[Federal Register Volume 66, Number 60 (Wednesday, March 28, 2001)]
[Notices]
[Pages 16921-16926]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 01-7520]


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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.

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

DATES: Comments, identified by docket 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: [email protected].

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

[[Page 16922]]

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: [email protected], 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.

[[Page 16923]]

    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

[[Page 16924]]

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.

[[Page 16925]]

    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

[[Page 16926]]

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]
BILLING CODE 6560-50-S