[Federal Register Volume 64, Number 163 (Tuesday, August 24, 1999)]
[Notices]
[Pages 46191-46197]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-21944]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-868; FRL-6069-6]
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-868, must
be received on or before September 23, 1999.
ADDRESSES: By mail submit written comments to: Public Information and
Records Integrity Branch, Information Resources and Services Division
(7502C), Office of Pesticides Programs, Environmental Protection
Agency, 401 M St., SW., Washington, DC 20460. In person bring comments
to: Rm. 119, 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: The product manager listed in the
table below:
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Office location/
Product Manager telephone number Address
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Kathryn Boyle................. Rm. Q616, CM #2, 703- 1921 Jefferson
305-6304, e- Davis Hwy,
mail:[email protected] Arlington, VA
amail.epa.gov.
Cynthia Giles-Parker (PM 22).. Rm. 229, CM #2, 703- Do.
305-7740, e-mail:
parker.cynthia@epamai.
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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 granting 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-868] (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 notice 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: August 13, 1999.
James Jones,
Director, Registration Division, Office of Pesticide Programs.
Summaries of Petitions
Petitioner summaries of the pesticide petitions are printed below
as required
[[Page 46192]]
by section 408(d)(3) of the FFDCA. The summaries of the petitions were
prepared by the petitioners and represent the views of the petitioners.
EPA is publishing the petition summaries verbatim without editing them
in any way. The petition summary announces the availability of a
description of the analytical methods available to EPA for the
detection and measurement of the pesticide chemical residues or an
explanation of why no such method is needed.
1. Centre Internationale d'Etudes du Lindane (C.I.E.L.) and its
member company Inquinosa S.A.
PP 9F5057
EPA has received a pesticide petition (9F5057) from Centre
Internationale d'Etudes du indane (C.I.E.L.) and its member company
Inquinosa S.A., c/o Charles A. O'Conner III, Esq., McKenna & Cuneo,
L.L.P., 1900 K Street, NW., Washington, DC 20006-1108, proposing
pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act
(FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 by establishing a
tolerance for residues of lindane in or on the raw agricultural
commodities (RAC) broccoli, brussels sprouts, cabbage, cauliflower,
celery, collards, kale, kohlrabi, lettuce, mustard greens, spinach, and
Swiss chard at 0.05 parts per million (ppm), corn (grain) at 0.01 ppm,
and corn (forage and fodder) and radish at 0.1 ppm. EPA has determined
that the petition contains data or information regarding the elements
set forth in section 408(d)(2) of the FFDCA; however, EPA has not fully
evaluated the sufficiency of the submitted data at this time or whether
the data supports granting of the petition. Additional data may be
needed before EPA rules on the petition.
A. Residue Chemistry
1. Plant metabolism. Use of lindane as a seed treatment results in
uptake of lindane and extensive metabolism within the plant. The
primary residue in RAC was parent lindane. Lindane metabolizes in
plants through the same processes found in mammalian animals, i.e.
dehydrogenation, dehydrochlorination, hydroxylation, and conjugation.
Thus, the terminal metabolites for plants and animals are the same
chorophenols, chlorobenzenes, etc. and conjugates of these classes of
compounds.
2. Analytical method. A multi-residue method is currently being
used by the United States food and drug administration (FDA) to
determine lindane residues in raw and processed agricultural
commodities, in order to monitor for tolerance compliance. The
pesticide analytical manual (PAM) method for non-fatty foods by GLC,
PAM 212.1, has also been validated for determination of lindane
residues.
3. Magnitude of residues. Lindane residues were determined in
mustard, radish, field corn, sweet corn, and spinach, using radio-
labeled lindane applied as a seed treatment. Residues of parent lindane
were: Radish roots; 0.030 ppm; mustard leaves, 0.017 ppm; field corn
foliage, 0.008 ppm; sweet corn foliage 0.012 ppm; field corn grain, < 0.01="" ppm;="" sweet="" corn="" grain,="">< 0.01="" ppm;="" and="" spinach,="">< 0.02="" ppm.="" residues="" in="" animal="" tissues,="" milk,="" and="" eggs="" will="" be="" negligible,="" based="" on="" transfer="" factors="" determined="" in="" animal="" feeding="" studies,="" the="" low="" residue="" levels="" in="" animal="" feed="" items,="" and="" the="" limited="" market="" share.="" b.="" toxicological="" profile="" 1.="" acute="" toxicity--i.="" a="" rat="" acute="" oral="" study="" with="" an="">50s of 88 to 150 milligram kilogram (mgkg) (Toxicity
Category II).
ii. A rabbit acute dermal study with an LD50 of 500 to
1,000 mg/kg (Toxicity Category II).
iii. A primary eye irritation study in the rabbit showing moderate
eye irritation, (EPA Category II).
iv. A primary dermal irritation study in the rabbit showing
moderate irritation, (EPA Category II).
2. Genotoxicty. Lindane has been subject to a large number of
gentoxicity assays using many different test systems. In vitro Ames/
Salmonella mutagenicity assays were negative for mutagenic potential.
Other point mutations assays in bacteria were also negative. The
induction of chromosomal aberrations was not observed in vivo assays
and in vitro assays were either negative or equivocal. Sister chromatid
exchange and micronucleus assays were negative. Dominant lethal assays
gave variable results.
3. Reproductive and developmental toxicity. Lindane is not
considered to be a reproductive or a developmental toxin. In a 2-
generation reproduction study, the no-observed adverse effect level
(NOAEL) for reproductive and developmental toxicity was 20 ppm. In a
developmental toxicity study, the rat maternal NOAEL and the
developmental NOAEL were 5 mg/kg/day. The developmental NOAEL for the
rabbit was 10 mg/kg/day while the maternal NOAEL was less than 5 mg/kg/
day based on reduced food consumption, reduced weight gain, slight
tachypnea and lethargy.
4. Subchronic toxicity. Ninety-day feeding studies were conducted
in mice and rats with lindane. The NOAEL for the mouse study was
greater than 10 ppm highest dose tested (HDT), for the rat study, the
NOAEL was 10 ppm (0.75 mg/kg/day). Renal effects observed were related
to a2u-globulin and are not relevant to human safety.
Hepatocellular hypertrophy and neurotoxicity were observed at the
higher dose levels. A 14 week inhalation study in mice had a NOAEL 0.3
mg/cubic meter. In a 90-day inhalation study in rats, the NOAEL was 0.6
mg/cubic meter. Ninety-day dermal toxicity studies have been conducted
in rats and rabbits. In both species, the NOAELs were 10 milligrams per
kilograms bodyweight per day (mg/kg bw/day).
5. Chronic toxicity. A 2-year feeding study was conducted in dogs
with lindane. The NOAEL was for this study 50 ppm. In a 2-year feeding
study in rats, hepatocellular hypertrophy and renal effects related to
a2u-globulin were observed above the NOAEL of 0.7 (males)
and 0.8 (females) mg/kg bw/day. Carcinogenicity - Lindane is not
carcinogenic to rats. A 2-year combined chronic toxicity/oncogenicity
study in the rat was negative for carcinogenicity and had a chronic
toxicity NOAEL of 10 ppm (0.47 mg/kg bw/day) based on a slight increase
in mortality and effects on the liver. A total of 8 mouse oncogenicity
studies have been conducted in several strains of mice. The results of
these studies have been variable and none of the studies are considered
by the Agency to be adequate for a cancer risk assessment. A ninth
study is in progress.
6. Animal metabolism. The metabolism of lindane has been thoroughly
investigated. Lindane does not appear to bioaccumulate in tissues.
Lindane is rapidly absorbed and metabolized. The metabolism of lindane
occurs via several different pathways. Major routes of metabolism
include stepwise elimination of chlorines and conjuations with sulfates
and glucuronides. Another pathway is via the formation of mercapurates.
7. Metabolite toxicology. Dietary residues are comprised of lindane
and a variety of metabolites. The dietary residues are qualitatively
the same as those formed in the rat and have thus been bioassayed in
the available toxicity studies. These metabolites are not considered to
present a significant toxicological risk.
8. Endocrine disruption. There was no evidence that exposure to
lindane had any effect on reproduction, fertility or mating indices,
development or maturation of embryos, or development, growth and
survival of offspring in the battery of short-term, chronic,
[[Page 46193]]
reproductive and, developmental mammalian, avian and aquatic studies
conducted. There were no gross or microscopic pathologic effects in
endocrine organs or endocrine-sensitive tissues, or in any reproductive
organs, tissues or endpoints that were considered related to exposure
to lindane. There is negligible risk of endocrine disruption in humans
or wildlife as a result of these proposed uses.
C. Aggregate Exposure
1. Dietary exposure--i. Food. Estimates of dietary exposure to
residues of lindane from the proposed uses are extremely low. A
reference dose (RfD) of 0.0047 was established by EPA based upon a 100-
fold uncertainty factor and the NOAEL in the chronic rat study. Maximum
dietary residues from the requested uses result in an exposure that is
less than 2% of the reference dose (RfD) for children 1-6 years, the
most sensitive sub-population.
ii. Drinking water. Given the use pattern (seed treatment) strong
soil binding characteristics and low soil mobility of lindane, the risk
of significant ground and surface water contamination and exposure via
drinking water is considered to be negligible.
2. Non-dietary exposure. There are no currently registered
pesticidal uses of lindane that would result in non-dietary exposure.
D. Cumulative Effects
Lindane falls into the common category of chlorinated hydrocarbon
insecticides however, there is no information to suggest that lindane
has a common mechanism of mammalian toxicity with any other pesticide.
It is not appropriate to combine exposures in this case.
E. Safety Determination
1. U.S. population. As presented above, the exposure of the U.S.
general population to lindane is low, and the risks, based on
comparisons to the reference dose, are negligible. Margins of safety
are very large.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of lindane, CIEL
considered data from developmental toxicity studies in the rat, and
rabbit and a 2-generation reproduction study in rats. No developmental
or reproductive effects were observed up in the absence of parental
toxicity in any of the three studies. Using the same conservative
assumptions that were made previously for the dietary exposure analysis
for the U.S. general population, the percent of the RfD utilized by
pre-adult sub-populations is less than 2%. CIEL concludes that there is
a reasonable certainty that no harm will result to infants and children
from aggregate exposure to lindane residues.
F. International Tolerances
International maximum residue levels (MRLs) have been established
for aproximately 30 commodities. The MRL values for commodities
represented in this petition include; 2 ppm on head lettuce and
spinach, 1 ppm on kohlrabi and radish, and 0.5 ppm on brussels sprouts,
cabbage, cauliflower, and cereal grain.
2. K-I Chemical U.S.A. Inc.
PP 8F4941
EPA has received a pesticide petition (8F4941) from K-I Chemical
U.S.A. Inc., Westchester Financial Center, 11 Martine Avenue, 9th
Floor, White Plains, NY, 10606 proposing, pursuant to section 408(d) of
the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to
amend 40 CFR part 180 by establishing a tolerance for residues of
prohexadione calcium (cyclohexanecarboxylic acid, 3, 5-dioxo-4-(1-
oxopropyl)-, ion(1-), calcium, calcium salt) in or on the raw
agricultural commodity peanut nutmeat at 1.0, peanut hay at 0.6, pome
fruit at 3.0, and cattle meat byproduct (kidney) at 0.1 parts per
million (ppm). EPA has determined that the petition contains data or
information regarding the elements set forth in section 408(d)(2) of
the FFDCA; however, EPA has not fully evaluated the sufficiency of the
submitted data at this time or whether the data supports granting of
the petition. Additional data may be needed before EPA rules on the
petition.
In the Federal Register of August 5, 1998 (63 FR 41828) (FRL-5799-
6) EPA issued a notice of filing of pesticide petition 8F4941 from K-I
Chemical U.S.A. Inc. at the above address proposing to amend 40 CFR
part 180 by establishing tolerances for residues of prohexadione
calcium in or on the raw agricultural commodities (RAC) peanut nutmeat
and hay at 0.8 and 0.4 ppm respectively. EPA has received an amendment
to PP 8F4941 from K-I Chemical U.S.A. Inc., proposing to amend the
earlier petition by increasing the tolerances for residues on peanut
nutmeat and hay, and by proposing to amend 40 CFR part 180 by
establishing tolerances on pome fruit and cattle meat byproducts. This
notice contains information submitted in addition to that contained in
the August 5, 1998 notice.
A. Residue Chemistry
1. Plant metabolism. The metabolism in plants (peanuts and apples)
and animals (goats and poultry) is adequately understood.
2. Analytical method. The proposed analytical method involves
homogenization, extraction, filtration, partition and cleanup,
methylation and analysis by a gas chromatography system with a mass
selective detector. The limit of quantitation (LOQ) is 0.05 ppm.
3. Magnitude of residues. Twelve peanut trials were conducted with
prohexadione calcium in the principle peanut growing regions of the
country (NC, SC, GA, AL, FL, OK, TX). Prohexadione calcium was applied
to peanuts three times at the rate of 0.125 lbs active ingredient acre
(ai/A). Peanut hay and nutmeat were analyzed for residues of
prohexadione (free acid). Prohexadione residues in the nutmeat ranged
from < 0.05="" to="" 0.30="" ppm.="" residues="" in="" hay="" ranged="" from="">< 0.05="" to="" 0.26="" ppm.="" the="" residue="" values="" in="" this="" study="" were="" reported="" as="" prohexadione="" free="" acid.="" the="" highest="" residue="" values="" for="" peanut="" nutmeat="" and="" hay="" were="" converted="" to="" prohexadione="" calcium="" equivalents="" for="" the="" tolerance="" expression.="" therefore,="" the="" proposed="" tolerance="" for="" prohexadione="" calcium="" in/on="" peanut="" nutmeat="" is="" 1.0="" ppm="" based="" on="" the="" conversion="" of="" the="" highest="" peanut="" nutmeat="" raw="" agricultural="" commodities="" (rac)="" ppm="" for="" prohexadione="" (0.795="" ppm)="" to="" prohexadione="" calcium="" equivalents="" (0.895="" ppm).="" the="" proposed="" tolerance="" for="" prohexadione="" calcium="" in/on="" peanut="" hay="" is="" 0.6="" ppm="" and="" it="" is="" based="" on="" the="" conversion="" the="" highest="" peanut="" hay="" rac="" ppm="" for="" prohexadione="" (0.457="" ppm)="" to="" prohexadione="" calcium="" equivalents="" (0.539="" ppm).="" a="" study="" was="" conducted="" to="" determine="" the="" level="" of="" prohexadione="" calcium="" derived="" residues="" in="" or="" on="" processed="" commodities.="" peanut="" samples="" treated="" at="" an="" exaggerated="" rate="" were="" processed="" into="" peanut="" meal="" and="" refined="" oil.="" peanut="" nutmeat="" and="" processed="" commodities="" were="" analyzed="" for="" prohexadione.="" residues="" in="" the="" meal="" were="" less="" than="" in="" the="" nuts,="" and="" no="" residues="" were="" detected="" in="" the="" refined="" oil.="" therefore,="" there="" was="" no="" concentration="" of="" prohexadione="" residues="" in="" processed="" commodities.="" twenty="" apple="" trials="" were="" conducted="" with="" prohexadione="" calcium="" in="" the="" principle="" apple="" growing="" regions="" of="" the="" country="" (ny,="" pa,="" nc,="" va,="" mi,="" wi,="" co,="" ut,="" ca,="" wa,="" id,="" and="" or)="" in="" order="" to="" determine="" the="" magnitude="" of="" prohexadione="" residues="" in/on="" apples.="" [[page="" 46194]]="" apple="" trees="" received="" two="" foliar="" applications="" of="" prohexadione="" calcium="" with="" a="" 21="" day="" interval="" between="" each="" application="" and="" the="" second="" application="" was="" made="" 45="" days="" prior="" to="" harvest="" (45="" day="" phi).="" the="" target="" rate="" for="" each="" application="" was="" 0.85="" lbs="" a.i./a="" and="" a="" maximum="" seasonal="" application="" rate="" of="" 1.7="" lbs="" a.i./a.="" prohexadione="" residues="" in="" apples="" ranged="" from="">< 0.05="" ppm="" to="" 2.23="" ppm.="" the="" residue="" values="" in="" this="" study="" were="" reported="" as="" prohexadione="" free="" acid.="" the="" highest="" apple="" rac="" ppm="" for="" prohexadione="" (2.23="" ppm)="" when="" converted="" to="" prohexadione="" calcium="" equivalents="" is="" 2.63="" ppm.="" apple="" samples="" treated="" with="" prohexadione="" calcium="" at="" an="" exaggerated="" rate="" were="" processed="" according="" to="" commercial="" practices="" into="" washed="" apples,="" wet="" pomace,="" and="" fresh="" juice.="" samples="" of="" unwashed="" apples,="" washed="" apples,="" wet="" pomace,="" and="" juice="" were="" analyzed="" for="" residues="" of="" prohexadione.="" residues="" of="" prohexadione="" in="" the="" washed="" apples,="" pomace="" and="" juice="" were="" less="" than="" in="" the="" unwashed="" whole="" fruit.="" therefore,="" there="" is="" no="" concentration="" of="" prohexadione="" residues="" in="" the="" processed="" commodities="" and="" separate="" tolerances="" for="" processed="" fractions="" are="" not="" necessary.="" eight="" pear="" trials="" were="" conducted="" with="" prohexadione="" calcium="" in="" the="" principle="" pear="" growing="" regions="" of="" the="" united="" states="" (ny,="" ca,="" wa,="" id,="" and="" or)="" to="" determine="" the="" magnitude="" of="" prohexadione="" calcium="" residues="" in/="" on="" pear="" raw="" agricultural="" commodity.="" pear="" trees="" received="" one="" foliar="" application="" of="" prohexadione="" calcium="" at="" an="" application="" rate="" of="" 1.7="" lbs="" a.i./a.="" pears="" were="" harvested="" 45="" days="" after="" the="" application="" (45="" day="" phi).="" prohexadione="" calcium="" residues="" in="" pears="" ranged="" from="" 0.220="" ppm="" to="" 0.985="" ppm.="" b.="" toxicological="" profile="" 1.="" acute="" toxicity.="" based="" on="" available="" acute="" toxicity="" data="" prohexadione="" calcium="" does="" not="" pose="" any="" acute="" toxicity="" risks.="" the="" acute="" toxicity="" studies="" place="" technical="" prohexadione="" calcium="" and="" its="" formulated="" end-use="" products="" in="" acute="" toxicity="" category="" iii="" for="" acute="" dermal;="" and="" in="" acute="" toxicity="" category="" iv="" for="" acute="" oral,="" acute="" inhalation,="" eye="" irritation,="" and="" skin="" irritation="" and="" the="" technical="" material="" is="" not="" a="" skin="" sensitizer.="" 2.="" genotoxicty.="" ames="" test="" (1="" study;="" point="" mutation):="" negative;="" in="" vitro="" v79="" cells="" ch/hgprt="" locus="" mammalian="" cell="" mutation="" assay="" (1="" study;="" point="" mutation):="" negative;="" in="" vitro="" cho="" cytogenetic="" assay="" (1="" study;="" chromosome="" damage):="" negative;="" in="" vivo="" mouse="" micronucleus="" (1="" study;="" chromosome="" damage):="" negative;="" in="" vivo="" rat="" bone="" marrow="" cytogenetic="" assay="" (1="" study;="" chromosomal="" damage):="" negative;="" rec="" assay="" (1="" study;="" dna="" damage="" and="" repair):="" negative;="" in="" vitro="" rat="" hepatocyte="" (1="" study;="" dna="" damage="" and="" repair):="" negative.="" prohexadione="" calcium="" has="" been="" tested="" in="" a="" total="" of="" 7="" genetic="" toxicology="" assays="" consisting="" of="" in="" vitro="" and="" in="" vivo="" studies.="" based="" on="" the="" results="" described="" above,="" it="" can="" be="" stated="" in="" summary="" that="" prohexadione="" calcium="" did="" not="" show="" any="" mutagenic="" activity="" when="" tested="" under="" the="" conditions="" of="" the="" studies="" mentioned="" above.="" therefore,="" prohexadione="" calcium="" does="" not="" pose="" a="" mutagenic="" hazard="" to="" humans.="" 3.="" reproductive="" and="" developmental="" toxicity.="" the="" reproductive="" and="" developmental="" toxicity="" of="" prohexadione="" calcium="" was="" investigated="" in="" a="" 2-="" generation="" rat="" reproduction="" study="" as="" well="" as="" in="" rat="" and="" rabbit="" teratology="" studies.="" the="" 2-generation="" rat="" reproduction="" study="" was="" conducted="" at="" dose="" levels="" of="" 0,="" 500,="" 5,000,="" and="" 50,000="" ppm.="" there="" were="" no="" adverse="" effects="" on="" reproduction="" parameters="" seen="" even="" at="" the="" dose="" level="" of="" 50,000="" ppm="" (5164="" milligram="" kilogram="" bodyweight="" (mg/kg="" bw)="" for="" males="" and="" 5,600="" mg/kg="" bw="" for="" females).="" the="" no-observed="" adverse="" effect="" level="" (noael)="" for="" parental="" systemic="" toxicity="" was="" 500="" ppm="" (48="" mg/kg="" bw="" for="" males="" and="" 51="" mg/kg="" bw="" for="" females)="" and="" the="" noael="" for="" developmental="" toxicity="" was="" 5,000="" ppm="" (270="" mg/kg="" bw="" for="" females).="" stomach="" lesions="" were="" observed="" at="" 5,000="" ppm.="" two="" mid-dose="" males="" and="" two="" males="" and="" one="" female="" of="" the="" high-dose="" from="" the="" fo="" died.="" body="" weight="" and="" food="" consumption="" changes="" and="" slight="" transient="" reduction="" in="" offspring="" growth="" were="" noted="" at="" 50,000="" ppm.="" no="" impairment="" of="" reproductive="" function="" was="" observed="" at="" any="" of="" the="" dose="" levels="" tested.="" prohexadione="" calcium="" had="" no="" teratogenic="" potential="" at="" dose="" levels="" as="" high="" as="" 1,000="" mg/kg="" bw="" in="" the="" rat="" and="" 350="" mg/kg="" bw="" in="" the="" rabbit.="" the="" noael="" for="" maternal="" toxicity="" in="" the="" teratogenicity="" studies="" is="" 100="" mg/kg="" bw="" (rabbit)="" and="" 1000="" mg/kg="" bw="" (rat),="" and="" the="" noael="" for="" fetotoxicity="" in="" the="" teratogenicity="" studies="" is="" 350="" mg/kg="" bw="" (rabbit)="" and="" 1,000="" mg/kg="" bw="" (rat).="" the="" reproductive="" and="" developmental="" studies="" are="" summarized="" below.="" a="" developmental="" study="" was="" conducted="" via="" oral="" gavage="" in="" rats="" at="" dose="" levels="" of="" 0,="" 100,="" 300,="" and="" 1,000="" highest="" dose="" tested="" (hdt)="" mg/kg="" bw.="" the="" noael="" for="" developmental="" and="" maternal="" toxicity="" was="" 1,000="" mg/kg="" bw,="" the="" hdt.="" this="" was="" based="" on="" the="" fact="" that="" there="" were="" no="" signs="" of="" maternal="" toxicity,="" fetotoxicity="" or="" teratogenic="" effects.="" a="" developmental="" study="" was="" conducted="" via="" oral="" gavage="" in="" rabbits="" at="" dose="" levels="" of="" 0,="" 40,="" 200,="" and="" 750="" hdt="" mg/kg="" bw.="" the="" noael="" for="" development="" toxicity="" was="" 40="" mg/kg="" bw="" and="" the="" noael="" for="" maternal="" toxicity="" was="" 40="" mg/kg="" bw="" based="" on="" the="" following="" findings.="" toxicity="" in="" the="" form="" of="" maternal="" mortality="" with="" values="" 16/20="" and="" 4/20="" was="" excessive="" in="" the="" mid-="" and="" high-dose="" group,="" respectively.="" fetal="" deaths="" also="" occurred.="" dose="" levels="" believed="" to="" exceed="" maximum="" tolerance="" dose="" (mtd);="" noaels="" for="" maternal="" and="" developmental="" effects="" are="" not="" considered="" reliable="" and="" useful="" for="" risk="" characterization.="" no="" teratogenic="" effects="" were="" noted="" in="" this="" study.="" an="" additional="" teratology="" study="" in="" the="" same="" strain="" of="" rabbits="" was="" conducted="" at="" dose="" levels="" of="" 0,="" 30,="" 75,="" and="" 150="" mg/kg="" bw.="" the="" noael="" for="" development="" toxicity="" was="" 150="" mg/kg="" bw="" and="" the="" noael="" for="" maternal="" toxicity="" was="" 30="" mg/kg="" bw="" based="" on="" the="" following="" findings.="" one="" low-,="" two="" mid-,="" and="" three="" high-dose="" animals="" died="" prior="" to="" day="" 29,="" however,="" at="" the="" high="" dose="" group="" one="" died="" of="" gavage="" error="" and="" another="" pneumonia,="" and="" the="" reason="" for="" the="" other="" deaths="" could="" not="" be="" determined.="" no="" teratogenic="" or="" fetoxtoxic="" effects="" were="" noted="" in="" this="" study.="" an="" oral="" range-finding="" gavage="" teratology="" study="" in="" the="" same="" strain="" of="" rabbits="" (5="" animals/dose="" level)="" was="" conducted="" in="" another="" independent="" laboratory.="" the="" dose="" levels="" selected="" were="" 0,="" 20,="" 100,="" 250,="" 500,="" and="" 1,000="" mg/kg="" bw.="" this="" range="" finding="" study="" was="" conducted="" with="" a="" limited="" number="" of="" animals="" and="" a="" limited="" scope="" of="" examination.="" based="" on="" these="" results="" the="" dose="" levels="" selected="" for="" the="" main="" study="" at="" this="" independent="" laboratory="" were="" 0,="" 30,="" 100,="" and="" 350="" mg/kg="" bw.="" the="" noael="" for="" development="" toxicity="" was="" 350="" mg/kg="" bw="" and="" the="" noael="" for="" maternal="" toxicity="" was="" 100="" mg/kg="" bw="" based="" on="" the="" following="" findings.="" at="" the="" 350="" mg/kg="" bw="" dose="" group="" transient="" bw="" decreases="" and="" two="" abortions="" were="" observed.="" no="" teratogenic="" or="" fetotoxic="" effects="" were="" noted="" in="" this="" study.="" conclusions="" from="" teratology="" studies.="" more="" than="" one="" definitive="" rabbit="" teratology="" study="" was="" conducted="" because="" issues="" associated="" with="" exceeding="" the="" mtd="" in="" the="" first="" study="" and="" spurious="" deaths,="" apparently="" not="" compound-related,="" in="" the="" second="" study="" confounded="" the="" determination="" of="" a="" noael="" for="" maternal="" toxicity.="" there="" were="" no="" signs="" of="" teratogenic="" or="" fetotoxic="" effects="" in="" any="" study="" other="" than="" the="" first="" definitive="" study="" in="" which="" maternal="" deaths="" above="" the="" mtd="" apparently="" occurred.="" it="" is="" basf's="" and="" k-1="" chemicals'="" opinion="" based="" on="" a="" thorough="" review="" of="" the="" teratology="" studies="" that="" the="" following="" overall="" noaels="" can="" be="" derived="" for="" the="" [[page="" 46195]]="" teratology="" studies:="" -="" noael="" maternal="" toxicity:="" 100="" mg/kg="" bw="" (rabbit)="" and,="" 1,000="" mg/kg="" bw="" (rat).="" -="" noael="" prenatal="" toxicity:="" 350="" mg/kg="" bw="" (rabbit)="" and,="" 1,000="" mg/kg="" bw="" (rat).="" the="" overall="" noael="" of="" 100="" mg/kg="" bw="" for="" maternal="" toxicity="" in="" rabbits="" is="" based="" on="" the="" last="" rabbit="" study,="" and="" is="" based="" on="" reduction="" of="" bw="" gain="" and="" food="" intake="" at="" dose="" levels="" of="" 250="" mg/kg="" bw="" onwards.="" the="" noael="" of="" 350="" mg/kg="" bw="" for="" fetotoxic="" effects="" in="" the="" rabbit="" is="" also="" based="" on="" a="" reduction="" in="" bw="" gain.="" based="" on="" the="" overall="" study="" results,="" it="" is="" concluded="" that="" there="" are="" no="" developmental="" effects="" of="" concern.="" based="" on="" preliminary="" discussions="" with="" epa="" concerning="" the="" rabbit="" teratology="" studies,="" epa="" concluded="" that="" the="" definitive="" noael="" for="" maternal="" toxicity="" considering="" all="" of="" the="" studies="" ranges="" from="" 30="" to="" 100="" mg/kg="" bw.="" agency="" scientists="" further="" stated="" that="" they="" needed="" to="" review="" the="" studies="" in="" detail="" to="" ultimately="" determine="" the="" definitive="" noael="" for="" maternal="" toxicity.="" this="" uncertainty="" associated="" with="" maternal="" toxicity="" in="" the="" rabbit="" teratology="" studies="" does="" not="" impact="" risk="" considerations="" since="" the="" risk="" assessment="" is="" based="" on="" a="" lower="" noael="" (20="" mg/kg="" bw)="" in="" the="" chronic="" dog="" study.="" 4.="" subchronic="" toxicity.="" the="" subchronic="" toxicity="" of="" prohexadione="" calcium="" was="" investigated="" in="" 90-day="" feeding="" studies="" with="" rats,="" mice,="" and="" dogs.="" in="" all="" these="" studies,="" prohexadione="" calcium="" displayed="" low="" toxicity.="" prohexadione="" calcium="" showed="" no="" signs="" of="" neurotoxicity="" in="" a="" 90-day="" neurotoxicity="" rat="" study.="" additionally,="" the="" results="" seen="" in="" four="" week="" feeding="" range-finding="" studies="" for="" rats="" and="" dogs="" were="" similar="" to="" the="" findings="" observed="" in="" the="" 90-day="" studies="" in="" the="" same="" animals.="" 5.="" chronic="" toxicity.="" based="" on="" review="" of="" the="" available="" data,="" the="" reference="" dose="" (rfd)="" for="" prohexadione="" calcium="" will="" be="" based="" on="" a="" 1-year="" feeding="" study="" in="" dogs="" with="" a="" threshold="" noael="" of="" 20="" mg/kg/day.="" using="" an="" uncertainty="" factor="" of="" 100,="" the="" rfd="" is="" calculated="" to="" be="" 0.2="" mg/kg/day.="" the="" following="" are="" summaries="" of="" studies="" submitted="" to="" epa.="" prohexadione="" calcium="" was="" administered="" to="" beagle="" dogs="" at="" dietary="" concentrations="" of="" 0,="" 20,="" 200,="" and="" 1,000="" mg/kg="" bw="" for="" 12="" months.="" slight="" changes="" were="" observed="" for="" hematological="" and="" clinical="" chemical="" parameters="" and="" dilated="" basophilic="" renal="" tubules="" (without="" histopathological="" concurrence)="" at="" dose="" levels="" greater="" than="" 200="" mg/kg="" bw.="" the="" noael="" was="" 20="" mg/kg="" bw="" for="" the="" males="" and="" female="" dogs.="" the="" 24-month="" fisher="" 344="" rat="" chronic/carcinogenic="" feeding="" study="" was="" conducted="" at="" dose="" levels="" of="" 0,="" 400,="" 2,000,="" 10,000,="" and="" 20,000="" ppm="" with="" 80="" male="" and="" 80="" female="" animals="" per="" dose="" group.="" after="" 26,="" 52,="" and="" 78="" weeks,="" 10="" animals="" were="" sacrificed="" (satellite="" groups).="" the="" remaining="" animals="" were="" autopsied="" after="" 104="" weeks="" of="" diet="" administration.="" the="" noael="" for="" chronic="" toxicity="" was="" 2,000="" ppm="" for="" males="" (93.9="" mg/kg="" bw)="" and,="" 2,000="" ppm="" for="" females="" (114="" mg/kg="" bw).="" the="" following="" effects="" were="" observed="" in="" the="" 10,000,="" and="" 20,000="" ppm="" groups:="" (1)="" decreased="" bws="" were="" observed="" in="" both="" male="" and="" female="" rats="" at="" the="" 20,000="" ppm="" dose="" level;="" (2)="" clinical="" chemical="" effects="" (i.e.,="" lower="" potassium,="" bilirubin,="" and="" glucose="" levels)="" were="" observed="" in="" male="" and="" female="" rats="" at="" the="" 20,000="" ppm="" dose="" level,="" in="" the="" 10,000="" ppm="" dose="" level,="" reduced="" glucose="" levels="" were="" only="" seen="" in="" the="" males,="" and="" increased="" albumin/globulin="" ratios,="" sodium,="" chloride="" and="" calcium="" levels="" were="" observed="" only="" in="" the="" females;="" (3)="" increased="" urine="" volumes="" and="" lower="" specific="" gravity="" were="" observed="" in="" the="" mid-high="" and="" high-dose="" groups="" for="" both="" male="" and="" female="" rats;="" (4)="" minor="" changes="" in="" organ="" weights="" were="" noted="" for="" animals="" of="" the="" high="" dose="" group="" only,="" which="" consisted="" of="" increased="" relative="" liver,="" adrenal="" and="" kidney="" weights,="" the="" latter="" also="" absolute="" in="" females="" only,="" at="" week="" 26;="" at="" the="" end="" of="" the="" study="" decreased="" liver="" weights="" and="" increased="" relative="" brain="" and="" testis="" weights="" were="" noted="" and="" these="" changes="" were="" considered="" to="" be="" associated="" with="" the="" decreased="" bws;="" (5)="" macroscopic="" findings="" revealed="" an="" increase="" of="" pituitary="" nodules="" in="" the="" high="" dose="" group="" for="" both="" male="" and="" female="" rats="" which="" was="" not="" confirmed="" histopathologically="" and="" submucosal="" ectopic="" tissue="" in="" the="" glandular="" stomach="" was="" found="" in="" both="" male="" and="" female="" rats="" in="" the="" highest="" dose="" levels="" that="" was="" confirmed="" by="" histopathology="" which="" showed="" an="" increase="" of="" squamous="" cell="" hyperplasia="" in="" males="" and="" of="" basal="" cell="" hyperplasia="" in="" the="" forestomach;="" (6)="" a="" higher="" incidence="" of="" cellular="" hyperplasia="" was="" observed="" in="" the="" thyroid="" in="" the="" mid-high="" and="" high="" dose="" levels="" for="" male="" and="" female="" rats;="" and="" (7)="" no="" increased="" incidence="" of="" neoplasms="" occurred="" at="" any="" dose="" levels="" tested="" in="" this="" study.="" in="" the="" 24-month="" b6c3f1="" mouse="" feeding="" study,="" conducted="" at="" dose="" levels="" of="" 0,="" 400,="" 2,000,="" 20,000,="" and="" 40,000="" ppm="" with="" interim="" sacrifices="" at="" 52="" and="" 78="" weeks,="" prohexadione="" calcium="" was="" negative="" for="" oncogenicity.="" the="" noael="" for="" chronic="" toxicity="" was="" 2,000="" ppm="" for="" males="" (279="" mg/kg="" bw)="" and="" 2,000="" ppm="" for="" females="" (351="" mg/kg="" bw).="" the="" following="" effects="" were="" observed="" in="" the="" 20,000="" and="" 40,000="" ppm="" groups:="" (1)="" statistically="" significant="" decreases="" in="" body="" weights="" were="" observed="" in="" male="" mice="" at="" the="" 20,000="" ppm="" dose="" level="" and="" in="" female="" mice="" at="" the="" 40,000="" ppm="" dose="" level;="" (2)="" a="" variety="" of="" changes="" in="" hematological="" parameters="" were="" noted="" in="" the="" respective="" investigations="" at="" weeks="" 52,="" 78,="" and="" 104,="" however,="" most="" of="" the="" changes="" were="" not="" dose="" related="" or="" consistent="" over="" time;="" (3)="" increased="" absolute="" and/or="" relative="" heart,="" brain,="" testes,="" liver,="" ovary,="" and="" kidney="" weights="" were="" observed="" in="" the="" mid-high="" and="" highest="" dose="" groups="" with="" a="" slight="" progression="" of="" severity="" to="" the="" highest="" dose="" group;="" (4)="" a="" higher="" incidence="" of="" splenomegaly="" was="" observed="" only="" in="" the="" male="" mice="" of="" the="" highest="" dose="" group;="" (5)="" histopathological="" examinations="" revealed="" an="" ectopic="" proliferation="" of="" the="" mucosal="" and="" glandular="" epithelium="" in="" the="" submucosal="" layer="" of="" the="" glandular="" stomach="" in="" male="" and="" female="" mice="" in="" the="" highest="" dose="" group="" tested,="" these="" changes="" were="" assessed="" to="" represent="" heteroplastic,="" ectopic="" proliferative="" changes="" accompanied="" by="" lumen="" dilatation="" and="" cytological="" degeneration;="" (6)="" a="" higher="" incidence="" of="" hyperkeratosis="" of="" the="" forestomach="" was="" observed="" in="" both="" male="" and="" female="" mice="" and="" hyperplasia="" of="" the="" squamous="" epithelium="" of="" the="" forestomach="" of="" female="" male="" mice="" was="" observed="" in="" the="" highest="" dose="" group="" tested;="" (7)="" vacuolic="" changes="" in="" the="" exocrine="" pancreas="" of="" the="" high="" dose="" female="" were="" observed;="" and="" (8)="" no="" increased="" incidence="" of="" neoplasms="" occurred="" at="" any="" dose="" levels="" tested="" in="" this="" study.="" 6.="" endocrine="" disruption.="" no="" specific="" tests="" have="" been="" conducted="" with="" prohexadione="" calcium="" to="" determine="" whether="" the="" chemical="" may="" have="" an="" effect="" in="" humans="" that="" is="" similar="" to="" an="" effect="" produced="" by="" a="" naturally="" occurring="" estrogen="" or="" other="" endocrine="" effects.="" however,="" there="" were="" no="" significant="" findings="" in="" other="" relevant="" toxicity="" studies="" (i.e.,="" subchronic="" and="" chronic="" toxicity,="" teratology="" and="" multi-generation="" reproductive="" studies)="" which="" would="" suggest="" that="" prohexadione="" calcium="" produces="" endocrine="" related="" effects.="" c.="" aggregate="" exposure="" 1.="" dietary="" exposure--i.="" food.="" for="" purposes="" of="" assessing="" the="" potential="" dietary="" exposure,="" k-i="" chemical="" has="" estimated="" aggregate="" exposure="" based="" on="" the="" theoretical="" maximum="" residue="" contribution="" (tmrc)="" from="" the="" proposed="" tolerances="" for="" prohexadione="" calcium="" in/on="" peanut="" nutmeat="" at="" 1.0="" ppm="" and="" apples="" (pome="" fruit)="" at="" 3.0="" ppm.="" a="" maximum="" residue="" level="" of="" 1.0="" ppm="" was="" used="" for="" pears.="" the="" tmrc="" is="" a="" ``worse="" case''="" estimate="" of="" dietary="" exposure="" since="" it="" is="" assumed="" that="" 100%="" of="" all="" crops="" for="" which="" tolerances="" are="" established="" are="" treated="" and="" that="" pesticide="" residues="" are="" always="" found="" at="" the="" tolerance="" levels.="" the="" tmrc="" from="" the="" proposed="" use="" of="" [[page="" 46196]]="" prohexadione="" calcium="" on="" peanuts,="" pears="" and="" apples="" is="" 0.002570="" mg/kg="" bw/="" day="" and="" utilizes="" 1.3%="" of="" the="" rfd="" for="" the="" overall="" u.s.="" population.="" the="" exposure="" of="" the="" most="" highly="" exposed="" subgroup="" in="" the="" population,="" non-="" nursing="" infants="">< 1="" year="" old),="" is="" 0.025758="" mg/kg="" bw/day="" and="" utilizes="" 12.9%="" of="" the="" rfd.="" dietary="" exposure="" to="" residues="" of="" prohexadione="" calcium="" in="" or="" on="" food="" will="" be="" limited="" to="" residues="" on="" peanuts,="" apples="" and="" pears.="" apple="" pomace,="" peanut="" meal="" and="" hay="" are="" fed="" to="" animals;="" thus="" exposure="" of="" humans="" to="" residues="" in="" feed="" items="" might="" result="" if="" such="" residues="" carry="" through="" to="" meat,="" milk,="" poultry,="" or="" eggs.="" however,="" k-i="" chemical="" has="" concluded="" that="" there="" is="" no="" reasonable="" expectation="" that="" measurable="" residues="" of="" prohexadione="" calcium="" will="" occur="" in="" meat,="" milk,="" poultry,="" or="" eggs="" from="" this="" use="" but="" residues="" can="" be="" expected="" to="" be="" slightly="" above="" the="" limit="" of="" quantitation="" for="" cow="" kidney.="" therefore,="" k-i="" chemical="" is="" proposing="" a="" tolerance="" in/on="" cattle="" meat="" byproduct="" (kidney)="" at="" 0.1="" ppm.="" there="" are="" no="" currently="" registered="" uses="" for="" prohexadione="" calcium="" on="" food="" or="" feed="" crops="" in="" the="" u.s.="" and="" thus,="" there="" are="" no="" established="" u.s.="" tolerances.="" the="" following="" table="" summarizes="" the="" mean="" dietary="" exposures="" and="" the="" percents="" of="" rfd="" occupied="" by="" these="" exposures.="" summary="" of="" chronic="" dietary="" exposure="" to="" prohexadione="" calcium="" ----------------------------------------------------------------------------------------------------------------="" dres="" (dietary="" risk="" evaluation="" system)="" group="" -----------------------------------------------------------="" mg/kg="" bw/day="" %="" rfd="" ----------------------------------------------------------------------------------------------------------------="" u.s.="" population.....................................="" 2.6="" 1.3="" nursing="" infants="">< 1="" year="" old)......................="" 19.3="" 9.7="" non-nursing="" infants="">< 1="" year="" old)..................="" 25.8="" 12.9="" children="" 1-6="" years="" old..............................="" 8.7="" 4.4="" children="" 7-12="" years="" old.............................="" 3.5="" 1.8="" ----------------------------------------------------------------------------------------------------------------="" ii.="" drinking="" water.="" based="" on="" studies="" submitted="" to="" epa="" for="" assessment="" of="" environmental="" risk,="" k-i="" chemical="" does="" not="" anticipate="" exposure="" to="" residues="" of="" prohexadione="" calcium="" in="" drinking="" water.="" there="" is="" no="" established="" maximum="" concentration="" level="" (mcl)="" or="" health="" advisory="" level="" (hal)="" for="" prohexadione="" calcium="" under="" the="" safe="" drinking="" water="" act="" (sdwa).="" 2.="" non-dietary="" exposure.="" k-i="" chemical="" has="" not="" estimated="" non-="" occupational="" exposure="" to="" prohexadione="" calcium="" since="" the="" only="" pending="" registration="" is="" limited="" to="" commercial="" crop="" production.="" prohexadione="" calcium="" products="" are="" not="" labeled="" for="" any="" residential="" uses,="" therefore="" eliminating="" the="" potential="" for="" residential="" exposure.="" thus,="" potential="" for="" non-occupational="" exposure="" of="" the="" general="" population="" to="" prohexadione="" calcium="" is="" not="" present.="" d.="" cumulative="" effects="" k-i="" chemical="" is="" aware="" of="" only="" one="" other="" registered="" compound,="" trinexapac-ethyl="" [4-(cyclopropyl-a-hydroxymethylene)-3,5-dioxo-="" cyclohexanecarboxylic="" acid="" ethylester],="" that="" has="" a="" structure="" similar="" to="" prohexadione="" calcium.="" however,="" k-i="" chemical="" has="" no="" information="" that="" would="" indicate="" that="" the="" two="" compounds="" have="" a="" common="" mechanism="" of="" toxicity.="" furthermore,="" trinexapac="" is="" registered="" for="" use="" only="" on="" turf.="" therefore,="" even="" if="" the="" compounds="" were="" considered="" similar="" there="" would="" be="" no="" cumulative="" dietary="" exposure="" issue="" because="" of="" the="" differences="" in="" use="" patterns.="" in="" summary,="" dietary="" exposure="" to="" prohexadione="" calcium="" should="" not="" result="" in="" cumulative="" toxicity="" with="" other="" known="" chemical="" compounds.="" e.="" safety="" determination="" 1.="" u.s.="" population.="" using="" the="" conservative="" exposure="" assumptions="" described="" above="" and="" based="" on="" the="" completeness="" and="" the="" reliability="" of="" the="" toxicity="" data,="" k-i="" chemical="" has="" estimated="" that="" aggregate="" exposure="" to="" prohexadione="" calcium="" will="" utilize="" 1.3%="" of="" the="" rfd="" for="" the="" u.s.="" population.="" k-i="" chemical="" concludes="" that="" there="" is="" a="" reasonable="" certainty="" that="" no="" harm="" will="" result="" from="" the="" aggregate="" exposure="" to="" residues="" of="" prohexadione="" calcium,="" including="" anticipated="" dietary="" exposure="" and="" non-="" occupational="" exposures.="" 2.="" infants="" and="" children--i.="" developmental="" toxicity="" in="" the="" rat.="" a="" developmental="" study="" was="" conducted="" via="" oral="" gavage="" in="" rats="" with="" dosages="" of="" 0,="" 100,="" 300,="" and="" 1,000="" hdt="" mg/kg/day="" with="" a="" noael="" of="" 1,000="" mg/kg/day="" the="" hdt="" for="" developmental="" and="" maternal="" toxicity="" based="" on="" the="" fact="" that="" no="" effects="" were="" observed="" for="" any="" test="" parameter="" measured="" in="" this="" study.="" therefore,="" these="" noael="" values="" are="" significantly="" higher="" than="" the="" noael="" from="" the="" 1-year="" feeding="" study="" in="" dogs="" used="" to="" establish="" the="" rfd.="" ii.="" developmental="" toxicity="" in="" the="" rabbit.="" a="" series="" of="" developmental="" studies="" were="" conducted="" via="" oral="" gavage="" in="" rabbits="" with="" dosages="" ranging="" from="" 0="" to="" 750="" mg/kg/day="" with="" a="" development="" toxicity="" noael="" of="" 350="" mg/kg/="" day="" and="" a="" maternal="" toxicity="" noael="" of="" 100="" mg/kg/day="" based="" on="" bw="" gain="" reductions.="" these="" noael="" values="" are="" higher="" than="" the="" noael="" from="" the="" 1-="" year="" feeding="" study="" in="" dogs="" used="" to="" establish="" the="" rfd.="" iii.="" reproductive="" toxicity.="" a="" 2-generation="" reproduction="" study="" with="" rats="" fed="" dosages="" of="" 0,="" 500,="" 5,000,="" and="" 50,000="" mg/kg/day="" resulted="" in="" a="" reproductive="" noael="" of="" 50,000="" ppm="" (5,300="" mg/kg="" bw/day),="" a="" developmental="" noael="" of="" 5,000="" ppm="" (270="" mg/kg="" bw/day),="" and="" a="" maternal="" toxicity="" noael="" of="" 500="" ppm="" (50="" mg/kg="" bw/day).="" the="" developmental="" noael="" was="" based="" on="" a="" slight,="" transient="" reduction="" in="" offspring="" growth.="" the="" maternal="" noael="" is="" similar="" and="" the="" reproductive="" noael="" is="" significantly="" higher="" (above="" the="" limit="" dose="" of="" 1,000="" mg/kg/day)="" than="" the="" noael="" from="" the="" 1-year="" feeding="" study="" in="" dogs="" used="" to="" establish="" the="" rfd.="" 3.="" reference="" dose.="" since="" developmental="" and="" reproductive="" toxicity="" occurs="" at="" levels="" above="" the="" levels="" shown="" to="" exhibit="" parental="" toxicity="" and="" since="" these="" levels="" are="" significantly="" higher="" than="" those="" used="" to="" calculate="" the="" rfd,="" k-i="" chemical="" believes="" the="" rfd="" of="" 0.20="" mg/kg/day="" (20="" mg/kg/day="" and="" an="" uncertainty="" factor="" of="" 100)="" is="" an="" appropriate="" measure="" of="" safety="" for="" infants="" and="" children.="" dietary="" exposure="" of="" the="" most="" highly="" exposed="" subgroup="" in="" the="" population,="" non-nursing="" infants="">< 1="" year="" old)="" is="" 0.025758="" mg/kg="" bw/="" day.="" this="" accounts="" for="" 12.9%="" of="" the="" rfd.="" there="" are="" no="" residential="" uses="" of="" prohexadione="" calcium="" and="" contamination="" of="" drinking="" water="" is="" extremely="" unlikely.="" in="" addition,="" there="" were="" no="" significant="" findings="" in="" relevant="" toxicity="" studies="" (i.e.,="" subchronic="" and="" chronic="" toxicity,="" teratology="" and="" multi-generation="" reproductive="" studies)="" which="" would="" suggest="" that="" prohexadione="" calcium="" produces="" endocrine="" related="" effects.="" therefore,="" based="" on="" the="" completeness="" and="" reliability="" of="" the="" toxicity="" data="" and="" the="" conservative="" exposure="" assessment,="" k-i="" chemical="" concludes="" that="" there="" is="" a="" [[page="" 46197]]="" reasonable="" certainty="" that="" no="" harm="" will="" result="" to="" infants="" and="" children="" from="" aggregate="" exposure="" to="" the="" residues="" of="" prohexadione="" calcium,="" including="" all="" anticipated="" dietary="" exposure="" and="" all="" other="" non-="" occupational="" exposures.="" f.="" international="" tolerances="" a="" maximum="" residue="" level="" (mrl)="" has="" not="" been="" established="" for="" prohexadione="" calcium="" in="" peanuts,="" apples="" or="" pears="" by="" the="" codex="" alimentarius="" commission.="" [fr="" doc.="" 99-21944="" filed="" 8-23-99;="" 8:45="" am]="" billing="" code="" 6560-50-f="">