[Federal Register Volume 63, Number 150 (Wednesday, August 5, 1998)]
[Notices]
[Pages 41828-41835]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-20768]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-817; FRL-5799-6]
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-817, must
be received on or before September 4, 1998.
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. 119 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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Hoyt Jamerson................. Rm. 268, CM #2, 703- 1921 Jefferson
308-9368, e- Davis Hwy,
mail:[email protected] Arlington, VA
amail.epa.gov.
Cynthia Giles-Parker.......... Rm. 247, CM #2, 703-
305-7740, e-
mail:parker.cynthia@epamai.
Jim Tomopkins................. Rm. 239, CM #2, 703- Do.
305-5697,e-
mail:tompkins.jim@epa.#
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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 support 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-817] (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 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: July 15, 1998.
James Jones,
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
[[Page 41829]]
measurement of the pesticide chemical residues or an explanation of why
no such method is needed.
1. BASF Corporation
PP 6F4695
EPA has received a pesticide petition (PP 6F4695) from BASF
Corporation, Agricultural Products, PO Box 13528, Research Triangle
Park, NC 27709, 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 tolerances for residues of sethoxydim (2-[1-
ethoxyimino]butyl)-5-[2-(ethylthio)propyl]-3-hydroxy-2-cyclohexen-1-
one) and its metabolites containing the 2-cyclohexen-1-one moiety
(calculated as the herbicide) in or on the raw agricultural commodities
(RACs) grapes at 1.0 part per million (ppm), succulent beans at 15.0
ppm, bean forage at 15.0 ppm, soybeans at 16.0 ppm, and raisins at 2.0
ppm. BASF Corporation also requested that the established tolerances
for raisin waste at 1.0 ppm and grape pomace (dry and wet) at 6.0 ppm
be revoked, since they are considered insignificant animal feed
commodities and are no longer of regulatory concern.
PP 4F4075
EPA has received a pesticide petition (PP 4F4075) from BASF
Corporation, 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 tolerances for residues of sethoxydim (2-[1-
ethoxyimino]butyl)-5-[2-(ethylthio)propyl]-3-hydroxy-2-cyclohexen-1-
one) and its metabolites containing the 2-cyclohexen-1-one moiety
(calculated as the herbicide) in or on the raw agricultural commodities
(RACs) rice grain at 0.1 ppm, rice straw at 0.5 ppm, rice hulls at 0.2
ppm, and rice bran at 0.2 ppm.
2. Interregional Research Project Number 4 (IR-4)
PP 6E4753, 6E4725, 6E4698, 6E4697
EPA has received pesticide petitions (PP 6E4753, 6E4725, 6E4698,
and 6E4697) from IR-4, New Jersey Agricultural Experiment Station,
Rutgers University, New Brunswick, New Jersey 08903 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 tolerances for
residues of the herbicide sethoxydim (2-[1-(ethoxyimino)butyl]-5-[2-
(ethylthio)propyl]-3-hydoxy-2-cyclohexen-1-one) and its metabolites
containing the 2-cyclohexen-1-one moiety (calculated as the herbicide))
in or on the raw agricultural commodities as follows:
PP 6E4753
Petition submitted on behalf of Agricultural Experiment Stations of
Oregon and Washington proposing tolerances for the leafy vegetable
(except Brassica) crop group at 4.0 ppm and cilantro at 4.0 ppm. The
petitioner also requested that established tolerances for combined
residues of sethoxydim and its metabolites on celery at 1.0 ppm, head
lettuce at 1.0 ppm, leaf lettuce at 2.0 ppm, spinach at 4.0 ppm, and
endive (escarole) at 2.0 ppm be removed, since these commodities are
members of the leafy vegetable (except Brassica) crop group.
PP 6E4725
Petition submitted on behalf of the Agricultural Experiment
Stations of California, Florida, Georgia, Illinois, Michigan, New York,
Oklahoma, Oregon, South Carolina, Virginia, Washington, and Wisconsin
proposing tolerances for the tuberous and corm vegetable subgroup at
4.0 ppm and garden beet at 1.0 ppm. The petitioner also requested that
established tolerances for combined residues of sethoxydim and its
metabolites in or on potato and sweet potato at 4.0 ppm be removed,
since these commodities are members to the tuberous and corm vegetable
subgroup.
PP 6E4698
Petition submitted on behalf of the Agricultural Experiment Station
of California proposing that the existing tolerance for combined
residues of sethoxydim and its metabolites in or on artichoke be
increased from 3.0 ppm to 5.0 ppm
PP 6E4697
Petition submitted on behalf of the Agricultural Experiment Station
of Oregon proposing a tolerance for the caneberry crop subgoup at 5.0
ppm. The petitioner also requested that the established tolerance for
combined residues of sethoxydim and its metabolites in or on raspberry
at 5.0 ppm be removed, since the caneberry subgroup includes raspberry.
EPA has determined that the petitions contain data or information
regarding the elements set forth in section 408(d)(2) of the FFDCA;
however, EPA has not fully evaluated the sufficiency of the submitted
data at this time or whether the data support granting of the
petitions. Additional data may be needed before EPA rules on the
petitions. This notice includes a summary of the petitions prepared by
BASF Corporation, Agricultural Products, P.O. Box 13528, Research
Triangle Park, NC 27709.
A. Residue Chemistry
1. Plant metabolism. The qualitative nature of the residues in
plants and animals is adequately understood for the purposes of
registration. Analytical method for detecting levels of sethoxydim and
its metabolites in or on food with a limit of detection that allows
monitoring of food with residues at or above the levels set in these
tolerances were submitted to EPA.
2. Analytical method. The proposed analytical method involves
extraction, partition, and clean-up. Samples are then analyzed by gas
chromatography with sulfur-specific flame photometric detection. The
limit of quantitation is 0.05 ppm.
B. Toxicological Profile
1. Acute toxicity. Based on the available acute toxicity data, BASF
concludes that sethoxydim does not pose any acute dietary risks. A
summary of the acute toxicity studies follows.
i. Acute oral toxicity--Rat. Toxicity Category III; lethal dose
(LD)50=3125 milligram/kilogram (mg/kg) (male), 2676 mg/kg
(female)
ii. Acute dermal toxicity-Rat. Toxicity Category III;
LD505,000 mg/kg (male and female)
iii. Acute inhalation toxicity--Rat. Toxicity Category III; lethal
concentration (LC)50 (4-hour)=6.03 mg/liter (L) (male), 6.28
mg/L (female)
iv. Primary eye irritation-rabbit. Toxicity Category IV; no
irritation
v. Primary dermal irritation-rabbit. Toxicity Category IV; no
irritation
vi. Dermal sensitization- guinea pig. Waived because no
sensitization was seen in guinea pigs dosed with the end-use product
Poast (18% active ingedient).
2. Genotoxicity. Ames assays were negative for gene mutation in
Salmonella typhimurium strains TA98, TA100, TA1535, and TA 1537, with
and without metabolic activity.
A Chinese hamster bone marrow cytogenetic assay was negative for
structural chromosomal aberrations at doses up to 5,000 mg/kg in
Chinese hamster bone marrow cells in vivo.
Recombinant assays and forward mutations tests in Bacillus
subtilis, Escherichia coli, and S typhimurium were all negative for
genotoxic effects at concentrations of greater than or equal to 100%.
3. Reproductive and developmental toxicity. A developmental
toxicity study
[[Page 41830]]
in rats fed dosages of 0, 50, 180, 650, and 1,000 mg/kg/day with a
maternal no-observed adverse effect level (NOAEL) of 180 mg/kg/day and
a maternal lowest effect level (LEL) of 650 mg/kg/day (irregular gait,
decreased activity, excessive salivation, and anogenital staining); and
a developmental NOAEL of 180 mg/kg/day, and a developmental LEL of 650
milligram/killograms/day (mg/kg/day) (21 to 22 percent decrease in
fetal weights, filamentous tail, and lack of tail due to the absence of
sacral and/or caudal vertebrae, and delayed ossification in the hyoids,
vertebral centrum and/or transverse processes, sternebrae and/or
metatarsals, and pubes).
A developmental toxicity study in rabbits fed doses of 0, 80, 160,
320, and 400 mg/kg/day with a maternal no-observed effect level (NOEL)
of 320 mg/kg/day and a maternal LOEL of 400 mg/kg/day (37% reduction in
body weight gain without significant differences in group mean body
weights and decreased food consumption during dosing); and a
developmental NOEL greater than 400 mg/kg/day (highest dose tested).
A 2-generation reproduction study with rats fed diets containing 0,
150, 600, and 3,000 ppm (approximately 0, 7.5, 30, and 150 mg/kg/day)
with no reproductive effects observed under the conditions of the
study.
4. Subchronic toxicity. A 21-day dermal study in rabbits with a
NOAEL of 1,000 mg/kg/day limit dose (LD). The only dose-
related finding was slight epidermal hyperplasia at the dosing site in
nearly all males and females dosed at 1,000 mg/kg/day. This was
probably an adaptive response.
5. Chronic toxicity. A summary of the chronic toxicity studies
follows.
A 1-year feeding study with dogs fed diets containing 0, 8.86/9.41,
17.5/19.9, and 110/129 mg/kg/day (males/females) with a NOEL of 8.86/
9.41 mg/kg/day (males/females) based on equivocal anemia in male dogs
at the 17.5-mg/kg/day dose level.
A 2-year chronic feeding/carcinogenicity study with mice fed diets
containing 0, 40, 120, 360, and 1,080 ppm (equivalent to 0, 6, 18, 54,
and 162 mg/kg/day) with a systemic NOEL of 120 ppm (18 mg/kg/day) based
on non-neoplastic liver lesions in male mice at the 360-ppm (54 mg/kg/
day) dose level. There were no carcinogenic effects observed under the
conditions of the study. The maximum tolerated dose (MTD) was not
achieved in female mice.
A 2-year chronic feeding/carcinogenic study with rats fed diets
containing 0, 2, 6, and 18 mg/kg/day with a systemic NOEL greater than
or equal to 18 mg/kg/day HDT. There were no carcinogenic effects
observed under the conditions of the study. This study was reviewed
under current guidelines and was found to be unacceptable because the
doses used were insufficient to induce a toxic response and a MTD was
not achieved.
A second chronic feeding/carcinogenic study with rats fed diets
containing 0, 360, and 1,080 ppm (equivalent to 18.2/23.0, and 55.9/
71.8 mg/kg/day (males/females). The dose levels were too low to elicit
a toxic response in the test animals and failed to achieve a MTD or
define a LEL. Slight decreases in body weight in rats at the 1,080-ppm
dose level, although not biologically significant, support a free-
standing NOAEL of 1,080 ppm (55.9/71.8 mg/kg/day (males/females)).
There were no carcinogenic effects observed under the conditions of the
study.
In a rat metabolism study, excretion was extremely rapid and tissue
accumulation was negligible.
6. Metabolite toxicology. As a condition to registration, BASF had
been asked to submit additional toxicology studies for the
hydroxymetabolites of sethoxydim. BASF's recommendation is to use the
most abundant metabolite, 5-OH-MSO2, as surrogate for all metabolites.
Based on these data, it was concluded that the toxicological potency of
the plant hydroxymetabolites is likely to be equal to or less than that
of the parent compound. The tolerance expression for sethoxydim
measures sethoxydim and its metabolites containing the 2-cyclohexen-1-
one moiety, measured as parent. Hence, the hydroxymetabolites are
figured into all tolerance calculations.
7. Endocrine disruption. No specific tests have been performed with
sethoxydim to determine whether the chemical may have an effect in
humans that is similar to an effect produced by naturally-occurring
estrogen or other endocrine effects.
C. Aggregate Exposure
1. Dietary exposure. For purposes of assessing the potential
dietary exposure, BASF has estimated aggregate exposure based on the
Theoretical Maximum Residue Contribution (TMRC) from existing and
pending tolerances for sethoxydim. (The TMRC is a ``worst 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 at the tolerance levels.) The TMRC from existing
tolerances for the overall US population is estimated at approximately
35% of the RfD. Dietary exposure to residues of sethoxydim in or on
food from these proposed tolerances increases the TMRC by approximately
8% of the RfD for the overall US population. BASF estimates indicate
that dietary exposure will not exceed the RfD for any population
subgroup for which EPA has data. This exposure assessment relies on
very conservative assumptions that 100% of crops will contain
sethoxydim residues and those residues would be at the level of the
tolerance which results in an overestimate of human exposure.
2. Food-other- exposure. Other potential sources of exposure of the
general population to residues of pesticides are residues in drinking
water and exposure from non-occupational sources. Based on the
available studies submitted to EPA for assessment of environmental
risk, BASF does not anticipate exposure to residues of sethoxydim in
drinking water. There is no established Maximum Concentration Level
(MCL) for residues of sethoxydim in drinking water under the Safe
Drinking Water Act (SDWA).
BASF has not estimated non-occupational exposure for sethoxydim.
Sethoxydim is labeled for use by homeowners on and around the following
use sites: flowers, evergreens, shrubs, trees, fruits, vegetables,
ornamental groundcovers, and bedding plants. Hence, the potential for
non-occupational exposure to the general population exists. However,
these use sites do not appreciably increase exposure. Protective
clothing requirements, including the use of gloves, adequately protect
homeowners when applying the product. The product may only be applied
through hose-end sprayers or tank sprayers as a 0.14% solution.
Sethoxydim is not a volatile compound so inhalation exposure during and
after application would be negligible. Dermal exposure would be minimal
in light of the protective clothing and the low application rate. Post-
treatment (re-entry) exposure would be negligible for these use sites
as contact with treated surfaces would be low. Dietary risks from
treated food crops are already adequately regulated by the established
tolerances. BASF concludes that the potential for non-occupational
exposure to the general population is insignificant.
D. Cumulative Effects
BASF also considered the potential for cumulative effects of
sethoxydim and other substances that have a common mechanism of
toxicity. BASF is aware of one other active ingredient which is
structurally similar, clethodim. However, BASF believes that
[[Page 41831]]
consideration of a common mechanism of toxicity is not appropriate at
this time. BASF does not have any reliable information to indicate that
toxic effects produced by sethoxydim would be cumulative with clethodim
or any other chemical; thus BASF is considering only the potential
risks of sethoxydim in its exposure assessment.
E. Safety Determination
1. U.S. population. Reference Dose (RfD) using the conservative
exposure assumptions described above, BASF has estimated that aggregate
exposure to sethoxydim will utilize 43% of the RfD for the U.S.
population. EPA generally has no concern for exposures below 100% of
the RfD. Therefore, based on the completeness and reliability of the
toxicity data, and the conservative exposure assessment, BASF concludes
that there is a reasonable certainty that no harm will result from
aggregate exposure to residues of sethoxydim, including all anticipated
dietary exposure and all other non-occupational exposures.
2. Infants and children--i. developmental toxicity. Developmental
toxicity was observed in a developmental toxicity study using rats but
was not seen in a developmental toxicity study using rabbits. In the
developmental toxicity study in rats a maternal NOAEL of 180 mg/kg/day
and a maternal LEL of 650 mg/kg/day (irregular gait, decreased
activity, excessive salivation, and anogenital staining) was
determined. A developmental NOAEL of 180 mg/kg/day and a developmental
LEL of 650 mg/kg/day (21 to 22% decrease in fetal weights, filamentous
tail and lack of tail due to the absence of sacral and/or caudal
vertebrae, and delayed ossification in the hyoids, vertebral centrum
and/or transverse processes, sternebrae and/or metatarsals, and pubes).
Since developmental effects were observed only at doses where maternal
toxicity was noted, BASF concludes that the developmental effects
observed are believed to be secondary effects resulting from maternal
stress.
ii. Reproductive toxicity. A 2-generation reproduction study with
rats fed diets containing 0, 150, 600, and 3,000 ppm (approximately 0,
7.5, 30, and 150 mg/kg/day) produced no reproductive effects during the
course of the study. Although the dose levels were insufficient to
elicit a toxic response, the Agency has considered this study usable
for regulatory purposes and has established a free-standing NOEL of
3,000 ppm (approximately 150 mg/kg/day) (ref. Proposed Rule 60 FR
13941).
iii. Reference dose. Based on the demonstrated lack of significant
developmental or reproductive toxicity BASF believes that the RfD used
to assess safety to children should be the same as that for the general
population, 0.09 mg/kg/day. Using the conservative exposure assumptions
described above, BASF has concluded that the most sensitive child
population is that of children ages 1 to 6. BASF calculates the
exposure to this group to be approximately 85% of the RfD for all uses
(including those proposed in this document). Based on the completeness
and reliability of the toxicity data and the conservative exposure
assessment, BASF concludes that there is a reasonable certainty that no
harm will result to infants and children from aggregate exposure to the
residues of sethoxydim, including all anticipated dietary exposure and
all other non-occupational exposures.
F. International Tolerances
A maximum residue level has not been established for sethoxydim on
artichoke, caneberry, leafy vegetables (except Brassica), root and
tuber vegetables, cilantro, grapes, succulent beans, bean forage,
soybeans or raisins by the Codex Alimentarius Commission. Individual
countries have established tolerances on beans ranging from 0.1 to 5.0
ppm and soybeans ranging from 0.05 ppm to 5.0 ppm. No tolerances have
been established for grapes in other countries. The proposed tolerances
for leafy vegetables (except Brassica), cilantro, and root and tuber
vegetables at 4.0 ppm are consistent with the international tolerances
as they fall within the range of established tolerances and reflect the
differences in application parameters and conditions (e.g., application
rate, pre-harvest intervals, and environmental conditions). (Hoyt
Jamerson).
3. K-I Chemical U.S.A., Inc.
PP 8F4941
EPA has received a pesticide petition (PP8F4941) 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, 21 U.S.C. 346a(d), to amend
40 CFR part 180 by establishing a tolerance for residues of
cyclohexanecarboxylic acid, 3, 5-dioxo-4-(1-oxopropyl)-, ion(1-),
calcium, calcium salt in or on the raw agricultural commodity peanut
nutmeat and hay at 0.8 and 0.4 ppm respectively. EPA has determined
that the petition contains data or information regarding the elements
set forth in section 408(d)(2) of the FFDCA; however, EPA has not fully
evaluated the sufficiency of the submitted data at this time or whether
the data supports granting of the petition. Additional data may be
needed before EPA rules on the petition.
A. Residue Chemistry
1. Plant metabolism. The metabolism in plants (peanuts) 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 is 0.05 ppm.
3. Magnitude of residues. 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 3- times at the rate of 0.125 lbs 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.="" a="" study="" was="" conducted="" to="" determine="" the="" level="" of="" prohexadione="" calcium="" derived="" resides="" in="" or="" on="" processed="" commodites.="" the="" proposed="" tolerance="" for="" prohexadione="" calcium="" in/on="" peanut="" nutmeat="" is="" 0.8="" ppm="" and="" it="" is="" calculated="" by="" converting="" the="" highest="" peanut="" nutmeat="" rac="" ppm="" for="" prohexadione="" (0.3="" ppm)="" to="" prohexadione="" calcium="" equivalents="" (0.36="" ppm),="" correcting="" for="" 50%="" storage="" stability="" loss="" (0.72),="" and="" rounding="" up="" to="" 0.8="" ppm.="" the="" proposed="" tolerance="" for="" prohexadione="" calcium="" in/on="" peanut="" hay="" is="" 0.4="" ppm="" and="" it="" is="" calculated="" by="" converting="" the="" highest="" peanut="" hay="" rac="" ppm="" for="" prohexadione="" (0.26="" ppm)="" to="" prohexadione="" calcium="" equivalents="" (0.31="" ppm)="" and="" rounding="" up="" to="" 0.4="" ppm.="" 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.="" 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="" in="" [[page="" 41832]]="" 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-developmental="" toxicity--="" i.="" rat.="" a="" developmental="" study="" was="" conducted="" via="" oral="" gavage="" in="" rats="" with="" dosages="" of="" 0,="" 100,="" 300,="" and="" 1,000="" higest="" dose="" tested="" (hdt)="" mg/kg/="" day="" with="" a="" no-adverse-effect="" level="" (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.="" rabbit.="" a="" developmental="" study="" was="" conducted="" via="" oral="" gavage="" in="" rabbits="" with="" dosages="" of="" 0,="" 40,="" 200,="" and="" 750="" (hdt)="" mg/kg/day="" with="" a="" development="" toxicity="" noael="" of="" 40="" mg/kg/day="" and="" a="" maternal="" toxicity="" noael="" of="" 40="" mg/kg/day="" based="" on="" the="" following:="" (a)="" excessive="" maternal="" mortality="" of="" 4/20="" and="" 16/20="" was="" observed="" in="" the="" 200="" and="" 750="" mg/kg/day="" dose="" levels="" tested,="" respectively;="" (b)="" significant="" weight="" loss="" was="" similarly="" observed="" in="" the="" 200="" and="" 750="" mg/kg/day="" dose="" group="" with="" accompanying="" clinical="" signs;="" (c)="" microscopic="" findings="" in="" the="" 750="" mg/kg/="" day="" dose="" group="" revealed="" stomach="" erosion="" and="" lung="" congestion="" in="" many="" of="" the="" animals="" that="" died;="" (d)="" in="" the="" 40="" mg/kg/day="" dose="" group="" a="" single="" rabbit="" lost="" its="" righting="" reflex="" and="" showed="" splayed="" limbs="" on="" day="" 25="" due="" to="" a="" back="" injury="" it="" sustained;="" and="" (e)="" no="" teratogenic="" effects,="" as="" well="" as="" incidence="" of="" malformations="" and="" developmental="" effects="" were="" observed="" at="" any="" dose="" level="" tested="" (dlt),="" however="" due="" to="" the="" mortality="" seen="" in="" the="" 200="" and="" 750="" mg/kg/day="" dose="" groups="" and="" limited="" number="" of="" fetuses="" produced="" at="" these="" dose="" levels,="" an="" additional="" study="" was="" performed.="" (it="" should="" be="" noted="" that="" a="" oral="" gavage="" range-finding="" study="" of="" six="" rabbits="" per="" dose="" level="" was="" performed="" at="" dose="" levels="" of="" 0,="" 100,="" 250,="" 500,="" and="" 1,000="" mg/kg/day,="" in="" which="" similar="" excessive="" mortality="" was="" observed="" in="" the="" 500="" and="" 1,000="" mg/kg/day="" dose="" groups="" test="" as="" shown="" above.="" additionally,="" body="" weight="" was="" affected="" for="" all="" dose="" groups="" tested="" and="" the="" clinical="" signs="" and="" macroscopic="" findings="" observed="" in="" the="" study="" discussed="" above="" were="" also="" noted="" in="" the="" range-finding="" study.="" however,="" body="" weight="" gain="" (bwg)="" was="" not="" affected="" in="" the="" lowest="" dose="" group="" tested.)="" the="" doses="" selected="" for="" the="" additional="" teratology="" study="" in="" the="" same="" strain="" of="" rabbits="" were="" 0,="" 30,75,="" and="" 150="" mg/kg/day="" with="" a="" development="" toxicity="" noael="" of="" 150="" mg/kg/day="" and="" a="" maternal="" toxicity="" noael="" that="" could="" not="" be="" determined="" in="" this="" study="" based="" on="" the="" following:="" (a)="" one="" low-,="" two="" mid-,="" and="" three="" high-dose="" animals="" died="" prior="" to="" cesarean="" section="" on="" day="" 29,="" however,="" at="" the="" high="" dose="" group="" one="" cause="" of="" death="" was="" determined="" to="" be="" due="" to="" gavage="" error="" during="" test="" substance="" administration,="" another="" dam="" in="" this="" dose="" level="" died="" as="" a="" result="" of="" pneumonia,="" and="" all="" other="" deaths="" could="" not="" be="" determined;="" (b)="" at="" cesarean="" section="" one="" to="" three="" animals/test="" group="" were="" found="" to="" be="" not="" pregnant,="" but="" this="" was="" not="" considered="" to="" be="" dose="" related;="" (c)="" as="" a="" result="" of="" the="" unusual="" sex="" ratio="" in="" the="" control="" group,="" a="" statistically="" significant="" change="" in="" sex="" distribution="" was="" found="" at="" the="" low="" dose="" group="" level,="" however,="" these="" finding="" in="" b="" and="" c="" were="" not="" dose="" dependent="" and="" were="" considered="" to="" be="" within="" the="" range="" of="" historical="" control="" data="" of="" this="" laboratory,="" they="" were="" not="" regarded="" as="" treatment="" related;="" and="" (d)="" no="" teratogenic="" effects,="" as="" well="" as="" incidence="" of="" malformations="" and="" developmental="" effects="" were="" observed="" at="" any="" dose="" level="" tested,="" however="" due="" to="" the="" inconsistent="" mortality="" (0="" (control)-1-2-1)="" seen="" at="" all="" treated="" dose="" levels,="" an="" additional="" study="" with="" a="" range-finder="" was="" performed="" at="" a="" different="" independent="" laboratory.="" an="" oral="" range-finding="" gavage="" teratology="" study="" in="" the="" same="" strain="" of="" rabbits="" (5="" animals/dose="" level)="" was="" examined="" in="" another="" independent="" laboratory.="" the="" dose="" levels="" selected="" were="" 0,="" 20,100,="" 250,="" 500,="" and="" 1000="" mg/kg/day.="" the="" finding="" in="" this="" study="" consist="" of="" the="" following:="" (a)="" one="" animal="" died="" in="" the="" 500="" and="" 1,000="" mg/kg/day="" dose="" groups,="" however,="" the="" animal="" which="" died="" in="" the="" 500="" mg/kg/day="" dose="" group="" was="" due="" to="" administration="" error="" detected="" after="" necropsy;="" (b)="" no="" clinical="" signs="" were="" noted="" and="" body="" weights="" was="" unaffected="" throughout="" gestation,="" however,="" bwg="" and="" food="" consumption="" was="" effected="" temporarily="" from="" 250="" mg/="" kg/day="" onwards="" during="" the="" early="" stages="" of="" test="" substance="" administration="" (day="" 6="" to="" 9="" of="" gestation);="" (c)="" the="" number="" of="" viable="" fetuses="" and="" fetal="" weights="" were="" unaffected;="" and="" (d)="" no="" teratogenic="" effects,="" as="" well="" as="" incidence="" of="" malformations="" and="" developmental="" effects="" were="" observed="" at="" any="" dose="" level="" tested.="" based="" on="" these="" results="" the="" dose="" levels="" selected="" for="" the="" main="" study="" at="" this="" independent="" laboratory="" were="" 0,="" 30,="" 100,="" and="" 350="" 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="" the="" following:="" (a)="" clinical="" signs="" were="" restricted="" to="" premature="" delivery="" in="" 2="" dams="" at="" the="" 350="" mg/kg/day="" dose="" level;="" (b)="" average="" body="" weights="" and="" food="" intake="" was="" not="" affected="" at="" any="" dose="" levels="" tested,="" however,="" body="" weight="" gain="" was="" temporarily="" affected="" at="" the="" beginning="" of="" test="" substance="" administration="" period="" at="" the="" high="" dose="" group="" level;="" and="" (c)="" no="" teratogenic="" effects,="" as="" well="" as="" incidence="" of="" malformations="" and="" developmental="" effects="" were="" observed="" at="" any="" dose="" level="" tested.="" 4.="" conclusions="" from="" the="" teratology="" studies.="" conflicting="" results="" have="" been="" reported="" from="" one="" laboratory="" (initial="" laboratory)="" at="" comparable="" dose="" levels="" using="" the="" same="" study="" protocol="" with="" respect="" to="" maternal="" toxicity="" in="" new="" zealand="" white="" rabbits.="" the="" conclusion="" from="" the="" second="" study="" that="" maternal="" toxicity="" is="" obvious="" by="" effects="" on="" body="" weight="" during="" test="" substance="" administration="" and="" the="" death="" of="" one="" out="" of="" 20="" does="" at="" the="" low="" dose="" level="" (30="" mg/kg/day)="" does="" not="" appear="" to="" be="" plausible="" because:="" i.="" mortalities="" in="" this="" study="" showed="" no="" dose="" depended="" trend="" (o="" (control)-l-2-1).="" the="" cause="" of="" death="" of="" the="" other="" four="" animals="" including="" the="" one="" of="" the="" 30="" mg/kg="" body="" weight="" group="" remained="" undetermined="" even="" after="" necropsy.="" typical="" treatment="" related="" signs="" (gastric="" lesions)="" as="" described="" at="" high="" doses="" in="" range-finding="" or="" main="" studies="" were="" not="" reported.="" furthermore="" no="" mortality="" was="" observed="" up="" to="" 350="" mg/kg/day="" (approximately="" 12-fold="" the="" noael="" of="" 30="" mg/kg="" in="" question)="" in="" a="" collective="" of="" 54="" dams="" (three="" test="" groups)="" of="" the="" same="" strain="" of="" rabbits="" under="" comparable="" experimental="" conditions="" in="" the="" independent="" different="" laboratory.="" [[page="" 41833]]="" ii.="" the="" effect="" on="" body="" weight="" gain="" showed="" no="" statistical="" significance="" at="" 30="" mg/kg="" body="" weight="" and="" the="" standard="" deviation="" was="" high.="" in="" addition,="" at="" the="" dose="" of="" 40="" mg/kg/day="" there="" was="" no="" effect="" in="" the="" same="" strain="" of="" rabbits="" examined="" by="" the="" same="" laboratory="" in="" a="" previous="" study="" and="" no="" effect="" on="" body="" weight,="" body="" weight="" gain="" or="" food="" consumption="" were="" noted="" at="" doses="" of="" 30="" or="" 100="" mg/kg/day="" in="" a="" study="" performed="" in="" the="" same="" animal="" strain="" by="" the="" independent="" laboratory.="" thus="" the="" following="" overall="" noaels="" can="" be="" derived="" for="" the="" teratology="" studies:="" a.="" noael="" maternal="" toxicity.="" 100="" mg/kg="" body="" weight="" (rabbit)="" and="" 1,000="" mg/kg="" body="" weight="" (rat).="" b.="" noael="" prenatal="" toxicity.="" 100="" mg/kg="" body="" weight="" (rabbit)="" and="" 1000="" mg/kg="" body="" weight="" (rat).="" the="" overall="" noael="" on="" maternal="" toxicity="" in="" rabbits="" is="" based="" on="" the="" independent="" laboratory="" rabbit="" study="" due="" to="" reduction="" of="" bwg="" and="" food="" intake="" at="" dose="" levels="" of="" 250="" mg/kg="" body="" weight="" onwards.="" the="" noael="" (100="" mg/kg="" body="" weight)="" for="" prenatal="" toxicity="" in="" rabbits="" is="" based="" on="" abortions="" observed="" at="" doses="" equal="" or="" above="" 200="" mg/kg="" body="" weight.="" the="" noael="" for="" malformations="" and="" other="" developmental="" effects="" is="" even="" higher="" (350="" mg/kg="" body="" weight).="" due="" to="" excessive="" lethality="" of="" dams="" at="" doses="" above="" this="" value,="" no="" evaluation="" of="" fetuses="" was="" possible.="" no="" teratogenic="" effects="" have="" been="" observed="" up="" to="" the="" hdt="" of="" 350="" mg/kg="" bw="" which="" could="" be="" evaluated="" for="" developmental="" effects.="" the="" teratogenicity="" study="" in="" rabbits="" resulted="" in="" a="" developmental="" toxicity="" noael="" of="" 100="" mg/kg="" and="" a="" maternal="" toxicity="" noael="" of="" 100="" mg/kg.="" these="" noael="" values="" are="" higher="" than="" the="" noael="" from="" the="" 1-year="" feeding="" study="" in="" dogs="" used="" to="" establish="" the="" rfd.="" b.="" reproductive="" toxicity="" a="" 2-generation="" reproduction="" study="" with="" rats="" fed="" dosages="" of="" 0,="" 500,="" 5,000,="" and="" 50,000="" ppm="" with="" a="" reproductive/developmental="" noael="" of="" 50,000="" ppm="" and="" a="" maternal/parental/offspring="" toxicity="" noael="" of="" 500="" ppm="" based="" on="" the="" following:="" (1)="" mortalities="" were="" noted="" for="" two="" mid-dose="" males="" (week="" 7="" or="" 11),="" two="" males="" and="" one="" female="" of="" the="" high-dose="" (week="" 1),="" and="" one="" female="" died="" on="" gestation="" day="" 13="" without="" visible="" abnormalities="" prior="" to="" death;="" (2)="" in="" the="" high-dose="" parental="" f0="" and="" f1="" statistically="" significant="" decreased="" body="" weights="" and="" increased="" water="" consumption="" was="" observed;="" (3)="" in="" the="" mid-dose="" level="" similar="" reduced="" body="" weights="" were="" observed="" in="" the="" f1="" offspring="" and="" f1="" parents="" and="" with="" increased="" water="" consumption="" being="" seen="" in="" the="" f0="" and="" f1="" animals;="" (4)="" for="" both="" high-dose="" generations,="" offspring="" growth="" was="" slightly="" reduced;="" (5)="" microscopic="" lesions="" in="" the="" glandular="" and="" non-glandular="" stomach="" consisting="" of="" papillary="" ancadthosis,="" diffuse="" ancanthosis,="" and="" hyperkeratosis="" were="" observed="" in="" male="" and="" female="" rats="" of="" the="" mid-dose="" and="" high-dose="" levels="" tested="" with="" slight="" progression="" of="" severity="" from="" the="" mid-="" to="" upper="" dose="" level;="" and="" (6)="" no="" effects="" on="" reproductive="" or="" fertility="" parameter="" was="" observed="" for="" any="" dose="" group="" tested.="" therefore,="" these="" noael="" values="" are="" similar="" for="" maternal="" toxicity="" and="" significantly="" higher="" for="" reproductive="" effects="" (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.="" 1.="" subchronic="" toxicity--="" teratology--="" 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.="" 2.="" teratology--="" rabbits.="" a="" developmental="" study="" was="" conducted="" via="" oral="" gavage="" in="" rabbits="" with="" dosages="" of="" 0,="" 40,="" 200,="" and="" 750="" (hdt)="" mg/kg/="" day="" with="" a="" development="" toxicity="" noael="" of="" 40="" mg/kg/day="" and="" a="" maternal="" toxicity="" noael="" of="" 40="" mg/kg/day="" based="" on="" the="" following:="" (a)="" excessive="" maternal="" mortality="" of="" 4/20="" and="" 16/20="" was="" observed="" in="" the="" 200="" and="" 750="" mg/kg/day="" dose="" levels="" tested,="" respectively;="" (b)="" significant="" weight="" loss="" was="" similarly="" observed="" in="" the="" 200="" and="" 750="" mg/kg/day="" dose="" group="" with="" accompanying="" clinical="" signs;="" (c)="" microscopic="" findings="" in="" the="" 750="" mg/kg/="" day="" dose="" group="" revealed="" stomach="" erosion="" and="" lung="" congestion="" in="" many="" of="" that="" animals="" that="" died;="" (d)="" in="" the="" 40="" mg/kg/day="" dose="" group="" a="" single="" rabbit="" lost="" its="" righting="" reflex="" and="" showed="" splayed="" limbs="" on="" day="" 25="" due="" to="" a="" back="" injury="" it="" sustained;="" and="" (e)="" no="" teratogenic="" effects,="" as="" well="" as="" incidence="" of="" malformations="" and="" developmental="" effects="" were="" observed="" at="" any="" dose="" level="" tested,="" however="" due="" to="" the="" mortality="" seen="" in="" the="" 200="" and="" 750="" mg/kg/day="" day="" dose="" groups="" and="" limited="" number="" of="" fetuses="" produced="" at="" these="" dose="" levels,="" an="" additional="" study="" was="" performed.="" (it="" should="" be="" noted="" that="" an="" oral="" gavage="" range-finding="" study="" of="" six="" rabbits="" per="" dose="" level="" was="" performed="" at="" dose="" levels="" of="" 0,="" 100,="" 250,="" 500,="" and="" 1,000="" mg/kg/day,="" in="" which="" similar="" excessive="" mortality="" was="" observed="" in="" the="" 500="" and="" 1,000="" mg/kg/day="" dose="" groups="" test="" as="" shown="" above.="" additionally,="" body="" weight="" was="" affected="" for="" all="" dose="" groups="" tested="" and="" the="" clinical="" signs="" and="" macroscopic="" findings="" observed="" in="" the="" study="" discussed="" above="" were="" also="" noted="" in="" the="" range-finding="" study.="" however,="" body="" weight="" gain="" was="" not="" affected="" in="" the="" lowest="" dose="" group="" tested.)="" the="" doses="" selected="" for="" the="" additional="" teratology="" study="" in="" the="" same="" strain="" of="" rabbits="" were="" 0,="" 30,="" 75,="" and="" 150="" mg/kg/day="" with="" a="" development="" toxicity="" noael="" of="" 150="" mg/kg/day="" and="" a="" maternal="" toxicity="" noael="" that="" could="" not="" be="" determined="" in="" this="" study="" based="" on="" the="" following:="" (a)="" one="" low-,="" two="" mid-,="" and="" three="" high-dose="" animals="" died="" prior="" to="" cesarean="" section="" on="" day="" 29,="" however,="" at="" the="" high="" dose="" group="" one="" cause="" of="" death="" was="" determined="" to="" be="" due="" to="" gavage="" error="" during="" test="" substance="" administration,="" another="" dam="" in="" this="" dose="" level="" died="" as="" a="" result="" of="" pneumonia,="" and="" all="" other="" deaths="" could="" not="" be="" determined;="" (b)="" at="" cesarean="" section="" one="" to="" three="" animals/test="" group="" were="" found="" to="" be="" not="" pregnant,="" but="" this="" was="" not="" considered="" to="" be="" dose="" related;="" (c)="" as="" a="" result="" of="" the="" unusual="" sex="" ratio="" in="" the="" control="" group,="" a="" statistically="" significant="" change="" in="" sex="" distribution="" was="" found="" at="" the="" low="" dose="" group="" level,="" however,="" these="" finding="" in="" (b)="" and="" (c)="" were="" not="" dose="" dependent="" and="" were="" considered="" to="" be="" within="" the="" range="" of="" historical="" control="" data="" of="" this="" laboratory,="" they="" were="" not="" regarded="" as="" treatment="" related;="" and="" (d)="" no="" teratogenic="" effects,="" as="" well="" as="" incidence="" of="" malformations="" and="" developmental="" effects="" were="" observed="" at="" any="" dose="" level="" tested,="" however="" due="" to="" the="" inconsistent="" mortality="" (0="" (control)-1-2-1)="" seen="" at="" all="" treated="" dose="" levels,="" an="" additional="" study="" with="" a="" range-finder="" was="" performed="" at="" a="" different="" independent="" laboratory.="" an="" oral="" range-finding="" gavage="" teratology="" study="" in="" the="" same="" strain="" of="" rabbits="" (5="" animals/dose="" level)="" was="" examined="" in="" another="" independent="" laboratory.="" the="" dose="" levels="" selected="" were="" 0,="" 20,="" 100,="" 250,="" 500,="" and="" 1000="" mg/kg/day.="" the="" finding="" in="" this="" study="" consist="" of="" the="" following:="" (a)="" one="" animal="" died="" in="" the="" 500="" and="" 1,000="" mg/kg/day="" dose="" groups,="" however,="" the="" animal="" which="" died="" in="" the="" 500="" mg/kg/day="" dose="" group="" was="" due="" to="" administration="" error="" detected="" after="" necropsy;="" (b)="" no="" clinical="" signs="" were="" noted="" and="" body="" weights="" was="" unaffected="" throughout="" gestation,="" however,="" body="" weight="" gain="" and="" food="" consumption="" was="" effected="" temporarily="" from="" 250="" mg/kg/day="" onwards="" during="" the="" early="" stages="" of="" test="" substance="" administration="" (day="" 6="" to="" 9="" of="" gestation);="" (c)="" the="" number="" of="" viable="" fetuses="" and="" fetal="" weights="" were="" unaffected;="" and="" (d)="" no="" teratogenic="" effects,="" as="" well="" as="" incidence="" of="" malformations="" and="" developmental="" [[page="" 41834]]="" effects="" were="" observed="" at="" any="" dose="" level="" tested.="" based="" on="" these="" results="" the="" dose="" levels="" selected="" for="" the="" main="" study="" at="" this="" independent="" laboratory="" were="" 0,="" 30,="" 100,="" and="" 350="" 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="" the="" following:="" (1)="" clinical="" signs="" were="" restricted="" to="" premature="" delivery="" in="" 2="" dams="" at="" the="" 350="" mg/kg/day="" dose="" level;="" (2)="" average="" body="" weights="" and="" food="" intake="" was="" not="" affected="" at="" any="" dose="" levels="" tested,="" however,="" body="" weight="" gain="" was="" temporarily="" affected="" at="" the="" beginning="" of="" test="" substance="" administration="" period="" at="" the="" high="" dose="" group="" level;="" and="" (3)="" no="" teratogenic="" effects,="" as="" well="" as="" incidence="" of="" malformations="" and="" developmental="" effects="" were="" observed="" at="" any="" dose="" level="" tested.="" 3.="" conclusions="" from="" the="" teratology="" studies.="" i.="" conflicting="" results="" have="" been="" reported="" from="" one="" laboratory="" (initial="" laboratory)="" at="" comparable="" dose="" levels="" using="" the="" same="" study="" protocol="" with="" respect="" to="" maternal="" toxicity="" in="" new="" zealand="" white="" rabbits.="" the="" conclusion="" from="" the="" second="" study="" that="" maternal="" toxicity="" is="" obvious="" by="" effects="" on="" body="" weight="" during="" test="" substance="" administration="" and="" the="" death="" of="" one="" out="" of="" 20="" does="" at="" the="" low="" dose="" level="" (30="" mg/kg/day)="" does="" not="" appear="" to="" be="" plausible="" because:="" i.="" mortalities="" in="" this="" study="" showed="" no="" dose="" depended="" trend="" (o="" (control)-l-2-1).="" the="" cause="" of="" death="" of="" the="" other="" four="" animals="" including="" the="" one="" of="" the="" 30="" mg/kg="" body="" weight="" group="" remained="" undetermined="" even="" after="" necropsy.="" typical="" treatment="" related="" signs="" (gastric="" lesions)="" as="" described="" at="" high="" doses="" in="" range-finding="" or="" main="" studies="" were="" not="" reported.="" furthermore="" no="" mortality="" was="" observed="" up="" to="" 350="" mg/kg/day="" (approximately="" 12-fold="" the="" noael="" of="" 30="" mg/kg="" in="" question)="" in="" a="" collective="" of="" 54="" dams="" (three="" test="" groups)="" of="" the="" same="" strain="" of="" rabbits="" under="" comparable="" experimental="" conditions="" in="" the="" independent="" different="" laboratory.="" ii.="" the="" effect="" on="" bwg="" showed="" no="" statistical="" significance="" at="" 30="" mg/="" kg="" body="" weight="" and="" the="" standard="" deviation="" was="" high.="" in="" addition,="" at="" the="" dose="" of="" 40="" mg/kg/day="" there="" was="" no="" effect="" in="" the="" same="" strain="" of="" rabbits="" examined="" by="" the="" same="" laboratory="" in="" a="" previous="" study="" and="" no="" effect="" on="" body="" weight,="" bwg="" or="" food="" consumption="" were="" noted="" at="" doses="" of="" 30="" or="" 100="" mg/kg/day="" in="" a="" study="" performed="" in="" the="" same="" animal="" strain="" by="" the="" independent="" laboratory.="" iii.="" thus="" the="" following="" overall="" noaels="" can="" be="" derived="" for="" the="" teratology="" studies:="" iv.="" noael="" maternal="" toxicity.="" 100="" mg/kg="" body="" weight="" (rabbit)="" and="" 1,000="" mg/kg="" body="" weight="" (rat).="" v.="" noael="" prenatal="" toxicity.="" 100="" mg/kg="" body="" weight="" (rabbit)="" and="" 1,000="" mg/kg="" body="" weight="" (rat).="" the="" overall="" noael="" on="" maternal="" toxicity="" in="" rabbits="" is="" based="" on="" the="" independent="" laboratory="" rabbit="" study="" due="" to="" reduction="" of="" bwg="" and="" food="" intake="" at="" dose="" levels="" of="" 250="" mg/kg="" body="" weight="" onwards.="" the="" noael="" (100="" mg/kg="" body="" weight)="" for="" prenatal="" toxicity="" in="" rabbits="" is="" based="" on="" abortions="" observed="" at="" doses="" equal="" or="" above="" 200="" mg/kg="" body="" weight.="" the="" noael="" for="" malformations="" and="" other="" developmental="" effects="" is="" even="" higher="" (350="" mg/kg="" body="" weight).="" due="" to="" excessive="" lethality="" of="" dams="" at="" doses="" above="" this="" value,="" no="" evaluation="" of="" fetuses="" was="" possible.="" no="" teratogenic="" effects="" have="" been="" observed="" up="" to="" the="" highest="" dose="" level="" of="" 350="" mg/kg="" body="" weight="" which="" could="" be="" evaluated="" for="" developmental="" effects.="" 4.="" 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.="" i.="" chronic="" feeding="" -="" nonrodent.="" a="" 1-year="" feeding="" study="" in="" dogs="" fed="" dosages="" of="" 0,="" 20,="" 200,="" or="" 1,000="" mg/kg/day="" (htd)="" with="" a="" noael="" of="" 20="" mg/="" kg/day="" for="" female="" and="" male="" dogs="" based="" on="" the="" following="" effects:="" (a)="" clinical="" signs="" consisting="" of="" pale="" colored="" feces="" were="" observed="" with="" the="" highest="" incidence="" being="" recorded="" at="" hdlt;="" (b)="" slightly="" reduced="" clinical="" chemical="" values="" were="" observed="" in="" high="" dose="" male="" and="" female="" dogs="" for="" serum="" albumin="" and="" potassium="" and="" increased="" phosphorus="" levels="" for="" both="" male="" and="" female="" dogs="" of="" the="" hdt;="" (c)="" red="" blood="" cell="" parameters="" (packed="" cell="" volume,="" hemoglobin,="" and="" red="" blood="" cell="" count)="" were="" slightly="" lower="" at="" the="" hdt="" for="" males="" and="" females="" dogs,="" only="" red="" blood="" cell="" counts="" were="" reduced="" in="" the="" male="" and="" female="" dogs="" at="" the="" 200="" mg/kg/day="" dose="" level="" in="" week="" 52;="" and="" (d)="" histopathological="" examination="" revealed="" dilated/="" basophilic="" renal="" cortical="" tubules="" with="" and="" without="" fibrosis="" in="" both="" male="" and="" female="" dogs="" at="" the="" 200="" and="" 1,000="" mg/kg/day="" dose="" levels.="" ii.="" chronic="" feeding/oncogenicity="" --="" rats.="" a="" combined="" chronic/="" oncogenicity="" in="" rats="" (fischer="" 344)="" fed="" dosages="" of="" 0,="" 18,="" 94,="" 469,="" and="" 968="" mg/kg/day="" for="" male="" rats="" and="" 0,="" 22,="" 114,="" 572,="" and="" 1,180="" mg/kg/day="" for="" female="" rats="" with="" a="" noael="" of="" 94="" mg/kg/day="" for="" male="" rats="" and="" 114="" mg/="" kg/day="" for="" female="" rats="" based="" on="" the="" following="" effects:="" (a)="" decreased="" in="" body="" weights="" were="" observed="" in="" both="" male="" and="" female="" rat="" at="" the="" 968="" and="" 1,180="" mg/kg/day="" dlt;="" (b)="" clinical="" chemical="" effects="" (i.e.,="" lower="" potassium,="" bilirubin,="" and="" glucose="" levels)="" were="" observed="" in="" male="" and="" female="" rats="" at="" the="" 968="" and="" 1,180="" mg/kg/day="" dlt,="" in="" the="" 469="" mg/kg/day="" 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="" 1,180="" mg/kg/day="" dose="" level="" in="" females;="" (c)="" increased="" urine="" volumes="" and="" lower="" specific="" gravity="" were="" observed="" in="" the="" mid-high="" and="" high-dose="" groups="" for="" both="" male="" and="" female="" rats;="" (d)="" 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="" body="" weights;="" (e)="" macroscopic="" finding="" revealed="" an="" increase="" of="" pituitary="" nodules="" in="" the="" high="" dose="" group="" tested="" for="" 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="" at="" this="" dose="" level;="" (f)="" 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="" (g)="" no="" increased="" incidence="" of="" neoplasms="" occurred="" at="" any="" dose="" levels="" tested="" in="" this="" study.="" iii.="" oncogenicity="" -="" mice.="" a="" carcinogenicity="" study="" in="" b6c3f1="" mice="" fed="" dosages="" of="" 0,="" 55,="" 279,="" 2,847,="" and="" 5,911="" mg/kg/day="" for="" male="" mice="" and="" 0,="" 68,="" 351,="" 3,489,="" and="" 7334="" mg/kg/day="" for="" female="" mice="" with="" a="" noael="" of="" 279="" mg/kg/day="" for="" male="" mice="" and="" 351="" mg/kg/day="" for="" female="" mice="" based="" on="" the="" following="" effects:="" (a)="" statistically="" significant="" decreases="" in="" body="" weights="" were="" observed="" in="" male="" mice="" at="" the="" 2,847="" and="" 5,911="" mg/kg/day="" dose="" levels="" and="" in="" female="" mice="" at="" the="" 7,334="" mg/kg/day="" dose="" levels="" tested;="" (b)="" a="" variety="" of="" changes="" in="" hematological="" parameter="" was="" noted="" in="" the="" respective="" investigations="" at="" weeks="" 52,="" 78,="" and="" 104,="" however,="" most="" of="" the="" changes="" were="" not="" dose="" related="" or="" consistent="" over="" time;="" (c)="" increased="" absolute="" and/or="" relative="" heart,="" brain,="" testes,="" liver,="" ovary,="" and="" kidney="" weights="" [[page="" 41835]]="" were="" observed="" in="" the="" mid-high="" and="" highest="" dose="" group="" test="" with="" a="" slight="" progression="" of="" severity="" to="" the="" highest="" dose="" group="" tested;="" (d)="" a="" higher="" incidence="" of="" splenomegaly="" was="" observed="" only="" in="" the="" male="" mice="" of="" the="" highest="" dose="" group;="" (e)="" 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;="" (f)="" 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;="" (g)="" vacuolic="" changes="" in="" the="" exocrine="" pancreas="" of="" the="" high="" dose="" female="" was="" observed;="" (h)="" no="" increased="" incidence="" of="" neoplasms="" occurred="" at="" any="" dose="" levels="" tested="" in="" this="" study.="" iv.="" carcinogenicity.="" prohexadione="" calcium="" was="" shown="" to="" be="" non-="" carcinogenic="" in="" mice,="" rats,="" and="" dogs.="" therefore,="" based="" on="" the="" results="" of="" the="" carcinogenicity="" studies="" in="" mice,="" rats,="" and="" dogs="" and="" the="" results="" of="" genotoxicity="" testing,="" the="" threshold="" approach="" to="" regulating="" prohexadione="" calcium="" is="" appropriate="" 5.="" animal="" metabolism.="" the="" metabolism="" in="" animals="" (goats="" and="" poultry)="" is="" adequately="" understood.="" 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.,="" teratology="" and="" multi-generation="" reproductive="" studies,="" which="" would="" suggest="" that="" prohexadione="" calcium="" produces="" endocrine="" related="" effects.="" c.="" aggregate="" exposure="" 1.="" dietary="" exposure.="" for="" purposes="" of="" assessing="" the="" potential="" dietary="" exposure,="" k-i="" has="" estimated="" aggregate="" exposure="" based="" on="" the="" theoretical="" maximum="" residue="" contribution="" (tmrc)="" from="" the="" proposed="" tolerance="" for="" prohexadione="" calcium="" in/on="" peanut="" nutmeat="" at="" 0.8="" ppm.="" 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.="" dietary="" exposure="" to="" residues="" of="" prohexadione="" calcium="" in="" or="" on="" food="" will="" be="" limited="" to="" residues="" on="" peanut="" nutmeat.="" peanut="" hay="" and="" meal="" are="" fed="" to="" animals;="" thus="" exposure="" of="" humans="" to="" residues="" in="" peanut="" hay="" and="" meal="" might="" result="" if="" such="" residues="" carry="" through="" to="" meat,="" milk,="" poultry,="" or="" eggs.="" however,="" k-i="" 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.="" there="" are="" no="" other="" established="" u.s.="" tolerances="" for="" prohexadione="" calcium,="" and="" there="" are="" no="" currently="" registered="" uses="" for="" prohexadione="" calcium="" on="" food="" or="" feed="" crops="" in="" the="" u.s.="" dietary="" exposure="" to="" residues="" of="" prohexadione="" calcium="" from="" the="" proposed="" tolerances="" on="" peanuts="" would="" account="" for="" less="" than="" 0.14%="" of="" the="" rfd="" (0.20="" mg/kg/day)="" for="" the="" general="" population="" of="" the="" us="" and="" all="" subpopulation="" groups.="" the="" most="" highly="" exposed="" group="" in="" the="" subpopulation="" groups="" would="" be="" non-nursing="" infants="">< 1="" year="" old),="" which="" uses="" 0.39%="" of="" the="" rfd.="" 2.="" drinking="" water.="" other="" potential="" sources="" of="" exposure="" to="" prohexadione="" calcium="" for="" the="" general="" population="" are="" residues="" in="" drinking="" water="" and="" exposure="" from="" non-occupational="" sources.="" exposure="" to="" residues="" of="" prohexadione="" calcium="" in="" drinking="" water="" is="" not="" anticipated.="" there="" is="" no="" established="" maximum="" concentration="" level="" (mcl)="" or="" health="" advisory="" level="" (hal)="" for="" prohexadione="" calcium="" under="" the="" safe="" drinking="" water="" act="" (sdwa).="" 3.="" non-dietary="" exposure.="" prohexadione="" calcium="" is="" not="" currently="" registered="" for="" any="" nonagricultural="" use.="" the="" potential="" for="" non-="" occupational="" exposure="" to="" the="" general="" population="" is="" therefore="" not="" present.="" d.="" cumulative="" effects="" the="" potential="" for="" cumulative="" effects="" of="" prohexadione="" calcium="" and="" other="" substances="" that="" have="" a="" common="" mechanism="" of="" toxicity="" has="" been="" considered.="" no="" evidence="" or="" information="" exists="" to="" suggest="" that="" toxic="" effects="" produced="" by="" prohexadione="" calcium="" would="" be="" cumulative="" with="" those="" of="" any="" other="" chemical="" compound.="" e.="" safety="" determination="" 1.="" u.s.="" population--="" reference="" dose="" (rfd).="" using="" the="" conservative="" exposure="" assumptions="" described="" above="" and="" based="" on="" the="" completeness="" and="" the="" reliability="" of="" the="" toxicity="" data,="" it="" has="" estimated="" that="" aggregate="" exposure="" to="" prohexadione="" calcium="" will="" utilize="" 0.14%="" of="" the="" rfd="" for="" the="" u.s.="" population.="" k-i="" 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.="" since="" developmental="" and="" reproductive="" toxicity="" occurs="" at="" levels="" at="" or="" above="" the="" levels="" shown="" to="" exhibit="" parental="" toxicity="" and="" since="" these="" levels="" are="" significantly="" higher="" than="" those="" used="" to="" calculate="" the="" rfd,="" k-i="" believes="" the="" rfd="" of="" 0.20="" mg/kg/day="" is="" an="" appropriate="" measure="" of="" safety="" for="" infants="" and="" children.="" using="" the="" conservative="" exposure="" assumptions="" described="" above,="" it="" is="" concluded="" that="" the="" portion="" of="" the="" rfd="" that="" will="" be="" utilized="" by="" aggregate="" exposure="" to="" residues="" of="" prohexadione="" calcium="" resulting="" from="" the="" proposed="" tolerances="" will="" be="" less="" than="" 0.14%="" for="" all="" populations="" of="" infants="" and="" children.="" the="" most="" highly="" exposed="" group="" in="" the="" subpopulation="" groups="" would="" be="" non-nursing="" infants="">< 1="" year="" old)="" which="" uses="" 0.39%="" of="" the="" rfd.="" 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="" the="" residues="" of="" prohexadione="" calcium,="" including="" all="" anticipated="" dietary="" exposure="" and="" all="" other="" non-occupational="" exposures.="" f.="" international="" tolerances="" a="" maximum="" residue="" level="" has="" not="" been="" established="" for="" prohexadione="" calcium="" by="" the="" codex="" alimentarius="" commission.="" [fr="" doc.="" 98-20768="" filed="" 8-4-98;="" 8:45="" am]="" billing="" code="" 6560-50-f="">