public docket.
    iii. Disk or CD ROM. You may submit comments on a disk or CD ROM 
that you mail to the mailing address identified in Unit I.C.2. These 
electronic submissions will be accepted in WordPerfect or ASCII file 
format. Avoid the use of special characters and any form of encryption.
    2. By mail. Send your comments to: Public Information and Records 
Integrity Branch (PIRIB) (7502C), Office of Pesticide Programs (OPP), 
Environmental Protection Agency, 1200 Pennsylvania Ave., NW., 
Washington, DC 20460-0001, Attention: Docket ID Number OPP-2004-0297.
    3. By hand delivery or courier. Deliver your comments to: Public 
Information and Records Integrity Branch (PIRIB), Office of Pesticide 
Programs (OPP), Environmental Protection Agency, Rm. 119, Crystal Mall 
2, 1801 S. Bell St., Arlington, VA, Attention: Docket ID 
Number OPP-2004-0297. Such deliveries are only accepted during the 
docket's normal hours of operation as identified in Unit I.B.1.

D. How Should I Submit CBI to the Agency?

    Do not submit information that you consider to be CBI 
electronically through EPA's electronic public docket or by e-mail. You 
may claim information that you submit to EPA as CBI by marking any part 
or all of that information as CBI (if you submit CBI on disk or CD ROM, 
mark the outside of the disk or CD ROM as CBI and then identify 
electronically within the disk or CD ROM the specific information that 
is 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 docket and EPA's electronic public docket. If you submit 
the copy that does not contain CBI on disk or CD ROM, mark the outside 
of the disk or CD ROM clearly that it does not contain CBI. Information 
not marked as CBI will be included in the public docket and EPA's 
electronic public docket without prior notice. If you have any 
questions about CBI or the procedures for claiming CBI, please consult 
the person listed 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 
ID 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 Cosmetic Act (FFDCA), 21 U.S.C. 346a. 
EPA has determined that this petition contains data or information 
regarding the elements set forth in FFDCA 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: December 29, 2004.
Betty Shackleford,
Acting Director, Registration Division, Office of Pesticide Programs.

Summary of Petition

    The petitioner summary of the pesticide petition is printed below 
as required by FFDCA section 408(d)(3). The summary of the petition was 
prepared by the petitioner and represents the view of the petitioner. 
The summary may have been edited by EPA if the terminology used was 
unclear, the summary contained extraneous material, or the summary 
unintentionally made the reader conclude that the findings reflected 
EPA's position and not the position 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.

The Associated Octel Company, Limited

PP 4E6818

    EPA has received a pesticide petition (4E6818) from The Associated 
Octel Company, Limited, P.O. Box 17, Oil Sites Road, Ellesmere Port, 
South Wirral L65 4HF, United Kingdom 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 [S,S]-
ethylene diamine disuccinic acid, CAS Reg. No. 20846-91-7. 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.

[[Page 3029]]

 Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

    1. Plant metabolism. [S,S]-Ethylene diamine disuccinic acid is a 
chelating agent that is used as a vehicle to deliver micronutrients 
essential for healthy and rapid growth, such as iron and cobalt, to 
plants. It is unknown whether or not plants would uptake [S,S]-ethylene 
diamine disuccinic acid that might leach into the soil when applied as 
a minor component of pesticide formulations. However, organic chelating 
agents are not absorbed normally by growing plants. It appears that the 
primary role the chelate plays is to hold the metallic cations near the 
root surface until direct absorption of the free cation can take place. 
Once the micronutrient cations are inside the plant, other organic 
chelates (such as citrates) may be carriers of these cations to 
different parts of the plant (Ref. 1). Therefore, it is unlikely that 
[S,S]-ethylene diamine disuccinic acid would accumulate within plant 
tissue through its application to the soil as a minor component of 
pesticide formulations.
    2. Analytical method. An analytical method has not been proposed 
because [S,S]-ethylene diamine disuccinic acid residues harmful to 
plants and animals are highly unlikely to occur when it is applied as 
part of the proposed pesticide formulation and according to that 
formulation's label directions for use.
    3. Magnitude of residues. A waiver of the residue data has been 
requested because [S,S]-ethylene diamine disuccinic acid is produced by 
actinomycetes, Amycolatopis japonica sp. nov. (Ref. 2) and 
Amycolatopsis orientalis (Ref. 3), which are naturally occurring 
bacteria, degrades rapidly and is completely mineralized in the soil, 
will have limited accessibility to plants in the proposed use pattern, 
and exhibits low mammalian toxicity. [S,S]-Ethylene diamine disuccinic 
acid is a siderophore produced by actinomycetes, and it functions 
symbiotically with plants to assist in the transport of soil metals to 
plant rootlets. The use of [S,S]-ethylene diamine disuccinic acid, 
therefore, does not constitute the addition of a foreign material to 
the soil; rather, it is a compound that soil microorganisms and plants 
already encounter. Natural mechanisms already exist for the degradation 
and/or utilization of [S,S]-ethylene diamine disuccinic acid in the 
soil/plant microsystem. Moreover, organic chelates are not absorbed 
normally by growing plants, and residues are not expected in plants.

B. Toxicological Profile

    1. Acute toxicity. The acute toxicity of [S,S]-ethylene diamine 
disuccinic acid was studied in several studies using male and female 
rats via the oral, dermal, and inhalation routes. In two acute oral 
toxicity studies, the lethal dose (LD)50 for both males and 
females was established at >2,700 milligrams/kilogram body weight (mg/
kg bwt) and >2,000 mg/kg bwt, respectively, which were the highest dose 
levels tested. For the two acute dermal toxicity studies, the 
LD50 for both males and females was established at >2,640 
mg/kg bwt and > 2,000 mg/kg bwt, respectively, which were the highest 
dose levels tested. For the acute inhalation study, the lethal 
concentration (LC)50 was established at >1.49 milligrams/
liter (mg/L), which was the highest concentration that could be 
produced using the procedures prescribed. [S,S]-Ethylene diamine 
disuccinic acid also was studied in several primary eye irritation, 
primary skin irritation, and dermal sensitization studies. In two 
primary eye irritation studies, two primary skin irritation studies and 
a 24-hour repeat application patch test, the substance was considered a 
non-irritant. In a dermal sensitization study and a human repeat insult 
patch test, the substance was found not to be a dermal sensitizer.
    2. Genotoxicty. [S,S]-Ethylene diamine disuccinic acid was shown 
not to be genotoxic in a battery of standard short-term studies. In a 
bacterial mutation assay, it was concluded that, when tested at dose 
levels up to 5,000 [mu]g/plate of histidine dependent auxotrophic 
mutants of Salmonella typhimurium in water, [S,S]-ethylene diamine 
disuccinic acid was not mutagenic. In a Salmonella/mammalian (Ames 
test) and Escherichia coli WP2 mutagenesis assay, [S,S]-ethylene 
diamine disuccinic acid was tested using tester strains TA98, TA100, 
TA1535, TA1537, TA1538, WP2 uvrA (pHM101), and WP2 (pHM101) in the 
presence and absence of Aroclor-induced rat liver microsomal enzymes at 
a maximum dose of 5,000 [mu]g per plate and was found not to cause a 
positive response. Further, [S,S]-ethylene diamine disuccinic acid was 
tested in a L5178Y TK+/- mouse lymphoma mutagenesis assay in the 
absence and presence of aroclor induced rat liver S-9, using doses of 
4,028 to 2,765 [mu]g/mL in the initial assay and 5,028 to 2,765 [mu]g/
mL in the confirmatory assay, and was found to be negative in both the 
absence and presence of exogenous metabolic activation. In an in vitro 
cytogenetics assay with Chinese hamster ovary (CHO) cells, in both 
definitive and confirmatory assays, the test system was exposed to dose 
levels of 79, 157, 313, 625, 1,250, 2,500, and 5,000 [mu]g/mL for 6 
hours with a 12-hour recovery period in the absence and presence of an 
S-9 reaction mixture. In addition, the test system was exposed to 5, 
10, 20, 40, 79, 157, 313, 625, and 1,250 [mu]g/mL continuously for 42 
hours in the absence of a S-9 reaction mixture. In the definitive 
assay, survival at the highest dose level was scored 82% in the non-
activated 6-hour treatment study, 70% in the non-activated 18-hour 
treatment study, 38% in the non-activated 42-hour study, and 84% in the 
S-9 activated study. The three highest doses with 200 scorable 
metaphase cells, i.e., 313, 625, and 1,250 [mu]g/mL in the 6-hour non-
activated study, 157, 313, and 625 [mu]g/mL in the 6-hour activated 
study, and 5, 10, and 20 [mu]g/mL in the 42-hour non-activated study, 
were selected for microscopic analysis. The test article did not induce 
a significant increase in structural chromosome aberrations in either 
the absence or presence of S-9 activation, regardless of the treatment 
condition or harvest time (p>=0.025, Fisher's exact test). However, in 
the non-activated 18-hour treatment study, there were no scorable 
metaphase cells in any of the test article dose groups. In addition, 
there was a statistically significant increase in numerical aberrations 
in the non-activated 42-hour study at 20 [mu]g/mL (p<0.025, Fisher's 
exact test). There was also a statistically significant dose response 
in numerical aberrations in the non-activated 42-hour study (p<0.05, 
Cochran-Armitage test). In the confirmatory assay, survival at the 
highest dose level scored was 78% in the non-activated 6-hour treatment 
study, 77% in the non-activated 18-hour study, 29% in the non-activated 
42-hour treatment study, and 109% in the S-9 activated study. The three 
highest doses with 200 scorable metaphase cells, i.e., 157, 313, and 
625 [mu]g/mL in the 6-hour treatment study, 313, 625, and 1,250 [mu]g/
mL in the 18-hour non-activated study, and 10, 20, and 40 [mu]g/mL in 
the non-activated 42-hour study, were selected for microscopic 
analysis. The test article did not induce a significant increase in 
structural or numerical chromosome aberrations in either the absence or 
presence of S-9 activation in the 6-hour or 18-hour treatment studies 
(p>=0.025, Fisher's exact test). There was a statistically significant 
increase in structural chromosome aberrations at the 40 [mu]g/mL dose 
level in the non-activated 42-hour study (p<0.025, Fisher's exact test) 
and a statistically

[[Page 3030]]

significant dose response (p<0.05, Cochran-Armitage test). This 
increase in the percentage of structural chromosome aberrations in this 
dose was within the acceptable range of the historical control values, 
and therefore this increase was not viewed as being biologically 
relevant. Last, in an in vivo cytogenetic assay in rats, male and 
female Sprague-Dawley rats were treated with [S,S]-ethylene diamine 
disuccinic acid by single-dose gavage administration of 200, 670, or 
2,000 mg/kg bwt. The percentage of structurally damaged first division 
metaphase cells was not significantly increased in the test-article-
treated groups, regardless of sex, dose, or sacrifice time (p<=0.025, 
Fisher's exact test). The percentage of numerically changed second 
division metaphase cells was not significantly increased in the test-
article-treated groups, regardless of sex, dose, or sacrifice time 
(p>0.025, Fisher's exact test). It was concluded that [S,S]-ethylene 
diamine disuccinic acid was negative in the in vivo cryogenic assay in 
rats.
    3. Reproductive and developmental toxicity. Two range-finding 
developmental toxicity studies, two developmental toxicity studies and 
one plasma mineral level study were conducted with rats. In the first 
range-finding study, mated Charles River CRl: CD VAF/Plus female rats 
were administered 2,000, 8,000, 16,000, 24,000, and 40,000 parts per 
million of the test substance in the diet on gestation days 6 through 
15. Maternal toxicity resulted at the 16,000 ppm level and higher, as 
evidenced by two test article-related deaths at the highest dose level, 
test article-related emaciation, soft stool, decreased defacation and 
no stool, and inhibited bodyweight gain, body weight loss, and dose-
related decreases in food consumption when compared with the control 
group. Developmental toxicity was evidenced at 16,000 ppm by reduced 
gravid uterine weight and at doses of 24,000 ppm and above by increases 
in post-implantation loss when compared with the controls, and a 
concomitant decrease in the numbers of live fetuses. Developmental 
toxicity also was evidenced from the fetuses found to be severely 
malformed in the 24,000 ppm group. Based on the results of this study, 
dosage levels of 0, 2,000, 8,000, and 16,000 ppm were selected by the 
sponsors for the definitive developmental toxicity study. In the second 
range-finding study, mated Charles River Crl:CD VAF/Plus female rats 
were administered dosage levels of the test article of 0, 50, 200, 400, 
600, and 1,000 mg/kg/day by gavage on gestation days 6 through 15. 
There were no significant observations of maternal toxicity at any 
dosage level. No indication of developmental toxicity was observed at 
the dose levels tested. The study's conclusion was the dose levels 
evaluated produced no apparent maternal or developmental toxicity that 
was test article related. In the first developmental toxicity study, 
mated Charles River Crl:CD VAF/Plus female rats were administered 
dosage levels of 2,000, 8,000, and 16,000 ppm of the test substance in 
their diet on gestation days 6 through 15. Maternal toxicity was 
evidenced at the high-dose level by body weight and food consumption 
inhibition as compared with the control group. Blood zinc levels were 
decreased in all treated groups, and iron and copper levels were 
reduced in the high-dose treated dams. Developmental toxicity was 
indicated by a statistically significant increase in post-implantation 
losses at the high-dose level. Post-implantation losses at the high-
dose appeared to selectively affect the sex ratio and, as a 
consequence, the percentage of live male fetuses was reduced while the 
percentage of live female fetuses was increased. Developmental toxicity 
also was indicated for the high-dose group by reduced fetal body 
weights. Administration of the test article resulted in teratogenicity 
in the majority of fetuses and litters at a concentration of 16,000 
ppm. Fetuses from this group were observed with singular or multiple 
external, visceral and/or skeletal malformations and developmental 
variations. All major organ systems and skeletal structures were 
affected. The developmental period affected covers the entire dose 
administration period; therefore, the results of the study indicate the 
test article is a non-selective teratogen capable of producing a 
variety of malformations and developmental changes. A depletion of one 
or more metals in the blood, most likely zinc, may be correlated with 
these changes. In conclusion, the no observed adverse effect level 
(NOAEL) for the test substance when administered orally via the diet to 
the mated rats was 8,000 ppm with regard to maternal toxicity and 
developmental toxicity. In the second developmental toxicity study, the 
test substance was administered to mated Charles River Crl:CD VAF/Plus 
female rats by oral gavage at dose levels of 0, 50, 400, and 1,000 mg/
kg/day on gestation days 6 through 15. Maternal toxicity was indicated 
at the 1,000 mg/kg/day dose level by a significant reduction in mean 
carcass weights, a significant reduction in food consumption, and an 
increased incidence of clinical observations; therefore, the NOAEL was 
considered to be 400 mg/kg/day. Developmental toxicity was not 
indicated at any dose level evaluated, and the NOAEL with respect to 
developmental toxicity was considered greater than 1,000 mg/kg/day. The 
plasma mineral levels in pregnant rats were evaluated. In this study, 
mated Charles River Crd:CD VAF/Plus female rats were used to determine 
the effect of the test substance on plasma levels of zinc, iron and 
copper in pregnant rats. Dose levels of 50, 400, and 1,000 mg/kg/day 
were administered by gavage as a single daily dose on gestation days 6 
through 15 at a volume of 10.0 mL/kg. This resulted in maternal 
toxicity at the 1,000 mg/kg/day dose level, as indicated by soft stool 
and reduced (non-statistically significant) weight gain during the 
treatment period. Treatment also resulted in a dose-dependant, 
statistically significant reduction in zinc plasma levels for all dose 
groups at both the 2 and 4 hour-time points, as compared with the 
control group, and a statistically significant dose-dependant reduction 
in plasma copper levels in all treated groups at 4 hours and at the two 
highest dose levels at 2 hours. Plasma levels of iron fluctuated in all 
treated groups at both the 2 and 4 hour-time points, as compared with 
the control group, and these changes were not considered due to 
treatment with the test article. Oral administration of the test 
article at dosages of 50, 400, and 1,000 mg/kg/day during gestation 
days 6 to 15 resulted in a dose-dependant reduction in plasma zinc and 
copper in samples obtained 2 and 4 hours after the last dose on 
gestation day 15. Plasma iron levels were reduced in the 50 and 400 mg/
kg/day groups in a dose-dependant fashion, as compared with the control 
group, from samples obtained at 2 and 4 hours following the last dose 
on gestation day 15. This trend was not observed at the 1,000 mg/kg/day 
dosage, and there was no treatment-related effect on plasma iron levels 
at this dose level. Administration of the test article during the 
period of gestation days 6 to 15 effectively lowered the plasma levels 
of zinc and copper in a dose-related fashion. There was no dose-related 
effect in plasma iron levels attributable to administration of the test 
article.
    4. Subchronic toxicity. Several short-term studies were conducted 
using male and female rats. In a 14-day oral feeding study, one control 
and four dose groups of male and female Wistar rats were administered 
0, 50, 500, 2,500, and

[[Page 3031]]

5,000 mg/kg/bwt/day of the test substance. In Group 5, the highest dose 
group, one male was found dead on day 9 of treatment. In groups 1, 2, 
3, and 4, no deaths occurred. Test article related clinical signs of 
reaction to treatment with the test substance were noted in Group 5 
before death or sacrifice; ruffled fur, diarrhea, emaciation, hunched 
posture, and sedation were noted. In Group 4, ruffled fur, diarrhea, 
emaciation and hunched posture were noted in both male and female 
animals at the end of the first week and during the second week. No 
clinical signs or symptoms of ill health were noted in the animals of 
Groups 1, 2, or 3. In a second 14-day oral feeding study with SFR-bred 
male Wistar rats administered dose levels of 0, 750, 1,000, and 1,250 
mg/kg/bwt/day, all animals survived until scheduled necropsy, and no 
test article related clinical signs were evident in any animal. The 
mean food consumption, body weight development and relative food 
consumption were unaffected by the test article. Based on the results 
of this study, the no observed effects level (NOEL) was considered to 
be above 1,250 mg/kg/bwt/day. In a sub chronic 13-week oral (feeding) 
toxicity study, male and female SPF-bred Wistar rats were fed nominal 
dose levels of the test substance of 0, 50, 300, 700, and 1,000 mg/kg/
bwt/day. Based on the results, the NOEL of the test substance was 
considered to be 300 mg/kg/bwt/day. A mineral balance 28-day oral 
toxicity (feeding) study using male rats fed dose levels of the test 
substance of 0, 50, 150, 300, and 400 mg/kg/bwt/day was conducted. Up 
to and including the highest dose level, there were no test article-
related death or sign of reaction to treatment. Food and water 
consumption were not affected by treatment with the test article. The 
clinical laboratory data, opthalmoscopic examination as well as the 
recording of organ weights gave no indication of test article related 
effects. At macroscopic and microscopic examinations, no treatment-
related histopathologic alterations in any of the organs or tissues 
examined were noted. There were no statistically significant changes in 
body weight or body weight gain. However, there was a trend towards a 
decreased body weight and body weight gain as the dose increased. The 
increased urinary output of minerals (Cu, Zn, Mg) was considered to be 
test article-related. This increase in urinary output was compensated 
by a decrease in fecal elimination of the respective minerals. There 
was no effect on total mineral output relative to control values. 
Tissue mineral (Cu, Zn, Mg) levels were not affected in the sternum, 
femur or liver. In the kidneys there was a statistically significant 
decrease in tissue Zn levels for two test groups. The lack of a dose-
response effect did not allow for a definitive statement, but in 
consideration of the effects of treatment on Zn elimination, a test 
article-related effect was not ruled out.
    5. Chronic toxicity. [S,S]-ethylene diamine disuccinic acid and its 
metabolites are not structurally related to a recognized carcinogen, 
and the weight-of-the-evidence from the reported genotoxicity and 
subchronic toxicity studies indicates that [S,S]-ethylene diamine 
disuccinic acid is not mutagenic and does not produce a morphologic 
effect in any organ that could lead to neoplastic change.
    6. Animal metabolism. The absorption, distribution and elimination 
of [S,S]-ethylene diamine disuccinic acid were evaluated in three 
studies. In the first study, succinate-14C(U)-[S,S]-ethylene diamine 
disuccinic acid sodium salt at 2,106 mg/kg was administered to male 
Wistar rats by oral (gavage) dosing. This resulted in increased levels 
of radioactivity in bone marrow over the first 24 hours followed by 
biphasic elimination. The identity of the radioactivity in tissues was 
not determined. The mean peak bone marrow radioactivity level was 37 
[mu]g [S,S]-ethylene diamine disuccinic acid sodium salt equivalents/g 
(ppm) at the 24-hour time point. Bone marrow radioactivity levels 
declined thereafter to 10 ppm at the end of the 72-hour study period. 
Results of this study demonstrate that bone marrow is exposed to [S,S]-
ethylene diamine disuccinic acid and/or its metabolites following oral 
(gavage) dosing under conditions similar to those employed in in vivo 
cytogenics studies. In the second study, female Wistar rats were dosed 
orally (gavage) with succinate-14C-(U)-S,S-[S,S]-ethylene diamine 
disuccinic acid sodium salt at 2053 mg/kg. This resulted in elevated 
levels of radioactivity in bone marrow during the 72-hour study period. 
The identity of the radioactivity in tissues was not determined. The 
highest mean bone marrow radioactivity level was 14 [mu]g [S,S]-
ethylene diamine disuccinic acid sodium salt equivalents/g (ppm) at the 
24-hour time point. Bone marrow radioactivity declined slowly 
thereafter to 5 ppm at the end of the 72-hour period. Results of this 
study demonstrate that bone marrow is exposed to [S,S]-ethylene diamine 
disuccinic acid and/or its metabolites following oral (gavage) dosing 
under conditions similar to those employed in in vivo cytogenics 
studies. In the third study, groups of male and female Wistar rats were 
administered 14C-[S,S]-[S,S]-ethylene diamine disuccinic acid sodium 
salt by oral gavage and dermal application. Target dosing for the 
groups varied between 10.0  0.3 uCi/rat and 18.6  0.5 uCi/rat. After oral administration of 14C-[S,S]-[S,S]-
ethylene diamine disuccinic acid sodium salt, radioactivity was rapidly 
eliminated, mainly via the feces. Based on the recovery of 
radioactivity in the urine, expired air and tissues, the oral 
absorption was less than approximately 5% of the dose in both gender 
groups. Based on the radioactivity recoveries in the excreta and the 
residue tissue content, approximately 11.1% of the applied dermal dose 
of 14C-[S,S]-[S,S]-ethylene diamine disuccinic acid sodium salt was 
absorbed by males and 5.18% was absorbed by females. During dermal 
exposure of 14C-[S,S]-[S,S]-ethylene diamine disuccinic acid sodium 
salt, the amount of radioactivity eliminated in the excreta of both 
gender groups was less than 9% of the dose. There was an apparent 
gender effect in the amount of absorbed radioactivity eliminated in the 
excreta for urine only. There was no statistically significant gender 
effect in the oral or dermal absorption of radioactivity on the basis 
of the radioactivity recoveries in the excreta and tissue. The overall 
recovery of radioactivity after oral administration of 14C-[S,S]-[S,S]-
ethylene diamine disuccinic acid sodium salt was 84.4  
1.52% (males) and 89.5  (females) and after dermal 
application was 59.1  8.03% (males) and 62.8  
18.6% (females) of the dose. There was no statistically-significant 
difference in the radioactivity recoveries between the male and female 
animals after both routes of administration.
    7. Metabolite toxicology. [S,S]-Ethylene diamine disuccinic acid 
occurs in nature and is a siderophore produced by the Actinomycetes, 
Amycolatopis japonica sp. nov. (Ref. 2) and Amycolatopsis orientalis 
(Ref 3). [S,S]-Ethylene diamine disuccinic acid is rapidly and 
completely mineralized (Ref. 4). The degradation pathway of [S,S]-
ethylene diamine disuccinic acid is not fully understood. However, the 
catabolism of [S,S]-ethylene diamine disuccinic acid was initiated by 
carbon-nitrogen lyase catalysing the non-hydrolytic cleavage of the C-N 
bond between the ethlenediamine part of the molecule and one of the 
succinyl residues without any collectors being required. The reaction 
led to the formation of fumarate and AEAA [N-(2-aminoethyl) aspartic 
acid]. The further degradation of AEAA remains still to be

[[Page 3032]]

unraveled. To date, one can merely speculate that, catalysed by DH 
(dehydrogenase) or a MO (monooxygenase), the C-N bond between the 
succinyl residue and the ethylene diamine part of the molecule is 
split, or that an aspartyl residue is removed by the cleavage of a C-N 
bond within the ethylenediamine part of AEAA. (Ref. 5). [S,S]-ethylene 
diamine disuccinic acid and related [S,S] homologues comply with 
internationally accepted criteria for ready biodegradability of 
chemicals ``ostensibly because the metabolic products of the 
biodegradation are naturally occurring biochemicals such as succinic 
acid'' (Ref. 6).
    8. Endocrine disruption. [S,S]-Ethylene diamine disuccinic acid 
does not belong to a class of chemicals known or suspected of having 
adverse effects on the endocrine system. There is no evidence that 
[S,S]-ethylene diamine disuccinic acid had any effect on endocrine 
function in the developmental or reproduction studies.

C. Aggregate Exposure

    1. Dietary exposure. As a minor formulation component, and given 
its rapid and complete mineralization, there is no reasonable 
expectation that [S,S]-ethylene diamine disuccinic acid will appear in 
the diet.
    i. Food. As a minor formulation component, and given its rapid and 
complete mineralization, there is no reasonable expectation that [S,S]-
ethylene diamine disuccinic acid will appear in the diet.
    ii. Drinking water. As a minor formulation component, and given its 
rapid and complete mineralization, there is no reasonable expectation 
that [S,S]-ethylene diamine disuccinic acid will appear in water.
    2. Non-dietary exposure. Non-dietary exposures to [S,S]-ethylene 
diamine disuccinic acid will be both occupational and residential. 
Occupational exposures include those to applicators and handlers of 
pesticides containing this substance. However, precautionary measures 
prescribed by the labels of pesticide products containing this 
substance will minimize these exposures. Also, [S,S]-ethylene diamine 
disuccinic acid is used in the U.S. in the metal treatment industry as 
a chelating agent. However, the precautionary measures prescribed by 
the product's material safety data sheet will minimize exposure to 
workers in this industry. [S,S]-Ethylene diamine disuccinic acid also 
is used in the U.S. in hair dye products as a chelating agent to 
stabilize the peroxide bleach portion. Exposure to [S,S]-ethylene 
diamine disuccinic acid in these residential products should be minimal 
because the products are used for limited periods and [S,S]-ethylene 
diamine disuccinic acid is used in minor amounts in the products.

D. Cumulative Effects

    The potential for [S,S]-ethylene diamine disuccinic acid and other 
substances that have a common mechanism of toxicity has been 
considered. [S,S]-Ethylene diamine disuccinic acid is a naturally 
occurring substance produced by certain common bacteria, and it is 
rapidly and completely mineralized in the environment. There is no 
reliable information to indicate that toxic effects produced by [S,S]-
ethylene diamine disuccinic acid would be cumulative with those of any 
other chemicals, including another pesticide. Therefore, the Associated 
Octel Corporation, Limited believes that it is appropriate to consider 
only the potential risks of [S,S]-ethylene diamine disuccinic acid in 
an aggregate risk assessment.

E. Safety Determination

    1. U.S. population. As presented previously, the exposures of the 
U.S. general population to [S,S]-ethylene diamine disuccinic acid are 
low, few hazards are presented by [S,S]-ethylene diamine disuccinic 
acid, and the risks are minimal. Use of [S,S]-ethylene diamine 
disuccinic acid as a minor component of pesticide formulations applied 
to growing crops would not contribute significantly to the level of 
[S,S]-ethylene diamine disuccinic acid found naturally in the 
environment and to which man is exposed. Further, there is adequate 
information to show that any toxicological concern raised by the 
potential contribution of [S,S]-ethylene diamine disuccinic acid to 
growing crops is minimal. Occupational exposure to [S,S]-ethylene 
diamine disuccinic acid is expected to be well controlled and limited 
if worker-safety procedures are routinely practiced. Residential 
exposure also should be minimal, because of the low levels of [S,S]-
ethylene diamine disuccinic acid contained in hair dyes and the 
infrequent, intermittent use of these products.
    2. Infants and children. The complete toxicological data base, 
including the developmental toxicity studies, was considered in 
assessing the potential for additional sensitivity of infants and 
children to residues of [S,S]-ethylene diamine disuccinic acid. The 
developmental toxicity studies did indicate an increased sensitivity of 
rats to in-utero exposure to [S,S]-ethylene diamine disuccinic acid. 
However, this increased sensitivity appeared at very high dose levels 
which also caused maternal toxicity, and these levels are not expected 
to appear in or on growing crops, because [S,S]-ethylene diamine 
disuccinic acid is a minor component of pesticide formulations and it 
will rapidly and completely mineralize after application.

F. International Tolerances

    There are no known international tolerances for residues of [S,S]-
ethylene diamine disuccinic acid in food or animal feed.

G. References

    1. Brady, N. C. 1990. The Nature and Properties of Soils. MacMillan 
Publishing Company. New York, New York.
    2. Goodfellow, M., A. B. Brown, J. Cai, J. Chun and M. D. Collins. 
1997. Amycolatopsis Japonicum sp. nov., and Actinomycete producing 
(S,S)-N,N'-ethylene diamine disuccinic acid. System. Appl. Microbiol. 
20,78-84.
    3. Zwicker, N., U. Theobald, H. Zahner and H-D Fielder. 1997. 
Optimization of fermantation conditions for the production of ethylene 
diamine disuccinic acid by Amycolatopsis orientalis. Journal of 
Industrial Microbiology & Biotechnology. 19, 280-285.
    4. Schowanek D., T. C. J. Feijtel, C. M. Perkins F.A. Hartman, T. 
W. Federle, R. J. Larson. 1997. Biodegradation of [S,S] [R,R] and mixed 
stereoisomers of ethylene diamine disuccinic acid (EDDS), a transition 
metal chelator. Chemosphere, Vol. 34, No. 11, pp 2375-2391.
    5. Bucheli-Witschel, M. and T. Egli. 2001. Environmental fate and 
microdegradation of aminopolycarboxylic acids. FEMS Microbiology 
Reviews. 25pp 69-106.
    6. Whitburn, J. S., S. D. Wilkinson and D. R. Williams. 1999. 
Chemical speciation of ethylene diamine-N, N'-disuccinic acid (EDDS) 
and its metal complexes in solution. Chemical Speciation and 
Bioavailability. 11(3) pp 85-93.
[FR Doc. 05-824 Filed 1-18-05; 8:45 am]
BILLING CODE 6560-50-S