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prohexadione-calcium (Viviful) Pesticide Petition Filing 3/01



ENVIRONMENTAL PROTECTION AGENCY


[PF-1004; FRL-6769-9]



Notice of Filing a Pesticide Petition to Establish a Tolerance
for a Certain Pesticide Chemical in or on Food


AGENCY: Environmental Protection Agency (EPA).


ACTION: Notice.


-----------------------------------------------------------------------


SUMMARY: This notice announces the initial filing of a pesticide
petition proposing the establishment of regulations for residues of a
certain pesticide chemical in or on various food commodities.


DATES: Comments, identified by docket control number PF-1004, must be
received on or before April 27, 2001.


ADDRESSES: Comments may be submitted by mail, electronically, or in
person. Please follow the detailed instructions for each method as
provided in Unit I.C. of the SUPPLEMENTARY INFORMATION. To ensure
proper receipt by EPA, it is imperative that you identify docket
control number PF-000 in the subject line on the first page of your
response.


FOR FURTHER INFORMATION CONTACT: By mail: Cynthia Giles-Parker,
Registration Support Branch, Registration Division (7505W), Office of
Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania
Ave., NW., Washington, DC 20460; telephone number: (703) 305-7740; e-
mail address: giles-parker.cynthia@epa.gov.


SUPPLEMENTARY INFORMATION:


I. General Information


A. Does this Action Apply to Me?


    You may be affected by this action if you are an agricultural
producer, food manufacturer or pesticide manufacturer. Potentially
affected categories and entities may include, but are not limited to:


------------------------------------------------------------------------
                                                          Examples of
           Categories                 NAICS codes         potentially
                                                      affected  entities
------------------------------------------------------------------------
Industry                          111                 Crop production
                                  112                 Animal production
                                  311                 Food manufacturing
                                  32532               Pesticide
                                                       manufacturing
------------------------------------------------------------------------


    This listing is not intended to be exhaustive, but rather provides
a guide for readers regarding entities likely to be affected by this
action. Other types of entities not listed in the table could also be
affected. The North American Industrial Classification System (NAICS)
codes have been provided to assist you and others in determining
whether or not this action might apply to certain entities. If you have
questions regarding the applicability of this action to a particular
entity, consult the person listed under FOR FURTHER INFORMATION
CONTACT.


B. How Can I Get Additional Information, Including Copies of this
Document and Other Related Documents?


    1. Electronically. You may obtain electronic copies of this
document, and certain other related documents that might be available
electronically, from the EPA Internet Home Page at http://www.epa.gov/.
To access this document, on the Home Page select ``Laws and Regulations
and Proposed Rule,'' and then look up the entry for this document under
the ``Federal Register--Environmental Documents.'' You can also go
directly to the Federal Register listings at http://www.epa.gov/
fedrgstr/.
    2. In person. The Agency has established an official record for
this action under docket control number PF-1004. The official record
consists of the documents specifically referenced in
this action, any public comments received during an applicable comment
period, and other information related to this action, including any
information claimed as confidential business information (CBI). This
official record includes the documents that are physically located in
the docket, as well as the documents that are referenced in those
documents. The public version of the official record does not include
any information claimed as CBI. The public version of the official
record, which includes printed, paper versions of any electronic
comments submitted during an applicable comment period, is available
for inspection in the Public Information and Records Integrity Branch
(PIRIB), Rm. 119, Crystal Mall #2, 1921 Jefferson Davis Highway,
Arlington, VA, from 8:30 a.m. to 4 p.m., Monday through Friday,
excluding legal holidays. The PIRIB telephone number is (703) 305-5805.


C. How and to Whom Do I Submit Comments?


    You may submit comments through the mail, in person, or
electronically. To ensure proper receipt by EPA, it is imperative that
you identify docket control number PF-1004 in the subject line on the
first page of your response.
    1. By mail. Submit your comments to: Public Information and Records
Integrity Branch (PIRIB), Information Resources and Services Division
(7502C), Office of Pesticide Programs (OPP), Environmental Protection
Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460.
    2. In person or by courier. Deliver your comments to: Public
Information and Records Integrity Branch (PIRIB), Information Resources
and Services Division (7502C), Office of Pesticide Programs (OPP),
Environmental Protection Agency, Rm. 119, Crystal Mall #2, 1921
Jefferson Davis Highway, Arlington, VA. The PIRIB is open from 8:30
a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The
PIRIB telephone number is (703) 305-5805.
    3. Electronically. You may submit your comments electronically by
e-mail to: opp-docket@epa.gov, or you can submit a computer disk as
described above. Do not submit any information electronically that you
consider to be CBI. Avoid the use of special characters and any form of
encryption. Electronic submissions will be accepted in Wordperfect 6.1/
8.0 or ASCII file format. All comments in electronic form must be
identified by docket control number PF-1004. Electronic comments may
also be filed online at many Federal Depository Libraries.


D. How Should I Handle CBI That I Want to Submit to the Agency?


    Do not submit any information electronically that you consider to
be CBI. You may claim information that you submit to EPA in response to
this document as CBI by marking any part or all of that information as
CBI. Information so marked will not be disclosed except in accordance
with procedures set forth in 40 CFR part 2. In addition to one complete
version of the comment that includes any information claimed as CBI, a
copy of the comment that does not contain the information claimed as
CBI must be submitted for inclusion in the public version of the
official record. Information not marked confidential will be included
in the public version of the official record without prior notice. If
you have any questions about CBI or the procedures for claiming CBI,
please consult the person identified under FOR FURTHER INFORMATION
CONTACT.


E. What Should I Consider as I Prepare My Comments for EPA?


    You may find the following suggestions helpful for preparing your
comments:
    1. Explain your views as clearly as possible.
    2. Describe any assumptions that you used.
    3. Provide copies of any technical information and/or data you used
that support your views.
    4. If you estimate potential burden or costs, explain how you
arrived at the estimate that you provide.
    5. Provide specific examples to illustrate your concerns.
    6. Make sure to submit your comments by the deadline in this
notice.
    7. To ensure proper receipt by EPA, be sure to identify the docket
control number assigned to this action in the subject line on the first
page of your response. You may also provide the name, date, and Federal
Register citation.


II. What Action is the Agency Taking?


    EPA has received a pesticide petition as follows proposing the
establishment and/or amendment of regulations for residues of a certain
pesticide chemical in or on various food commodities under section 408
of the Federal Food, Drug, and Comestic Act (FFDCA), 21 U.S.C. 346a.
EPA has determined that this petition contains data or information
regarding the elements set forth in section 408(d)(2); however, EPA has
not fully evaluated the sufficiency of the submitted data at this time
or whether the data support granting of the petition. Additional data
may be needed before EPA rules on the petition.


List of Subjects


    Environmental protection, Agricultural commodities, Feed additives,
Food additives, Pesticides and pests, Reporting and recordkeeping
requirements.


    Dated: March 12, 2001.
James Jones,
Director, Registration Division, Office of Pesticide Programs.


Summary of Petition


    The petitioner summary of the pesticide petition is printed below
as required by section 408(d)(3) of the FFDCA. The summary of the
petition was prepared by the petitioner and represents the view of the
petitioners. EPA is publishing the petition summary verbatim without
editing it 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.


K-I Chemical U.S.A. Inc. (K-I Chemical)


0F06127


    EPA has received a pesticide petition (0F06127) from K-I Chemical
U.S.A. Inc. (K-I Chemical), 11 Martine Avenue, 9th floor, White Plains,
New York 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 calcium 3-
oxido-5-oxo-4-propionylcyclohex-3-enecarboxylate (prohexadione calcium)
in or on the raw agricultural commodities grass forage at 0.1, grass
hay at 0.1, grass straw at 1.2 and grass seed screenings at 3.5 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.


A. Residue Chemistry


    1. Plant metabolism. The metabolism in plants (peanuts and apples)
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. Twelve grass grown for seed trials were
conducted with prohexadione calcium in the major cool season grass
seed-growing regions of the United States (Nebraska, Minnesota,
Montana, Idaho, Oregon and Washington) to determine the magnitude of
prohexadione calcium residues in/on grass forage, straw, hay and seed
screenings. Grass grown for seed plots received one foliar application
of prohexadione calcium at the target rate of 0.5 pounds active
ingredient per acre (lb ai/A). The application was applied
approximately 35 days prior to the anticipated seed harvest date. All
sprays were applied in combination with a locally-available, non-
silicone spray adjuvant. Prohexadione calcium residues ranged from 0.05
to 3.38 ppm in seed screenings, 0.05 to 1.04 ppm in straw, 0.05 to 0.06
ppm in forage, and 0.05 to 0.08 ppm in hay. Control samples did not
exhibit resides above the limit of quantitation (LOQ) of 0.05 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. Genotoxicity. 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 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 F0 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.
    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 the 1,000 highest dose tested (HDT) mg/kg
bw. The No Observed Adverse Effect Level (NOAEL) for developmental and
maternal toxicity was 1,000 mg/kg bw, 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 MTD; NOAELs for maternal and
developmental effects are not considered reliable and useful for risk
characterization. No teratogenic effects were noted in this study.
    i. Teratogenicity. 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 1,000 mg/kg bw
(rat), and the NOAEL for fetotoxicity in the teratogenicity studies is
350 mg/kg bw (rabbit) and 1000 mg/kg bw (rat).
    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.
    ii. Oral teratology 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 body weight
decreases and two abortions were observed. No teratogenic or fetotoxic
effects were noted in this study.
    iii. Conclusions from teratology studies. More than one definitive
rabbit teratology study was conducted because issues associated with
exceeding the maximum tolerated dose (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 teratology studies:
    a. NOAEL maternal toxicity. 100 mg/kg body weight (rabbit) and
1,000 mg/kg body weight (rat).
    b.  NOAEL prenatal toxicity. 350 mg/kg body weight (rabbit) and
1,000 mg/kg body weight (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 body weight gain and food intake at dose levels of 250 mg/
kg body weight onwards. The NOAEL of 350 mg/kg bw for fetotoxic effects
in the rabbit is also based on a reduction in body weight 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 No Adverse Effect Level (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:
    i. Decreased body weights were observed in both male and female
rats at the 20,000 ppm dose level;
    ii. 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;
    iii. Increased urine volumes and lower specific gravity were
observed in the mid-high and high-dose groups for both male and female
rats;
    iv. 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;
    v. 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;
    vi. 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
    vii. 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:
    i. 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;
    ii. 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;
    iii. 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;
    iv. A higher incidence of splenomegaly was observed only in the
male mice of the highest dose group;
    v. 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;
    vi. 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;
    vii. Vacuolic changes in the exocrine pancreas of the high dose
female were observed; and
    viii. No increased incidence of neoplasms occurred at any dose
levels tested in this study.
    a. Threshold effects. Based on review of the available chronic
toxicity data, K-I Chemical believes EPA will establish the Reference
Dose(RfD) for prohexadione calcium at 0.20 mg/kg/day. This RfD for
prohexadione calcium is based on the 1-year feeding study in dogs with
a threshold NOEL of 20 mg/kg/day in male and female dogs. Using an
uncertainty factor of 100, the RfD is calculated to be 0.20 mg/kg/day.
Based on the acute toxicity data K-I Chemical believes that
prohexadione calcium does not pose any dietary risks.
    b. Non-threshold effects. Based on EPA Proposed Guidelines For
Carcinogen Risk Assessment, K-I Chemical believes that prohexadione
calcium will be classified as ``Not Likely a Human Carcinogen''. Under
the current assessment method K-I Chemical believes that EPA will
classify prohexadione calcium as Group E, no evidence of
carcinogenicity based on studies in two species. There was no evidence
of carcinogenicity in mice and rat 24-month feeding studies at the
dosage levels tested. The doses tested were adequate for identifying a
cancer risk.
    6. Animal metabolism. The metabolism in animals (goats and poultry)
is adequately understood.


    7. 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 percent 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 prohexadione calcium on peanuts, pears and
apples is 0.002570 mg/kg bw/day and utilizes 1.28% 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 12.88% of the RfD. K-I Chemical
believes that the use of prohexadione calcium on grass grown for seed
will not impact the TMRC.
    Prohexadione calcium is currently registered for use on peanuts,
apples and pears. Thus, 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 these registered uses but residues can be
expected to be slightly above the limit of quantitation for kidney of
cattle, goats, hogs, horses, and sheep. The Agency has established
tolerances in or on the raw agricultural commodities peanuts at 1.0
ppm, peanut hay at 0.6 ppm, pome fruit at 3.0 ppm, kidney of cattle,
goats, hogs, horses, and sheep, at 0.10 ppm and meat byproducts except
kidney of cattle, goats, hogs, horses, and sheep at 0.05 ppm. The use
of prohexadione calcium on grass grown for seed will require tolerances
on grass forage, hay, straw and seed screenings, but will not require
an increase in the tolerances for kidney or meat byproducts. Thus, K-I
Chemical believes there will not be an increase in human dietary
exposure to prohexadione calcium from this use.
    The following table summarizes the mean dietary exposures and the
percents of RfD occupied by these exposures.


       Summary: Chronic Dietary Exposure to Prohexadione Calcium.
------------------------------------------------------------------------
                                   DRES(Dietary Risk
              Group               Evaluation System)         % RfD
                                     mg/kg bw/day
------------------------------------------------------------------------
 U.S. Population                  2.6                 1.3
 Nursing Infants (1 Year Old)     19.3                9.7
 Non-Nursing Infants (1 Year      25.8                12.9
 Old)
 Children 1-6 Years Old           8.7                 4.4
 Children 7-12 Years Old          3.5                 1.8
------------------------------------------------------------------------


    ii. Drinking water. Other potential sources of exposure for the
general population to prohexadione calcium are residues in drinking
water and exposure from non-occupational sources. 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 No-Adverse-Effect
Level (NOAEL) of 1,000 mg/kg/day the highest dose tested 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 body weight
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 two-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 one-year feeding study in dogs
used to establish the RfD.
    iv. 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 Reference Dose, K-I Chemical believes the Reference Dose
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 percent 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 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, pears or grass grown for seed
by the Codex Alimentarius Commission.


[FR Doc. 01-7520 Filed 3-27-01; 8:45 am]