[Federal Register Volume 62, Number 92 (Tuesday, May 13, 1997)]
[Notices]
[Pages 26305-26313]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-12472]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-731; FRL-5714-3]
Notice of Filing of Pesticide Petitions
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 the docket control number PF-731, must
be received on or before June 12, 1997.
ADDRESSES: By mail submit written comments to: Public Information and
Records Integrity Branch, Information Resources and Services Division
(7506C), Office of Pesticides Programs, Environmental Protection
Agency, 401 M St., SW., Washington, DC 20460. In person bring comments
to: Rm. 1132, CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
Comments and data may also be submitted electronically by following
the instructions under ``SUPPLEMENTARY INFORMATION.'' No confidential
business information should be submitted through e-mail.
Information submitted as a comment concerning this document may be
claimed confidential by marking any part or all of that information as
``Confidential Business Information'' (CBI). CBI should not be
submitted through e-mail. Information marked as CBI will not be
disclosed except in accordance with procedures set forth in 40 CFR part
2. A copy of the comment that does not contain CBI must be submitted
for inclusion in the public record. Information not marked confidential
may be disclosed publicly by EPA without prior notice. All written
comments will be available for public inspection in Rm. 1132 at the
address given above, from 8:30 a.m. to 4 p.m., Monday through Friday,
excluding legal holidays.
FOR FURTHER INFORMATION CONTACT: By mail: Philip Errico, Product
Manager (PM-25), Registration Division (7505C), Office of Pesticide
Programs, Environmental Protection Agency, 401 M St., S.W., Washington,
D.C. 20460.
[[Page 26306]]
Office Location, telephone number, and e-mail address: Rm. 241 Crystal
Mall #2, 1921 Jefferson Davis Highway, Arlington, VA 22202, (703) 305-
6800; e-mail: errico.phil@epamail.epa.gov.
SUPPLEMENTARY INFORMATION: 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 grantinig of
the petition. Additional data may be needed before EPA rules on the
petition.
The official record for this notice of filing, as well as the
public version, has been established for this notice of filing under
docket control number [PF-731] (including comments and data submitted
electronically as described below). A public version of this record,
including printed, paper versions of electronic comments, which does
not include any information claimed as CBI, is available for inspection
from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal
holidays. The official record is located at the address in
``ADDRESSES'' at the beginning of this document.
Electronic comments can be sent directly to EPA at:
opp-docket@epamail.epa.gov
Electronic comments must be submitted as an ASCII file avoiding the
use of special characters and any form of encryption. Comment and data
will also be accepted on disks in Wordperfect 5.1 file format or ASCII
file format. All comments and data in electronic form must be
identified by the docket number (insert docket number) and appropriate
petition number. Electronic comments on this proposed rule may be filed
online at many Federal Depository Libraries.
List of Subjects
Environmental protection, Agricultural commodities, Food additives,
Feed additives, Pesticides and pests, Reporting and recordkeeping
requirements.
Dated: April 30, 1997.
James Jones,
Acting Director, Registration Division, Office of Pesticide Programs.
Summaries of Petitions
Petitioner summaries of the pesticide petitions are printed below
as required 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. DowElanco
PP 4F4412
EPA has received a pesticide petition (PP 4F4412) from DowElanco
9330 Zionsville Road Indianapolis, IN 46254 proposing pursuant to
section 408(d) of the Federal Food, Drug and Cosmetic Act, 21 U.S.C.
346a(d), to amend 40 CFR part 180 by establishing a tolerance for
inadvertent residues of the herbicide picloram in or on the raw
agricultural commodity grain sorghum grain, forage, and stover at 0.3,
0.2, and 0.5 ppm, respectively. The proposed analytical method is ACR
73.3.S2. Pursuant to the sect 408(d)(2)(A)(i) of the FFDCA, as amended,
Company has submitted the following summary of information, data and
arguments in support of their pesticide petition. This summary was
prepared by DowElanco and EPA has not fully evaluated the merits of the
petition. EPA edited the summary to clarify that the conclusions and
arguments were the petitioner's and not necessarily EPA's and to remove
certain extraneous material.
Picloram provides control of deep rooted perennial weeds either in
grainland, fallowland or on CRP acres. With the addition of the
proposed tolerance, grain sorghum could be considered as a rotational
crop option for the producer. The Agency has completed the
reregistration review of picloram, culminating in publication of the
Reregistration Eligibility Decision (RED) for picloram which was
received on October 5, 1995. The RED concludes that picloram and its
derivatives can be used without causing unreasonable adverse effects to
humans or the environment. Therefore, all uses of products containing
picloram acid and its derivatives were judged eligible for
reregistration. In view of this comprehensive regulatory review, as
well as the lack of human dietary consumption of grain sorghum and the
negligible dietary impact on livestock associated with this proposed
use, establishment of these tolerances will not cause exposure to
exceed the levels at which there is an appreciable risk.
A. Residue Chemistry
1. Plant metabolism. The qualitative nature of the residue in
plants is understood based on a wheat metabolism study. The residue of
concern in wheat forage, straw and grain is conjugated picloram, which
is hydrolyzable by acid, base and B-glucosidase. The minor metabolites
that were identified in grain and straw were 4-amino-6-hydroxy-3,5-
dichloropicolinic acid and 4-amino-2,3,5-trichloropyridine.
2. Analytical method. The analytical portions of the magnitude of
residue studies were performed at DowElanco in Midland, MI. The
analytical method utilized for the determination of picloram residue
levels in the submitted studies was ACR 73.3.S2. There is a practical
analytical method for detecting and measuring levels of picloram in or
on food with a limit of quantitation that allows monitoring of food
with residues at or above the levels set in these tolerances. EPA has
provided information on this method to FDA. The method is available to
anyone who is interested in pesticide residue enforcement.
3. Magnitude of residues.
Table --Summary Of Residues Of Picloram (ppm) Found In Grain Sorghum
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Matrix Range
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Grain NDa0.23
Forage ND-0.17
Fodder ND-0.44
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aND = less than one-half of the validated lower limit of quantitation of
0.05 g/g in grain and 0.1 g/g in forage and fodder.
B. Toxicological Profile
1. Acute toxicity. Studies for acute toxicity indicate that
picloram is classified as category III for acute oral toxicity,
category III for acute dermal toxicity, category I/II (depending on
whether acid or salts) for acute inhalation toxicity, category IV for
skin irritation potential, and category III for eye irritation
potential. The potassium salt is classified as a skin sensitizer. In
addition, picloram has a low vapor pressure.
Picloram potassium salt has low acute toxicity. The rat oral
LD50 is 3,536
[[Page 26307]]
milligrams per kilogram (mg/kg) or greater for males and females. The
rabbit dermal LD50 is >2,000 mg/kg and the rat inhalation
LC50 is >1.63 mg/L air (the highest attainable
concentration). Picloram potassium salt is a positive skin sensitizer
in guinea pigs but is not a dermal irritant. Technical picloram
potassium salt is a moderate ocular irritant but ocular exposure to the
technical material would not normally be expected to occur to infants
or children or the general public. End use formulations of picloram
have similar low acute toxicity profiles plus low ocular toxicity as
well. Therefore based on the available acute toxicity data, picloram
does not pose any acute dietary risks.
2. Genotoxicity. Picloram acid was evaluated in the Ames test using
Salmonella typhimurium. Doses ranged up to 5,000 ug/plate, with and
without metabolic activation. The test substance did not produce a
mutagenic response either in the presence or absence of activation.
Picloram acid was evaluated for gene mutation in mammalian cells
(HGPRT/CHO). As evaluated up to toxic levels (750 ug/ml without
metabolic activation; 1,250 ug/ml with metabolic activation), the
compound was found to be negative for inducing forward mutation in
Chinese hamster ovary (CHO) cells.
Picloram acid was evaluated for cytogenetic effects on bone marrow
cells of rats via intragastric administration at dosage levels of 0
(vehicle), 20, 200 or 2,000 mg/kg. The test material did not produce
cytogenetic effects in the study.
Picloram acid was evaluated for genotoxic potential as administered
to primary rat hepatocyte cultures at concentrations of 0 (vehicle),
10, 33.3, 100, 333.3 or 1,000 ug/ml. The test material was negative for
unscheduled DNA synthesis (UDS, a measure of DNA damage/repair) treated
up to cytotoxic levels of (1,000 ug/ml).
3. Reproductive and developmental toxicity. The HED RfD Peer Review
Committee concluded that there was no evidence, based on the available
data, that picloram and its salts were associated with significant
reproductive or developmental toxicity under the testing conditions.
In the following developmental toxicity studies, the dose levels
that appear in parenthesis are picloram acid equivalents where the
conversion factor employed was 0.86 as applied to doses of potassium
salt.
Picloram potassium salt was administered to New Zealand rabbits by
oral Savage at dosage levels of 0, 40, 200 and 400 milligram per
kilogram per day (mg/kg/day) (picloram acid equivalents) during days 6
to 18 of gestation. The maternal NOEL is 40 (34) mg/kg/day, where the
LOEL is 200 (172) mg/kg/day based on reduced maternal weight gain
during gestation. The developmental NOEL is 400 mg/kg/day and the LOEL
was not determined.
The potassium salt of picloram was administered to CD rats by
gastric intubation at dosage levels of 0, 35 (30), 174 (150) and 347
(298) mg/kg/day during day 6-15 of gestation: The test vehicle was
distilled water. There was no evidence of developmental toxicity at
doses up to and including the high dose of 347 (298) mg/kg/day. The
maternal LOEL is 347 (298) mg/kg/day based upon excessive salivation in
the dams of the high dose group. Hence, the developmental toxicity NOEL
is greater than or equal to 347 (298) mg/kg/day. The maternal toxicity
LOEL is 347 (298) mg/kg/day and NOEL is 174 (150) mg/kg/day.
Picloram acid was evaluated in a 2-generation reproduction study in
the CD rat. Dosage levels employed were 0, 20, 200 or 1,000 mg/kg/day.
The parental LOEL is 1,000 mg/kg/day based on histopathological lesions
in the kidney of males of both generations and some females. In males
of both generations, blood in the urine, decreased urine specific
gravity, increased absolute and relative kidney weight, and increased
body weight gain was observed at the high dose. The parental LOEL is
1,000 mg/kg/day and the NOEL is 200 mg/kg/day. The reproductive LOEL
was not identified and the NOEL is 1,000 mg/kg/day.
4. Subchronic toxicity. In a 90-day oral toxicity study, picloram
acid was administered via the diet to groups of 15 F344 rats/sex/dose
at dosage levels of 0, 15, 50, 150, 300 or 500 mg/kg/day. Based upon
liver weight changes and minimal microscopic changes in the liver, the
systemic LOEL is 150 mg/kg/day. The NOEL is 50 mg/kg/day.
In a 1982 6-month dog dietary study, picloram acid was evaluated at
dosage levels of 0, 7, 35 or 175 mg/kg/day. The systemic NOEL is 35 mg/
kg/day and the LOEL is 175 mg/kg/day based on decreases in the
following: body weight gain, food consumption, liver weights
(relative), alkaline phosphatase and alanine transaminase. Increased
liver to body weight ratios and absolute weights were observed in only
two males at the 35 mg/kg/day dosage level.
In a 21-day dermal toxicity study, the potassium salt of picloram
was administered dermally to groups of five New Zealand white rabbits
of each sex at doses of 0 (vehicle control), 75.3, 251 or 753 mg/kg/day
(O. 65, 217 or 650 mg/kg/day picloram acid equivalents) for a total of
15 applications over the 21-day period. The NOEL is greater than or
equal to 753 mg/kg/day for both sexes: hence, a LOEL was not
established for either sex. Although the limit dose of 1,000 mg/kg/day
was not achieved, practical difficulties precluded administering more
test material. The study revealed the non-systemic effects of dermal
irritation and very slight to well defined edema and/or erythema in
both sexes at all dose levels.
5. Chronic toxicity. In a 1988 1-year chronic feeding study in the
dog, picloram acid was administered orally via the diet at dosage
levels of 0, 7, 35 or 175 mg/kg/day The LOEL is 175 mg/kg/day based on
increased liver weight (absolute and relative). The NOEL is 35 mg/kg/
day.
In a chronic toxicity/carcinogenicity feeding study conducted in
the F344 rat, picloram acid (technical grade 93% containing 197 ppm
hexachlorobenzene as an impurity) was evaluated at 0, 20, 60 or 200 mg/
kg/day for 2 years. The chronic toxicity LOEL was 60 mg/kg/day as
evidenced by altered size and tinctorial properties of centrilobular
hepatocytes and increased absolute and/or relative liver weights in
both sexes. The NOEL was 20 mg/kg/day. The study was negative for
carcinogenicity, but due to concerns that a MTD may not have been
achieved and the fact that the test material contained 197 ppm
hexachlorobenzene impurity, the study was not considered to fulfill
adequately the carcinogenicity testing requirement.
In response to the deficiencies cited in the study above, an
additional 2-year dietary chronic/carcinogenicity study was conducted
(in 1992) using F344 rats administered picloram acid at dosage levels
of 0, 250 or 500 mg/kg/day for 104 weeks. Chronic toxicity was observed
at 250 mg/kg/day among males only (increased incidence and severity of
glomerulonephritis, blood in urine, decreased specific gravity of
urine, increased size of hepatocytes that often had altered staining
properties). Among females there were chronic effects only at 500 mg/
kg/day (increased glomerulonephropathy, increased absolute and relative
kidney weight). There was no evidence of carcinogenicity in this study.
It should be noted that use of the Osborne-Mendel rat was waived due to
lack of availability of the strain of rat. In addition, the level of
hexachlorobenzene in the test material employed in this study was 12
ppm. These two studies fulfill the guidelines 83-l(a) and 83-2(a) for
rats.
In a 1992 2-year dietary carcinogenicity study in B6C3F1 mice,
[[Page 26308]]
picloram acid was evaluated at doses of 0, 100, 500 or 1,000 mg/kg/day.
The systemic NOEL in this study is 500 mg/kg/day based on a significant
increase in absolute and relative kidney weights in males (at the high
dose level). No histopathological lesions were found to corroborate
these changes. There was no evidence of carcinogenicity.
The dose levels tested in the 1992 carcinogenicity studies in rats
and mice were considered adequate for carcinogenicity testing. The
treatment did not alter the spontaneous tumor profile in mice or
different strains of rats tested under the testing conditions. The
chemical was classified as a ``Group E - Evidence of Non-
Carcinogenicity for humans.'' This classification applies to the
picloram acid and potassium salt forms for which acceptable
carcinogenicity studies were available for review by the HED
Carcinogenicity Peer Review Committee (5/26/88).
Using its Guidelines for Carcinogen Risk Assessment published
September 24, 1986 (51 FR 33992), picloram is classified as Group ``E''
for carcinogenicity (no evidence of carcinogenicity) based on the
results of the carcinogenicity studies. The dose levels tested in the
1992 carcinogenicity studies in rats and mice were considered adequate
for carcinogenicity testing. The treatment did not alter the
spontaneous tumor profile in mice or different strains of rats tested
under the testing conditions. The chemical was classified as a ``Group
E - Evidence of Non-Carcinogenicity for humans.'' This classification
applies to the picloram acid and potassium salt forms for which
acceptable carcinogenicity studies were available for review by the HED
Carcinogenicity Peer Review Committee (5/26/88). Thus, a cancer risk
assessment would not be appropriate.
6. Animal metabolism. The absorption, distribution, metabolism and
excretion of picloram acid was evaluated in female rats administered a
single i.v. or oral gavage dose of 10 mg/kg, an oral gavage dose of
1,000 mg/kg 14C-picloram, or 1 mg/kg/day unlabeled picloram
by gavage for 14 days followed by a single oral gavage dose of 10 mg/kg
14C-picloram on day 15. The study demonstrates that
14C-picloram is rapidly absorbed, distributed and excreted
following oral and i.v. administration. This study alone is not
adequate; however, this study is acceptable when considered in
conjunction with a male rat metabolism study which yielded similar
results.
C. Aggregate Exposure
1. Dietary exposure-- i. Food. For purposes of assessing the
potential dietary exposure under these tolerances, aggregate exposure
is estimated based on the TMRC from the existing and future potential
tolerances for picloram on food crops. The TMRC is obtained by
multiplying the tolerance level residues (existing and proposed) by the
consumption data which estimates the amount of those food products
eaten by various population subgroups. Exposure of humans to residues
could also result if such residues are transferred to meat, milk,
poultry or eggs. The following assumptions were used in conducting this
exposure assessment: 100% of the crops were treated, the RAC residues
would be at the level of the tolerance, and certain processed food
residues would be at anticipated (average) levels based on processing
studies (see attached Dietary Risk Evaluation for Picloram). This
results in an overestimate of human exposure and a conservative
assessment of risk. As mentioned previously, 0.9% of the RfD is
utilized using these assumptions.
The chronic dietary exposure/risk estimates for picloram are
extremely low. For the United States population as a whole, the
Theoretical Maximum Residue Contribution (TMRC) is 0.001845 milligrams
per kilogram of body weight per day (mg/kg bw/day), only 0.9% of the
RfD. For this same group, the Anticipated Residue Contribution (ARC) is
0.001053 mg/kg bw/day, only 0.5% of the RfD. The subgroup with the
greatest routine chronic exposure/risk is non-nursing infants (less
than 1 year old), which has a TMRC of 0.004753 mg/kg bw/day (2.4% of
the RfD) and an ARC of 0.003805 mg/kg bw/day (1.9% of the RfD).
There is currently no form of sorghum observed in human consumption
surveys utilized by EPA in their DRES assessments. Therefore, sorghum
tolerances will have no effect on the human dietary consumption of
picloram, and the proposed action, as well as existing tolerances, pose
no concern with regards to chronic dietary exposure to food residues of
picloram.
ii. Drinking water. An additional potential source of dietary
exposure to residues of pesticides are residues in drinking water. The
Maximum Contaminant Level for residues of picloram in drinking water
has been established at 500 g/L and a 1-10 day Health Advisory
of 20,000 g/L. Monitoring data available from the Pesticides
in Ground Water Database indicate that picloram has been detected in
ground water at concentrations ranging up to 30 g/L. Results
reported in this database typically were focused on highly vulnerable
areas and in many cases, the database reports information from poorly
constructed or damaged wells. These wells are at high risk because of
the potential for surface residues to be carried directly down the
casing into the ground water. Recognizing these high risk situations,
an analysis of this database shows that less than 3% of the wells
sampled were found to contain picloram. No distinction has been made
between point and non point sources of material. Many of the
detection's are known to be related to point source contamination
including spills at mixing/loading sites, near wells and back siphoning
events. Of the detection's which may have resulted from non-point
sources, none are documented to occur on sites where application would
be recommended based on current labeling. Nearly 99% of the ground
water detection's are at levels of less than 1% of the Maximum
Contaminant Level ( i.e., < 5="">g/L) established for human
consumption by the EPA Office of Drinking Water. The STORET database
maintained by the USEPA Office of Drinking Water indicates that
picloram has been reported in surface water samples before 1988. Of
these detections, 85% were at concentrations 0.13 g/L or lower
and the maximum was 4.6 g/L. The maximum concentration
reported was 4.6 g/L.
The impact of potential residues of picloram in drinking water on
the aggregate risk of the herbicide is minimal. If it is assumed that
all of the drinking water in the U.S. contains 30 g/L of
picloram, the maximum observed in the groundwater data base, its
contribution to the TMRC would be 0.000280 mg/kg bw/day for the general
U.S. population, or 0.14% of the RfD. For the most sensitive population
subgroup, Non-nursing Infants (<1 yr.="" old),="" the="" contribution="" to="" the="" tmrc="" would="" be="" 0.002855="" mg/kg="" bw/day,="" or="" 1.4%="" of="" the="" rfd.="" in="" reality,="" the="" likelihood="" of="" drinking="" water="" being="" contaminated="" with="" picloram="" is="" extremely="" remote,="" and="" actual="" contribution="" to="" the="" dietary="" exposure="" of="" picloram="" is="" virtually="" nil.="" in="" summary,="" these="" data="" on="" potential="" water="" exposure="" indicate="" insignificant="" additional="" dietary="" intake="" and="" risk="" for="" picloram.="" 2.="" non-dietary="" exposure.="" this="" is="" a="" restricted="" use="" chemical="" that="" has="" no="" residential="" uses="" at="" this="" time;="" therefore,="" there="" are="" no="" human="" risks="" associated="" with="" residential="" uses.="" entry="" into="" a="" treated="" area="" soon="" after="" the="" application="" of="" picloram="" is="" expected="" to="" be="" rare="" given="" the="" cultural="" practices="" typically="" associated="" with="" the="" use-sites="" (rights-of-way,="" forestry,="" pastures,="" range="" [[page="" 26309]]="" lands,="" and="" small="" grains)="" defined="" by="" the="" picloram="" labels="" at="" this="" time.="" furthermore,="" if="" entry="" should="" occur,="" the="" potential="" exposures="" are="" expected="" to="" be="" minimal="" due="" to="" the="" characteristics="" of="" those="" use-sites="" d.="" cumulative="" effects="" the="" potential="" for="" cumulative="" effects="" of="" picloram="" and="" other="" substances="" that="" have="" a="" common="" mechanism="" of="" toxicity="" was="" considered.="" the="" mammalian="" toxicity="" of="" picloram="" is="" well="" defined.="" however,="" the="" biochemical="" mechanism="" of="" toxicity="" of="" this="" compound="" is="" not="" well="" known.="" no="" reliable="" information="" exists="" to="" indicate="" that="" toxic="" effects="" produced="" by="" picloram="" would="" be="" cumulative="" with="" those="" of="" any="" other="" chemical="" compounds.="" therefore,="" consideration="" of="" a="" common="" mechanism="" of="" toxicity="" with="" other="" compounds="" is="" not="" appropriate.="" thus="" only="" the="" potential="" risks="" of="" picloram="" are="" considered="" in="" the="" aggregate="" exposure="" assessment.="" e.="" safety="" determination="" 1.="" u.s.="" population.="" in="" the="" meeting="" of="" september="" 30,="" 1993,="" the="" opp="" rfd="" peer="" review="" committee="" recommended="" that="" the="" rfd="" for="" this="" chemical="" be="" based="" on="" a="" noel="" of="" 20="" mg/kg/day="" for="" a="" dose-related="" increase="" in="" size="" and="" altered="" tinctorial="" properties="" of="" centrilobular="" hepatocytes="" in="" males="" and="" females="" at="" 60="" and="" 200="" mg/kg/day="" in="" a="" chronic="" toxicity="" study="" in="" rats.="" an="" uncertainty="" factor="" (uf)="" of="" 100="" was="" used="" to="" account="" for="" the="" inter-="" species="" extrapolation="" and="" intra-species="" variability.="" on="" this="" basis,="" the="" rfd="" was="" calculated="" to="" be="" 0.20="" mg/kg/day.="" the="" theoretical="" maximum="" residue="" contribution="" (tmrc)="" from="" existing="" tolerances="" is="" 0.001845="" mg/kg/="" day.="" existing="" tolerances="" utilize="" 0.9%="" of="" the="" rfd.="" it="" should="" be="" noted="" that="" no="" regulatory="" value="" has="" been="" established="" for="" this="" chemical="" by="" the="" world="" health="" organization="" (who)="" up="" to="" this="" date.="" the="" committee="" classified="" picloram="" as="" a="" ``group="" e''="" chemical,="" no="" evidence="" of="" carcinogenicity="" for="" humans.="" using="" the="" conservative="" exposure="" assumptions="" described="" above="" and="" based="" on="" the="" completeness="" and="" reliability="" of="" the="" toxicity="" data,="" it="" is="" concluded="" that="" aggregate="" exposure="" to="" picloram="" will="" utilize="" approximately="" 1="" percent="" of="" the="" rfd="" for="" the="" u.s.="" population.="" generally,="" exposures="" below="" 100="" percent="" of="" the="" rfd="" are="" of="" no="" concern="" because="" the="" rfd="" represents="" the="" level="" at="" or="" below="" which="" daily="" aggregate="" dietary="" exposure="" over="" a="" lifetime="" will="" not="" pose="" appreciable="" risk="" to="" human="" health.="" thus,="" there="" is="" a="" reasonable="" certainty="" that="" no="" harm="" will="" result="" from="" aggregate="" exposure="" to="" picloram="" residues.="" 2.="" infants="" and="" children.="" in="" assessing="" the="" potential="" for="" additional="" sensitivity="" of="" infants="" and="" children="" to="" residues="" of="" picloram,="" data="" from="" developmental="" toxicity="" studies="" in="" the="" rat="" and="" rabbit="" and="" a="" 2-generation="" reproduction="" study="" in="" the="" rat="" were="" considered.="" the="" developmental="" toxicity="" studies="" are="" designed="" to="" evaluate="" adverse="" effects="" on="" the="" developing="" organism="" during="" prenatal="" development="" resulting="" from="" pesticide="" exposure="" to="" one="" or="" both="" parents.="" reproduction="" studies="" provide:="" (1)="" information="" relating="" to="" effects="" from="" exposure="" to="" the="" pesticide="" on="" the="" reproductive="" capability="" of="" mating="" animals="" and="" (2)="" data="" on="" systemic="" toxicity.="" developmental="" toxicity="" was="" studied="" using="" rats="" and="" rabbits.="" the="" developmental="" study="" in="" rats="" resulted="" in="" a="" developmental="" noel="" of="">298
mg/kg/day and a maternal toxicity NOEL of 280 mg/kg/day. A study in
rabbits resulted in a maternal NOEL of 34 mg/kg/day and a developmental
NOEL of 344 mg/kg/day. Based on all of the data for picloram, there is
no evidence of developmental toxicity at dose levels that do not result
in maternal toxicity.
In a 2-generation reproduction study in rats, The NOEL for parental
systemic toxicity is 200 mg/kg/day. There was no effect on reproductive
parameters at 1,000 mg/kg/day nor was there an adverse effect on the
morphology, growth or viability of the offspring; thus, the
reproductive NOEL is 1,000 mg/kg/day.
FFDCA section 408 provides that EPA may apply an additional safety
factor for infants and children in the case of threshold effects to
account for pre- and post-natal toxicity and the completeness of the
database. Based on the current toxicological data requirements, the
database relative to pre- and post-natal effects for children is
complete. Therefore, it is concluded that an additional uncertainty
factor is not warranted and that the RfD at 0.2 mg/kg/day is
appropriate for assessing aggregate risk to infants and children.
Using the conservative exposure assumption previously described, it
is concluded that the percent of the RfD that will be utilized by
aggregate exposure to residues of picloram will be less than 4 percent
of the RfD for all populations and subgroups. Since this estimate
represents the ``worst case'' exposure for a given population (non-
nursing infants, <1 year="" old),="" exposures="" will="" be="" less="" for="" all="" other="" sub-populations="" e.g.="" children,="" 1-6="" years.="" therefore,="" based="" on="" the="" completeness="" and="" reliability="" of="" the="" toxicity="" data="" and="" the="" conservative="" exposure="" assessment,="" it="" is="" concluded="" that="" there="" is="" a="" reasonable="" certainty="" that="" no="" harm="" will="" result="" to="" infants="" and="" children="" from="" aggregate="" exposure="" to="" picloram="" residues.="" other="" considerations="" f.="" international="" tolerances="" there="" are="" no="" codex="" maximum="" residue="" levels="" established="" for="" residues="" of="" picloram.="" 1.="" endocrine="" effects.="" an="" evaluation="" of="" the="" potential="" effects="" on="" the="" endocrine="" systems="" of="" mammals="" has="" not="" been="" determined;="" however,="" no="" evidence="" of="" such="" effects="" were="" reported="" in="" the="" chronic="" or="" reproductive="" toxicology="" studies="" described="" above.="" there="" was="" no="" observed="" pathology="" of="" the="" endocrine="" organs="" in="" these="" studies.="" there="" is="" no="" evidence="" at="" this="" time="" that="" picloram="" causes="" endocrine="" effects.="" 2.="" data="" gaps.="" data="" gaps="" currently="" exist="" for="" residue="" data="" for="" sorghum="" aspirated="" grain="" fractions.="" based="" on="" the="" toxicological="" data="" and="" the="" levels="" of="" exposure,="" epa="" has="" determined="" that="" the="" proposed="" tolerances="" will="" be="" safe.="" 2.="" novartis="" crop="" protection="" pp="" 6f4688="" epa="" has="" received="" a="" pesticide="" petition="" (pp="" 6f4688)="" from="" novartis="" crop="" protection,="" inc.,="" p.="" o.="" box="" 18300,="" greensboro,="" north="" carolina="" 27419,="" proposing="" pursuant="" to="" section="" 408(d)="" of="" the="" federal="" food,="" drug="" and="" cosmetic="" act,="" 21="" u.s.c.="" 346a(d),="" to="" amend="" 40="" cfr="" part="" 180="" by="" establishing="" a="" tolerance="" for="" residues="" of="" the="" herbicide="" cga-277476,="" benzoic="" acid,="" 2-[[[[4,6-dimethyl-2-pyrimidinyl)-="" amino]carbonyl]amino]sulfonyl]-,3-oxetanylester="" in="" or="" on="" the="" raw="" agricultural="" commodity="" soybeans="" at="" 0.01="" ppm.="" the="" proposed="" analytical="" method="" involves="" homogenization,="" filtration,="" partition="" and="" cleanup="" with="" analysis="" by="" high="" performance="" liquid="" chromatography="" using="" uv="" detection.="" 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.="" as="" required="" by="" section="" 408(d)="" of="" the="" ffdca,="" as="" recently="" amended="" by="" the="" food="" quality="" protection="" act="" (fqpa)="" pub.l.="" 104-170,="" novartis="" crop="" protection="" included="" in="" the="" petition="" a="" summary="" of="" the="" petition="" and="" authorization="" for="" the="" summary="" to="" be="" published="" in="" the="" federal="" register="" in="" a="" notice="" of="" receipt="" of="" the="" petition.="" the="" summary="" represents="" the="" views="" of="" novartis="" crop="" protection.="" epa="" is="" in="" the="" process="" of="" evaluating="" the="" petition.="" as="" [[page="" 26310]]="" required="" by="" section="" 408(d)(3)="" of="" the="" ffdca,="" epa="" is="" including="" the="" summary="" as="" a="" part="" of="" this="" notice="" of="" filing.="" epa="" has="" made="" minor="" edits="" to="" the="" summary="" for="" the="" purpose="" of="" clarity.="" a.="" metabolism="" the="" qualitative="" nature="" of="" the="" metabolism="" of="" cga-277476="" in="" plants="" and="" animals="" is="" well="" understood="" for="" the="" purposes="" of="" the="" proposed="" tolerance.="" metabolism="" proceeds="" through="" hydrolysis="" of="" the="" oxetane="" ring="" with="" subsequent="" cleavage="" of="" the="" oxetane="" ester="" and="" the="" sulfonylurea="" bridge.="" metabolic="" pathways="" in="" plants="" (soybeans),="" rats,="" ruminants="" (goats),="" and="" poultry="" are="" similar.="" parent="" cga-277476="" is="" the="" residue="" of="" concern.="" b.="" analytical="" methodology="" novartis="" crop="" protection,="" inc.="" has="" submitted="" a="" practical="" analytical="" method="" involving="" homogenization,="" filtration,="" partition="" and="" cleanup="" with="" analysis="" by="" high="" performance="" liquid="" chromatography="" using="" uv="" detection.="" the="" methodology="" accounts="" for="" residues="" of="" cga-277476.="" the="" limit="" of="" quantitation="" (loq)="" for="" the="" method="" is="" 0.01="" ppm="" for="" cga-277476.="" this="" method="" has="" undergone="" a="" successful="" method="" trial="" and="" is="" available="" for="" enforcement.="" c.="" residue="" twenty="" field="" trials="" were="" conducted="" in="" typical="" soybean="" growing="" areas="" across="" the="" u.s.="" either="" a="" single="" preplant="" or="" preemergence="" application="" (57="" grams="" ai/a)="" or="" a="" split="" application="" made="" preemergence="" followed="" by="" a="" post="" broadcast="" application="" (total="" of="" 81="" grams="" ai/a)="" was="" made.="" no="" residues="">1><0.01 ppm)="" were="" found="" in="" the="" dry="" beans="" (1x)="" and="" no="" residues="" were="" found="" in="" the="" processed="" commodities="" at="" rates="" up="" to="" 5x.="" no="" residues="">0.01><0.01 ppm)="" were="" found="" in="" rotational="" crops="" treated="" at="" the="" 1x="" rate.="" a="" prohibition="" against="" grazing="" forage,="" hay="" and="" silage="" will="" be="" placed="" in="" the="" label,="" as="" will="" a="" 60="" day="" preharvest="" interval.="" d.="" international="" mrl's="" there="" are="" no="" codex="" alimentarius="" commission="" (codex)="" maximum="" residue="" levels="" (mrl's)="" established="" for="" residues="" of="" cga-277476="" in="" or="" on="" raw="" agricultural="" commodities.="" e.="" toxicological="" profile="" 1.="" acute="" toxicity.="" cga-277476="" has="" a="" low="" order="" of="" acute="" toxicity.="" the="" rat="" oral="">0.01>50 is > 5,000 mg/kg, the acute rabbit dermal
LD50 is > 2,000 mg/kg and the rat inhalation LC50
is > 5.08 mg/L. CGA 277476 is moderately irritating to the skin but not
irritating to the eye. It is not a skin sensitizer in guinea pigs. The
commercial formulation (75WG) of CGA-277476 has a similar acute
toxicity profile, with both technical and formulated product carrying a
Category III CAUTION Signal Word.
2. Genotoxicity. Assays for genotoxicity were comprised of tests
evaluating the potential of CGA-277476 to induce point mutations
(Salmonella assay and a Chinese hamster V79 lung tissue assay),
chromosome aberrations (mouse micronucleus and a Chinese hamster ovary
study) and the ability to induce either scheduled or unscheduled DNA
synthesis in rat hepatocytes. The results indicate that CGA-277476 is
not mutagenic or clastogenic and does not induce unscheduled DNA
synthesis.
3. Developmental/reproductive effects. The developmental and
teratogenic potential of CGA-277476 was investigated in rats and
rabbits. The results indicate that CGA-277476 was not maternally or
developmentally toxic in the rabbit. Minimal developmental toxicity was
observed at the limit dose (1,000 mg/kg) in the rat; the developmental
no observed effect level in the rat was 300 mg/kg/day. No evidence of
teratogenicity was observed at the limit dose of 1,000 mg/kg in either
the rat or rabbit.
A 2-generation reproduction study was conducted with CGA-277476 at
feeding levels of 0, 20, 200, 5,000 or 20,000 ppm (0, 1, 10, 250 or
1,000 mg/kg/day). The reproductive NOEL was established at a feeding
level of 5,000 ppm (equivalent to approximately 250 mg/kg/day). Reduced
fertility observed at the highest dose tested (20,000 ppm) was
associated with degenerative changes in the seminiferous tubules and
atypical spematogenesis in males and severe effects on kidneys in
females. The NOEL for parental toxicity was established at the 200 ppm
feeding level based on slight effects on body weight parameters at the
next highest dose tested (i.e. 5,000 ppm).
4. Subchronic toxicity. The subchronic toxicity of CGA-277476 was
evaluated in studies in the rat, mouse and dog at high doses. Target
organs included the liver, spleen, blood, kidney, urogenital tract,
testes, epididymis and peripheral nerves and muscles. No observable
effect levels have been established for all end-points in subchronic
studies. The dog appears to be the most sensitive species (NOEL = 40
ppm; 1 mg/kg) with treatment related effects on testes, peripheral
nerve and muscle appearing at doses 5,000 ppm ( 125 mg/kg/
day).
5. Chronic effects. The chronic toxicity of CGA-277476 was
investigated in long term studies in the rat, mouse and dog. Target
organs included the central and peripheral nervous systems, skeletal
muscle, liver, kidney, gallbladder, testes, and blood. No observed
effect levels (NOELS) have been established in each study. The dog is
the most sensitive species with a NOEL = 40 ppm (1.3 mg/kg/day). Based
on these data, it is expected the EPA will establish a RfD for CGA-
277476 at 0.01 mg/kg/day using the NOEL of 1.3 mg/kg/day and an
uncertainty factor of 100.
6. Carcinogenicity. The carcinogenicity studies conducted with CGA-
277476 showed no evidence of an oncogenic response in either mouse or
rat at doses that did not exceed the maximum tolerated dose. Dose
levels in the mouse study were 2.25, 150, 525, and 1,050 mg/kg/day. In
the rat study, dose levels were 1, 10, 100, 500, 750 (females), and
1,000 (males) mg/kg/day. At the end of the chronic rat study, a
statistically significant increased incidence of schwannomas was found
in the heart of the 1,000 mg/kg/day male rats (7/59) compared to the
control group (0/60). Based on the Guidelines for Carcinogenic Risk
Assessment published by EPA September 24, 1986 (51 FR 33992), Novartis
Crop Protection believes that CGA-277476 should be classified as Class
E because the neoplastic response (marginal increased incidence of
schwannomas) was observed only in male rats at a dose exceeding the
maximum tolerated dose of 500 mg/kg/day. No effect was observed at
doses 500 mg/kg/day.
F. Threshold Effects
1. Chronic effects. Based on the available chronic toxicity data,
it is expected the EPA will establish a RfD for CGA-277476 at 0.01 mg/
kg/day based on the results obtained in the 1-year feeding study in
dogs using the No-Observed Effect Level (NOEL) of 1.3 mg/kg/day and an
uncertainty factor of 100.
2. Acute toxicity. Based on the available acute toxicity data,
Novartis Crop Protection believes CGA-277476 does not pose any acute
dietary risks.
G. Nonthreshold Effects.
Carcinogenicity. Based on the Guidelines for Carcinogenic Risk
Assessment published by EPA September 24, 1986 (51 FR 33992), Novartis
Crop Protection believes that CGA-277476 should be classified as Class
E because the neoplastic response (marginal increased incidence of
schwannomas) was observed only in male rats at a dose exceeding the
maximum tolerated dose of 500 mg/kg/day. No effect was observed at
doses 500 mg/kg/day.
[[Page 26311]]
H. Endocrine Effects.
CGA-277476 belongs to the sulfonylurea class of chemicals, one not
known or suspected of having adverse effects on the endocrine system.
Reduced fertility observed in high dose females (20,000 ppm) in the rat
reproduction study was associated with degenerative changes in the
seminiferous tubules and a typical spermatogenesis observed in high
dose males. Evidence of impaired spermatogenesis was also observed at
high doses ( 125 mg/kg/day) in the subchronic dog study.
I. Aggregate Exposure
1. Dietary exposure. For purposes of assessing the potential
dietary exposure to CGA-277476, Novartis Crop Protection has estimated
aggregate exposure based on the Theoretical Maximum Residue
Contribution from the use of CGA-277476 in or on raw agricultural
commodities for which tolerances have been proposed (0.01 ppm on
soybeans). In conducting this exposure assessment, Novartis has
conservatively assumed that 100% of soybeans will contain CGA-277476
residues at the proposed level of 0.01 ppm. No residues are anticipated
in animal commodities and therefore, tolerances in meat, meat
byproducts, milk, poultry and eggs are not proposed.
2. Drinking water exposure. Another potential source of exposure of
the general population to residues of pesticides are residues in
drinking water. The potential for CGA-277476 to enter surface or ground
water sources of drinking water is limited because of the low use rate.
This is supported by the results of two small-scale prospective ground
water monitoring studies which did not show any quantifiable residues
of CGA-277476 in ground water samples. The Maximum Contaminant Level
Guideline (MCLG) calculated for CGA-277476 according to EPA's procedure
leads to an exposure value (7 ppb) substantially greater than any level
expected to reach ground water based on study results.
3. Non-occupational exposure. Novartis Crop Protection has
evaluated the estimated non-occupational exposure to CGA-277476 and
concludes that the potential for non-occupational exposure to the
general population is unlikely because CGA-277476 is not planned to be
used in or around the home, including home lawns, schools, recreation
facilities or parks.
J. Cumulative Risk.
Novartis Crop Protection has also considered the potential for
cumulative effects of CGA-277476 and other chemicals belonging to this
chemical class (sulfonylureas) that may have a common mechanism of
toxicity. It is concluded that consideration of a common mechanism of
toxicity is not appropriate at this time because there is no reliable
data to establish whether a common mechanism exists.
K. Safety Determinations.
1. U.S. general population. Using the conservative exposure
assumptions described above, based on the completeness and reliability
of the toxicity data, Novartis Crop Protection has concluded that
aggregate exposure to CGA-277476 will utilize 0.07 percent of the RfD
for the U.S. population based on chronic toxicity endpoints. Because
EPA generally has no concern for exposures below 100 percent of the
RfD, it is concluded that there is a reasonable certainty that no harm
to the general population will result from aggregate exposure to CGA-
277476.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of CGA-277476, Novartis
Crop Protection has considered data discussed above from developmental
toxicity studies conducted with CGA-277476 in the rat and rabbit and a
2-generation rat reproduction study. The developmental toxicity studies
are designed to evaluate adverse effects on the developing organism
resulting from chemical exposure during prenatal development to one or
both parents. Reproduction studies provide information relating to
effects from exposure to a chemical on the reproductive capability of
mating animals and data on systemic toxicity.
FFDCA section 408 provides that EPA may apply an additional safety
factor for infants and children in the case of threshold effects to
account for pre- and post-natal toxicity and the completeness of the
database. Based on the current toxicological data requirements, the
database relative to pre- and post-natal effects for children is
complete. Further, for CGA-277476, the NOEL of 1.3 mg/kg/day from the
chronic dog study, which was used to calculate the RfD (discussed
above), is at least an order of magnitude lower than the developmental
NOEL of 300 mg/kg/day from the rat teratogenicity study or the
reproductive NOEL of 250 mg/kg/day from the multigeneration
reproduction study. There is no evidence to suggest that developing
organisms are more sensitive to the effects of CGA-277476 than are
adults.
However, Novartis Crop Protection has determined that when an
additional tenfold safety margin is used, the percent of the RfD that
will be utilized by aggregate exposure to residues of CGA-277476 is 0.8
percent for nursing infants less than 1 year old, 3.5 percent for non-
nursing infants, 1.4 percent for children 1 to 6 years old and 1.1
percent for children 7 to 12 years old. Therefore, based on the
completeness and reliability of the toxicity data and the conservative
exposure assessment, it is concluded that there is a reasonable
certainty that no harm to infants and children will result from
aggregate exposure to CGA-277476 residues.
3. Siemer and Associates
PP 6F4789
EPA has received a pesticide petition (PP 6F4789) from Siemer &
Associates, Inc. on behalf of National Chelating, 4672 West Jennifer,
Suite 103, Fresno, CA 93722, proposing pursuant to section 408(d) of
the Federal Food, Drug and Cosmetic Act, 21 U.S.C. 346a(d), to amend 40
CFR part 180 by establishing an exemption from the requirements for a
tolerance for ammonium thiosulfate when used for blossom thinning on
apples.
Pursuant to the section 408(d)(2)(A)(i) of the FFDCA, as amended,
Siemer & Associates, Inc. on behalf of National Chelating has submitted
the following summary of information, data and arguments in support of
their pesticide petition. This summary was prepared by Siemer &
Associates, Inc. and EPA has not fully evaluated the merits of the
petition. EPA edited the summary to clarify that the conclusions and
arguments were the petitioner's and not necessarily EPA's and to remove
certain extraneous material.
On August 30, 1996 Siemer & Associates on behalf of National
Chelating petitioned the EPA, under pesticide petition 6F4789, for a
permanent exemption from the requirements of a tolerance for ammonium
thiosulfate on apples.
Section 408(b)(2)(A) of the amended Federal Food, Drug, and
Cosmetic Act allows the EPA to establish an exemption from the
requirements for a tolerance only if the Administrator determines that
there is a ``reasonable certainty that no harm will result from the
aggregate exposure to the pesticide chemical residue, including all
anticipated dietary exposures and all other exposures for which there
is reliable information.''
The available information indicates that there is a reasonable
certainty that no harm will result from various types of exposure.
Requests for waivers from the requirements of performing studies for
known chemistry are presented and
[[Page 26312]]
substantiated. The following is a summary of the information submitted
to the EPA to support the establishment, under Section 408(b)(2)(D) of
the amended FFDCA, of a tolerance for ammonium thiosulfate on apples.
A. Residue Chemistry
1. Plant metabolism. The qualitative nature of the residues of
ammonium thiosulfate in apple is adequately understood. The requirement
for residue studies was waived by EPA based on the knowledge that
ammonium thiosulfate has been used as a soil applied and foliar applied
fertilizer for many years. Prior experience and numerous publications
teach that ammonium thiosulfate ionizes when placed into water, forming
an ammonium ion and a thiosulfate ion which further degrades to form
elemental sulfur and a sulfate ion. The sulfur is further oxidized to
form a sulfate ion. The ammonium and sulfate ions thus formed are
absorbed into the growing plant and moved into the naturally occurring
nitrogen and sulfate pools that occur naturally in growing plants. Once
applied to the plant, without isotope identification, it is not
possible to separate the ammonium and sulfate ions that will occur from
those that already occur naturally in the plant. On this basis, an
exemption from the requirements of a tolerance is justified. There is
no analytical method needed since there is no practical way to separate
the ammonium and sulfate ions from those that naturally occur.
2. Analytical method. The need for an analytical method is waived
on the basis that there is no need for analyzing for the component of
ammonium and sulfate ion applied for blossom thinning purposes.
3. Magnitude of residues. No residues of ammonium thiosulfate will
be identified separately from those ammonium and sulfate ions naturally
occurring. This result supports the proposed exemption from the
requirements for a tolerance.
B. Toxicological Profile
A request to waive the battery of mammalian toxicity studies for
ammonium thiosulfate is based on and justified by the following:
1. Acute toxicity. Based on EPA criteria, ammonium thiosulfate
previously registered for a non-food use as an ornamental herbicide has
been shown to be relatively non-toxic and has been registered for non-
food use purposes as a Category III herbicide. These data have
previously been supplied to the agency.
2. Genotoxicity. A request for a waiver from the following
requirements is made on the basis that sodium thiosulfate is on the FDA
Generally Recognized as Safe (GRAS) list at 21 CFR 184.1807, and
ammonium thiosulfate is already exempted from the requirements of a
tolerance when used in accordance with good agricultural practices as
inert (or occasionally active) ingredients in pesticide formulations
applied to growing crops or to raw agricultural commodities after
harvest (at 40 CFR 180.1001(c)). Ammonium thiosulfate ionizes to form
ammonium ion and thiosulfate ion in water with neither of these ions
being mutagenic or genotoxic. On that basis the following tests are
requested to be waived.
i. Gene Mutation - Ames.
ii. In vitro Structural chromosomal aberration assay.
iii. In vitro CHO/HGPRT assay.
iv. In vivo micronucleus aberration assay.
3. Reproductive and developmental toxicity. A request for waiving
the data requirements for the following is made on the basis listed
above for ``B''. In addition, all of the tests listed below rely on
feeding the test substance, to animals that have acidic stomachs.
Placing ammonium thiosulfate into an acidic environment will cause near
instantaneous ion formation giving rise to ammonium and thiosulfate
ions, which ultimately breaks down to elemental sulfur and sulfite.
These sulfur forms will be quickly oxidized under acidic conditions to
sulfate, which will be incorporated into the normal sulfate pool that
exists within the metabolic system of the various animal test systems.
The ammonium ion will react with the acidic component, most likely
forming ammonium chloride which will be metabolized in a well
understood pathway in the systems of the various animal test systems.
The new moiety formed in this acidic medium is the sulfite ion which
also is well understood and is quickly oxidized to sulfate. The FDA
instituted studies in 1975 and 1985 on the GRAS status of sulfite and,
as a result of these studies, has substantiated the GRAS status except
for a few individuals that might be allergic to sulfite. In this
proposed usage however, the sulfite will not reach the possibly
allergic people, since the sulfite will be metabolized to sulfate in
the plant system before reaching any sensitive people who may consume
the treated tissue. The data waivers requested are as follows:
i. Teratology in rats.
ii. Teratology in rabbits.
iii. 2-Generation reproduction in rats.
4. Subchronic Toxicity. The data requirements listed below are
requested to be waived on the basis illustrated above at paragraph 3.
i. 28-Day dermal in rats.
ii. 13-Week oral feeding in rats.
iii. 90-Day oral feeding in dogs.
5. Chronic toxicity. The data requirements listed below are
requested to be waived for reasons listed above at paragraph 3.
i. 1-Year chronic toxicity in dogs.
ii. 18-Month chronic toxicity & carcinogenicity in mice.
iii. 24-Month chronic toxicity & carcinogenicity in rats.
6. Animal metabolism. The metabolism of ammonium thiosulfate is
well understood in animals. As listed above, this substance rapidly
ionizes in the acidic portion of the animal gut, giving rise to
ammonium ion and sulfate ion. Both of these substances are required and
occur in the metabolism of animals.
7. Metabolite toxicology. No toxicologically significant
metabolites will be detected in plant or animal metabolism studies
using ammonium thiosulfate. Therefore, no metabolites are required to
be regulated.
8. Endocrine effects. There is no information available that
suggest that ammonium thiosulfate would be associated with endocrine
effects.
C. Aggregate Exposure
1. Dietary exposure--i. Food. There will be no residues of ammonium
thiosulfate that will reach any portion of the US population as a
result of using ammonium thiosulfate as a blossom thinner on apples.
The ammonium and sulfate ions that will arise will not be different
from the naturally occurring forms of the ions, which exceed by far the
amount that will be applied as a result of the use of the ammonium
thiosulfate.
ii. Drinking water. Ammonium and sulfate ions that arise from
ammonium thiosulfate use will add no additional burden to the drinking
water. The end points of the two ions formed as a result of ammonium
thiosulfate use will both be used in plant nutrition. The ammonium form
of nitrogen resists leaching by binding to the colloid fraction in the
soil to resist ground water contamination. The amount of sulfate added
as a result of the described use will add an imperceptible amount to
the sulfate level already in existence in the soil.
There is a reasonable certainty that no harm will result from
dietary exposure to ammonium thiosulfate, because dietary exposures to
residues on food cannot be differentiated from those that
[[Page 26313]]
will occur naturally in food, and exposure through drinking water is
expected to be insignificant.
2. Non-dietary exposure. There is no non-dietary exposure expected,
since any ammonium thiosulfate finding its way onto the plants or
around any plants will be absorbed and metabolized into naturally
occurring plant constituents.
D. Cumulative Effects
There are no cumulative effects expected since the ammonium
thiosulfate metabolites are all incorporated into naturally occurring
constituents found in all plant systems.
E. Safety Determination
1. U.S. population. The natural occurrence of the metabolites of
the ammonium and sulfate ions in all plants and in humans is the basis
for the Generally Recognized As Safe characterization of the
thiosulfate ion and the use of the ammonium ion as a component in
nearly all fertilizers, supports the conclusion that there is a
``reasonable certainty of no harm'' from aggregate exposure to ammonium
thiosulfate.
2. Infants and children. No developmental, reproductive or
fetotoxic effects have been associated with ammonium thiosulfate and
its use as a fertilizer. The calculation of safety margins with respect
to ammonium thiosulfate is unnecessary since the ammonium and sulfate
ions that will arise from the use of ammonium thiosulfate will add only
slightly to the already naturally occurring nitrogen and sulfur pools
in existence in various plants. Since there will be no residues of
toxicological significance resulting from ammonium thiosulfate,
calculations of safety margins are not necessary based on the lack of
any unnatural residues.
F. International Tolerances
There is no Codex maximum residue level established for ammonium
thiosulfate on apple. However, ammonium thiosulfate is widely used as a
nutrient in many parts of the world.
[FR Doc. 97-12472 Filed 5-12-97; 8:45 am]
BILLING CODE 6560-50-F
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