[Federal Register Volume 64, Number 163 (Tuesday, August 24, 1999)]
[Notices]
[Pages 46191-46197]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-21944]


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ENVIRONMENTAL PROTECTION AGENCY

[PF-868; FRL-6069-6]


Notice of Filing of Pesticide Petitions

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

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

DATES: Comments, identified by the docket control number PF-868, must 
be received on or before September 23, 1999.

ADDRESSES: By mail submit written comments to: Public Information and 
Records Integrity Branch, Information Resources and Services Division 
(7502C), Office of Pesticides Programs, Environmental Protection 
Agency, 401 M St., SW., Washington, DC 20460. In person bring comments 
to: Rm. 119, CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
    Comments and data may also be submitted electronically by following 
the instructions under ``SUPPLEMENTARY INFORMATION.'' No confidential 
business information should be submitted through e-mail.
    Information submitted as a comment concerning this document may be 
claimed confidential by marking any part or all of that information as 
``Confidential Business Information'' (CBI). CBI should not be 
submitted through e-mail. Information marked as CBI will not be 
disclosed except in accordance with procedures set forth in 40 CFR part 
2. A copy of the comment that does not contain CBI must be submitted 
for inclusion in the public record. Information not marked confidential 
may be disclosed publicly by EPA without prior notice. All written 
comments will be available for public inspection in Rm. 1132 at the 
address given above, from 8:30 a.m. to 4 p.m., Monday through Friday, 
excluding legal holidays.

FOR FURTHER INFORMATION CONTACT: The product manager listed in the 
table below:

------------------------------------------------------------------------
                                   Office location/
        Product Manager            telephone number          Address
------------------------------------------------------------------------
Kathryn Boyle.................  Rm. Q616, CM #2, 703-   1921 Jefferson
                                 305-6304, e-            Davis Hwy,
                                 mail:boyle.kathryn@ep   Arlington, VA
                                 amail.epa.gov.
Cynthia Giles-Parker (PM 22)..  Rm. 229, CM #2, 703-    Do.
                                 305-7740, e-mail:
                                 giles-
parker.cynthia@epamai
l.epa.gov.
------------------------------------------------------------------------

SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions as 
follows proposing the establishment and/or amendment of regulations for 
residues of certain pesticide chemicals in or on various food 
commodities under section 408 of the Federal Food, Drug, and Comestic 
Act (FFDCA), 21 U.S.C. 346a. EPA has determined that these petitions 
contain data or information regarding the elements set forth in section 
408(d)(2); however, EPA has not fully evaluated the sufficiency of the 
submitted data at this time or whether the data supports granting of 
the petition. Additional data may be needed before EPA rules on the 
petition.
    The official record for this notice of filing, as well as the 
public version, has been established for this notice of filing under 
docket control number [PF-868] (including comments and data submitted 
electronically as described below). A public version of this record, 
including printed, paper versions of electronic comments, which does 
not include any information claimed as CBI, is available for inspection 
from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal 
holidays. The official record is located at the address in 
``ADDRESSES'' at the beginning of this document.
    Electronic comments can be sent directly to EPA at:
    [email protected]


    Electronic comments must be submitted as an ASCII file avoiding the 
use of special characters and any form of encryption. Comment and data 
will also be accepted on disks in Wordperfect 5.1 file format or ASCII 
file format. All comments and data in electronic form must be 
identified by the docket number (insert docket number) and appropriate 
petition number. Electronic comments on this notice may be filed online 
at many Federal Depository Libraries.


List of Subjects

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

    Dated: August 13, 1999.

James Jones,

Director, Registration Division, Office of Pesticide Programs.

Summaries of Petitions

    Petitioner summaries of the pesticide petitions are printed below 
as required

[[Page 46192]]

by section 408(d)(3) of the FFDCA. The summaries of the petitions were 
prepared by the petitioners and represent the views of the petitioners. 
EPA is publishing the petition summaries verbatim without editing them 
in any way. The petition summary announces the availability of a 
description of the analytical methods available to EPA for the 
detection and measurement of the pesticide chemical residues or an 
explanation of why no such method is needed.

1. Centre Internationale d'Etudes du Lindane (C.I.E.L.) and its 
member company Inquinosa S.A.

PP 9F5057

    EPA has received a pesticide petition (9F5057) from Centre 
Internationale d'Etudes du indane (C.I.E.L.) and its member company 
Inquinosa S.A., c/o Charles A. O'Conner III, Esq., McKenna & Cuneo, 
L.L.P., 1900 K Street, NW., Washington, DC 20006-1108, proposing 
pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act 
(FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 by establishing a 
tolerance for residues of lindane in or on the raw agricultural 
commodities (RAC) broccoli, brussels sprouts, cabbage, cauliflower, 
celery, collards, kale, kohlrabi, lettuce, mustard greens, spinach, and 
Swiss chard at 0.05 parts per million (ppm), corn (grain) at 0.01 ppm, 
and corn (forage and fodder) and radish at 0.1 ppm. EPA has determined 
that the petition contains data or information regarding the elements 
set forth in section 408(d)(2) of the FFDCA; however, EPA has not fully 
evaluated the sufficiency of the submitted data at this time or whether 
the data supports granting of the petition. Additional data may be 
needed before EPA rules on the petition.

A. Residue Chemistry

    1. Plant metabolism. Use of lindane as a seed treatment results in 
uptake of lindane and extensive metabolism within the plant. The 
primary residue in RAC was parent lindane. Lindane metabolizes in 
plants through the same processes found in mammalian animals, i.e. 
dehydrogenation, dehydrochlorination, hydroxylation, and conjugation. 
Thus, the terminal metabolites for plants and animals are the same 
chorophenols, chlorobenzenes, etc. and conjugates of these classes of 
compounds.
    2. Analytical method. A multi-residue method is currently being 
used by the United States food and drug administration (FDA) to 
determine lindane residues in raw and processed agricultural 
commodities, in order to monitor for tolerance compliance. The 
pesticide analytical manual (PAM) method for non-fatty foods by GLC, 
PAM 212.1, has also been validated for determination of lindane 
residues.
    3. Magnitude of residues. Lindane residues were determined in 
mustard, radish, field corn, sweet corn, and spinach, using radio-
labeled lindane applied as a seed treatment. Residues of parent lindane 
were: Radish roots; 0.030 ppm; mustard leaves, 0.017 ppm; field corn 
foliage, 0.008 ppm; sweet corn foliage 0.012 ppm; field corn grain, < 
0.01 ppm; sweet corn grain, < 0.01 ppm; and spinach, < 0.02 ppm. 
Residues in animal tissues, milk, and eggs will be negligible, based on 
transfer factors determined in animal feeding studies, the low residue 
levels in animal feed items, and the limited market share.

B. Toxicological Profile

    1. Acute toxicity--i. A rat acute oral study with an 
LD50s of 88 to 150 milligram kilogram (mgkg) (Toxicity 
Category II).
    ii. A rabbit acute dermal study with an LD50 of 500 to 
1,000 mg/kg (Toxicity Category II).
    iii. A primary eye irritation study in the rabbit showing moderate 
eye irritation, (EPA Category II).
    iv. A primary dermal irritation study in the rabbit showing 
moderate irritation, (EPA Category II).
    2. Genotoxicty. Lindane has been subject to a large number of 
gentoxicity assays using many different test systems. In vitro Ames/
Salmonella mutagenicity assays were negative for mutagenic potential. 
Other point mutations assays in bacteria were also negative. The 
induction of chromosomal aberrations was not observed in vivo assays 
and in vitro assays were either negative or equivocal. Sister chromatid 
exchange and micronucleus assays were negative. Dominant lethal assays 
gave variable results.
    3. Reproductive and developmental toxicity. Lindane is not 
considered to be a reproductive or a developmental toxin. In a 2-
generation reproduction study, the no-observed adverse effect level 
(NOAEL) for reproductive and developmental toxicity was 20 ppm. In a 
developmental toxicity study, the rat maternal NOAEL and the 
developmental NOAEL were 5 mg/kg/day. The developmental NOAEL for the 
rabbit was 10 mg/kg/day while the maternal NOAEL was less than 5 mg/kg/
day based on reduced food consumption, reduced weight gain, slight 
tachypnea and lethargy.
    4. Subchronic toxicity. Ninety-day feeding studies were conducted 
in mice and rats with lindane. The NOAEL for the mouse study was 
greater than 10 ppm highest dose tested (HDT), for the rat study, the 
NOAEL was 10 ppm (0.75 mg/kg/day). Renal effects observed were related 
to a2u-globulin and are not relevant to human safety. 
Hepatocellular hypertrophy and neurotoxicity were observed at the 
higher dose levels. A 14 week inhalation study in mice had a NOAEL 0.3 
mg/cubic meter. In a 90-day inhalation study in rats, the NOAEL was 0.6 
mg/cubic meter. Ninety-day dermal toxicity studies have been conducted 
in rats and rabbits. In both species, the NOAELs were 10 milligrams per 
kilograms bodyweight per day (mg/kg bw/day).
    5. Chronic toxicity. A 2-year feeding study was conducted in dogs 
with lindane. The NOAEL was for this study 50 ppm. In a 2-year feeding 
study in rats, hepatocellular hypertrophy and renal effects related to 
a2u-globulin were observed above the NOAEL of 0.7 (males) 
and 0.8 (females) mg/kg bw/day. Carcinogenicity - Lindane is not 
carcinogenic to rats. A 2-year combined chronic toxicity/oncogenicity 
study in the rat was negative for carcinogenicity and had a chronic 
toxicity NOAEL of 10 ppm (0.47 mg/kg bw/day) based on a slight increase 
in mortality and effects on the liver. A total of 8 mouse oncogenicity 
studies have been conducted in several strains of mice. The results of 
these studies have been variable and none of the studies are considered 
by the Agency to be adequate for a cancer risk assessment. A ninth 
study is in progress.
    6. Animal metabolism. The metabolism of lindane has been thoroughly 
investigated. Lindane does not appear to bioaccumulate in tissues. 
Lindane is rapidly absorbed and metabolized. The metabolism of lindane 
occurs via several different pathways. Major routes of metabolism 
include stepwise elimination of chlorines and conjuations with sulfates 
and glucuronides. Another pathway is via the formation of mercapurates.
    7. Metabolite toxicology. Dietary residues are comprised of lindane 
and a variety of metabolites. The dietary residues are qualitatively 
the same as those formed in the rat and have thus been bioassayed in 
the available toxicity studies. These metabolites are not considered to 
present a significant toxicological risk.
    8. Endocrine disruption. There was no evidence that exposure to 
lindane had any effect on reproduction, fertility or mating indices, 
development or maturation of embryos, or development, growth and 
survival of offspring in the battery of short-term, chronic,

[[Page 46193]]

reproductive and, developmental mammalian, avian and aquatic studies 
conducted. There were no gross or microscopic pathologic effects in 
endocrine organs or endocrine-sensitive tissues, or in any reproductive 
organs, tissues or endpoints that were considered related to exposure 
to lindane. There is negligible risk of endocrine disruption in humans 
or wildlife as a result of these proposed uses.

C. Aggregate Exposure

    1. Dietary exposure--i. Food. Estimates of dietary exposure to 
residues of lindane from the proposed uses are extremely low. A 
reference dose (RfD) of 0.0047 was established by EPA based upon a 100-
fold uncertainty factor and the NOAEL in the chronic rat study. Maximum 
dietary residues from the requested uses result in an exposure that is 
less than 2% of the reference dose (RfD) for children 1-6 years, the 
most sensitive sub-population.
    ii. Drinking water. Given the use pattern (seed treatment) strong 
soil binding characteristics and low soil mobility of lindane, the risk 
of significant ground and surface water contamination and exposure via 
drinking water is considered to be negligible.
    2. Non-dietary exposure. There are no currently registered 
pesticidal uses of lindane that would result in non-dietary exposure.

D. Cumulative Effects

    Lindane falls into the common category of chlorinated hydrocarbon 
insecticides however, there is no information to suggest that lindane 
has a common mechanism of mammalian toxicity with any other pesticide. 
It is not appropriate to combine exposures in this case.

E. Safety Determination

    1. U.S. population. As presented above, the exposure of the U.S. 
general population to lindane is low, and the risks, based on 
comparisons to the reference dose, are negligible. Margins of safety 
are very large.
    2. Infants and children. In assessing the potential for additional 
sensitivity of infants and children to residues of lindane, CIEL 
considered data from developmental toxicity studies in the rat, and 
rabbit and a 2-generation reproduction study in rats. No developmental 
or reproductive effects were observed up in the absence of parental 
toxicity in any of the three studies. Using the same conservative 
assumptions that were made previously for the dietary exposure analysis 
for the U.S. general population, the percent of the RfD utilized by 
pre-adult sub-populations is less than 2%. CIEL concludes that there is 
a reasonable certainty that no harm will result to infants and children 
from aggregate exposure to lindane residues.

F. International Tolerances

    International maximum residue levels (MRLs) have been established 
for aproximately 30 commodities. The MRL values for commodities 
represented in this petition include; 2 ppm on head lettuce and 
spinach, 1 ppm on kohlrabi and radish, and 0.5 ppm on brussels sprouts, 
cabbage, cauliflower, and cereal grain.

2. K-I Chemical U.S.A. Inc.

PP 8F4941

    EPA has received a pesticide petition (8F4941) from K-I Chemical 
U.S.A. Inc., Westchester Financial Center, 11 Martine Avenue, 9th 
Floor, White Plains, NY, 10606 proposing, pursuant to section 408(d) of 
the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to 
amend 40 CFR part 180 by establishing a tolerance for residues of 
prohexadione calcium (cyclohexanecarboxylic acid, 3, 5-dioxo-4-(1-
oxopropyl)-, ion(1-), calcium, calcium salt) in or on the raw 
agricultural commodity peanut nutmeat at 1.0, peanut hay at 0.6, pome 
fruit at 3.0, and cattle meat byproduct (kidney) at 0.1 parts per 
million (ppm). EPA has determined that the petition contains data or 
information regarding the elements set forth in section 408(d)(2) of 
the FFDCA; however, EPA has not fully evaluated the sufficiency of the 
submitted data at this time or whether the data supports granting of 
the petition. Additional data may be needed before EPA rules on the 
petition.
    In the Federal Register of August 5, 1998 (63 FR 41828) (FRL-5799-
6) EPA issued a notice of filing of pesticide petition 8F4941 from K-I 
Chemical U.S.A. Inc. at the above address proposing to amend 40 CFR 
part 180 by establishing tolerances for residues of prohexadione 
calcium in or on the raw agricultural commodities (RAC) peanut nutmeat 
and hay at 0.8 and 0.4 ppm respectively. EPA has received an amendment 
to PP 8F4941 from K-I Chemical U.S.A. Inc., proposing to amend the 
earlier petition by increasing the tolerances for residues on peanut 
nutmeat and hay, and by proposing to amend 40 CFR part 180 by 
establishing tolerances on pome fruit and cattle meat byproducts. This 
notice contains information submitted in addition to that contained in 
the August 5, 1998 notice.

A. Residue Chemistry

    1. Plant metabolism. The metabolism in plants (peanuts and apples) 
and animals (goats and poultry) is adequately understood.
    2. Analytical method. The proposed analytical method involves 
homogenization, extraction, filtration, partition and cleanup, 
methylation and analysis by a gas chromatography system with a mass 
selective detector. The limit of quantitation (LOQ) is 0.05 ppm.
    3. Magnitude of residues. Twelve peanut trials were conducted with 
prohexadione calcium in the principle peanut growing regions of the 
country (NC, SC, GA, AL, FL, OK, TX). Prohexadione calcium was applied 
to peanuts three times at the rate of 0.125 lbs active ingredient acre 
(ai/A). Peanut hay and nutmeat were analyzed for residues of 
prohexadione (free acid). Prohexadione residues in the nutmeat ranged 
from < 0.05 to 0.30 ppm. Residues in hay ranged from < 0.05 to 0.26 
ppm. The residue values in this study were reported as prohexadione 
free acid. The highest residue values for peanut nutmeat and hay were 
converted to prohexadione calcium equivalents for the tolerance 
expression. Therefore, the proposed tolerance for prohexadione calcium 
in/on peanut nutmeat is 1.0 ppm based on the conversion of the highest 
peanut nutmeat raw agricultural commodities (RAC) ppm for prohexadione 
(0.795 ppm) to prohexadione calcium equivalents (0.895 ppm). The 
proposed tolerance for prohexadione calcium in/on peanut hay is 0.6 ppm 
and it is based on the conversion the highest peanut hay RAC ppm for 
prohexadione (0.457 ppm) to prohexadione calcium equivalents (0.539 
ppm).
    A study was conducted to determine the level of prohexadione 
calcium derived residues in or on processed commodities. Peanut samples 
treated at an exaggerated rate were processed into peanut meal and 
refined oil. Peanut nutmeat and processed commodities were analyzed for 
prohexadione. Residues in the meal were less than in the nuts, and no 
residues were detected in the refined oil. Therefore, there was no 
concentration of prohexadione residues in processed commodities.
    Twenty apple trials were conducted with prohexadione calcium in the 
principle apple growing regions of the country (NY, PA, NC, VA, MI, WI, 
CO, UT, CA, WA, ID, and OR) in order to determine the magnitude of 
prohexadione residues in/on apples.

[[Page 46194]]

 Apple trees received two foliar applications of prohexadione calcium 
with a 21 day interval between each application and the second 
application was made 45 days prior to harvest (45 day PHI). The target 
rate for each application was 0.85 lbs a.i./A and a maximum seasonal 
application rate of 1.7 lbs a.i./A. Prohexadione residues in apples 
ranged from < 0.05 ppm to 2.23 ppm. The residue values in this study 
were reported as prohexadione free acid. The highest apple RAC ppm for 
prohexadione (2.23 ppm) when converted to prohexadione calcium 
equivalents is 2.63 ppm.
    Apple samples treated with prohexadione calcium at an exaggerated 
rate were processed according to commercial practices into washed 
apples, wet pomace, and fresh juice. Samples of unwashed apples, washed 
apples, wet pomace, and juice were analyzed for residues of 
prohexadione. Residues of prohexadione in the washed apples, pomace and 
juice were less than in the unwashed whole fruit. Therefore, there is 
no concentration of prohexadione residues in the processed commodities 
and separate tolerances for processed fractions are not necessary.
    Eight pear trials were conducted with prohexadione calcium in the 
principle pear growing regions of the United States (NY, CA, WA, ID, 
and OR) to determine the magnitude of prohexadione calcium residues in/
on pear raw agricultural commodity. Pear trees received one foliar 
application of prohexadione calcium at an application rate of 1.7 lbs 
a.i./A. Pears were harvested 45 days after the application (45 day 
PHI). Prohexadione calcium residues in pears ranged from 0.220 ppm to 
0.985 ppm.

B. Toxicological Profile

    1. Acute toxicity. Based on available acute toxicity data 
prohexadione calcium does not pose any acute toxicity risks. The acute 
toxicity studies place technical prohexadione calcium and its 
formulated end-use products in acute toxicity category III for acute 
dermal; and in acute toxicity category IV for acute oral, acute 
inhalation, eye irritation, and skin irritation and the technical 
material is not a skin sensitizer.
    2. Genotoxicty. Ames Test (1 Study; point mutation): Negative; In 
Vitro V79 Cells CH/HGPRT Locus Mammalian Cell Mutation Assay (1 Study; 
point mutation): Negative; In Vitro CHO Cytogenetic Assay (1 Study; 
Chromosome Damage): Negative; In Vivo Mouse Micronucleus (1 Study; 
Chromosome Damage): Negative; In Vivo Rat Bone Marrow Cytogenetic Assay 
(1 Study; Chromosomal Damage): Negative; Rec Assay (1 Study; DNA damage 
and repair): Negative; In Vitro Rat Hepatocyte (1 Study; DNA damage and 
repair): Negative.
    Prohexadione calcium has been tested in a total of 7 genetic 
toxicology assays consisting of in vitro and in vivo studies. Based on 
the results described above, it can be stated in summary that 
prohexadione calcium did not show any mutagenic activity when tested 
under the conditions of the studies mentioned above. Therefore, 
prohexadione calcium does not pose a mutagenic hazard to humans.
    3. Reproductive and developmental toxicity. The reproductive and 
developmental toxicity of prohexadione calcium was investigated in a 2-
generation rat reproduction study as well as in rat and rabbit 
teratology studies. The 2-generation rat reproduction study was 
conducted at dose levels of 0, 500, 5,000, and 50,000 ppm. There were 
no adverse effects on reproduction parameters seen even at the dose 
level of 50,000 ppm (5164 milligram kilogram bodyweight (mg/kg bw) for 
males and 5,600 mg/kg bw for females). The no-observed adverse effect 
level (NOAEL) for parental systemic toxicity was 500 ppm (48 mg/kg bw 
for males and 51 mg/kg bw for females) and the NOAEL for developmental 
toxicity was 5,000 ppm (270 mg/kg bw for females). Stomach lesions were 
observed at 5,000 ppm. Two mid-dose males and two males and one female 
of the high-dose from the Fo died. Body weight and food consumption 
changes and slight transient reduction in offspring growth were noted 
at 50,000 ppm. No impairment of reproductive function was observed at 
any of the dose levels tested.
    Prohexadione calcium had no teratogenic potential at dose levels as 
high as 1,000 mg/kg bw in the rat and 350 mg/kg bw in the rabbit. The 
NOAEL for maternal toxicity in the teratogenicity studies is 100 mg/kg 
bw (rabbit) and 1000 mg/kg bw (rat), and the NOAEL for fetotoxicity in 
the teratogenicity studies is 350 mg/kg bw (rabbit) and 1,000 mg/kg bw 
(rat). The reproductive and developmental studies are summarized below.
    A developmental study was conducted via oral gavage in rats at dose 
levels of 0, 100, 300, and 1,000 highest dose tested (HDT) mg/kg bw. 
The NOAEL for developmental and maternal toxicity was 1,000 mg/kg bw, 
the HDT. This was based on the fact that there were no signs of 
maternal toxicity, fetotoxicity or teratogenic effects.
    A developmental study was conducted via oral gavage in rabbits at 
dose levels of 0, 40, 200, and 750 HDT mg/kg bw. The NOAEL for 
development toxicity was 40 mg/kg bw and the NOAEL for maternal 
toxicity was 40 mg/kg bw based on the following findings. Toxicity in 
the form of maternal mortality with values 16/20 and 4/20 was excessive 
in the mid- and high-dose group, respectively. Fetal deaths also 
occurred. Dose levels believed to exceed maximum tolerance dose (MTD); 
NOAELs for maternal and developmental effects are not considered 
reliable and useful for risk characterization. No teratogenic effects 
were noted in this study.
    An additional teratology study in the same strain of rabbits was 
conducted at dose levels of 0, 30, 75, and 150 mg/kg bw. The NOAEL for 
development toxicity was 150 mg/kg bw and the NOAEL for maternal 
toxicity was 30 mg/kg bw based on the following findings. One low-, two 
mid-, and three high-dose animals died prior to day 29, however, at the 
high dose group one died of gavage error and another pneumonia, and the 
reason for the other deaths could not be determined. No teratogenic or 
fetoxtoxic effects were noted in this study.
    An oral range-finding gavage teratology study in the same strain of 
rabbits (5 animals/dose level) was conducted in another independent 
laboratory. The dose levels selected were 0, 20, 100, 250, 500, and 
1,000 mg/kg bw. This range finding study was conducted with a limited 
number of animals and a limited scope of examination. Based on these 
results the dose levels selected for the main study at this independent 
laboratory were 0, 30, 100, and 350 mg/kg bw. The NOAEL for development 
toxicity was 350 mg/kg bw and the NOAEL for maternal toxicity was 100 
mg/kg bw based on the following findings. At the 350 mg/kg bw dose 
group transient bw decreases and two abortions were observed. No 
teratogenic or fetotoxic effects were noted in this study.
    Conclusions from teratology studies. More than one definitive 
rabbit teratology study was conducted because issues associated with 
exceeding the MTD in the first study and spurious deaths, apparently 
not compound-related, in the second study confounded the determination 
of a NOAEL for maternal toxicity. There were no signs of teratogenic or 
fetotoxic effects in any study other than the first definitive study in 
which maternal deaths above the MTD apparently occurred. It is BASF's 
and K-1 Chemicals' opinion based on a thorough review of the teratology 
studies that the following overall NOAELs can be derived for the

[[Page 46195]]

teratology studies: - NOAEL maternal toxicity: 100 mg/kg bw (rabbit) 
and, 1,000 mg/kg bw (rat). - NOAEL prenatal toxicity: 350 mg/kg bw 
(rabbit) and, 1,000 mg/kg bw (rat).
    The overall NOAEL of 100 mg/kg bw for maternal toxicity in rabbits 
is based on the last rabbit study, and is based on reduction of bw gain 
and food intake at dose levels of 250 mg/kg bw onwards. The NOAEL of 
350 mg/kg bw for fetotoxic effects in the rabbit is also based on a 
reduction in bw gain. Based on the overall study results, it is 
concluded that there are no developmental effects of concern.
    Based on preliminary discussions with EPA concerning the rabbit 
teratology studies, EPA concluded that the definitive NOAEL for 
maternal toxicity considering all of the studies ranges from 30 to 100 
mg/kg bw. Agency scientists further stated that they needed to review 
the studies in detail to ultimately determine the definitive NOAEL for 
maternal toxicity. This uncertainty associated with maternal toxicity 
in the rabbit teratology studies does not impact risk considerations 
since the risk assessment is based on a lower NOAEL (20 mg/kg bw) in 
the chronic dog study.
    4. Subchronic toxicity. The subchronic toxicity of prohexadione 
calcium was investigated in 90-day feeding studies with rats, mice, and 
dogs. In all these studies, prohexadione calcium displayed low 
toxicity. Prohexadione calcium showed no signs of neurotoxicity in a 
90-day neurotoxicity rat study. Additionally, the results seen in four 
week feeding range-finding studies for rats and dogs were similar to 
the findings observed in the 90-day studies in the same animals.
    5. Chronic toxicity. Based on review of the available data, the 
reference dose (RfD) for prohexadione calcium will be based on a 1-year 
feeding study in dogs with a threshold NOAEL of 20 mg/kg/day. Using an 
uncertainty factor of 100, the RfD is calculated to be 0.2 mg/kg/day. 
The following are summaries of studies submitted to EPA. Prohexadione 
calcium was administered to Beagle dogs at dietary concentrations of 0, 
20, 200, and 1,000 mg/kg bw for 12 months. Slight changes were observed 
for hematological and clinical chemical parameters and dilated 
basophilic renal tubules (without histopathological concurrence) at 
dose levels greater than 200 mg/kg bw. The NOAEL was 20 mg/kg bw for 
the males and female dogs.
    The 24-month Fisher 344 rat chronic/carcinogenic feeding study was 
conducted at dose levels of 0, 400, 2,000, 10,000, and 20,000 ppm with 
80 male and 80 female animals per dose group. After 26, 52, and 78 
weeks, 10 animals were sacrificed (satellite groups). The remaining 
animals were autopsied after 104 weeks of diet administration. The 
NOAEL for chronic toxicity was 2,000 ppm for males (93.9 mg/kg bw) and, 
2,000 ppm for females (114 mg/kg bw). The following effects were 
observed in the 10,000, and 20,000 ppm groups: (1) Decreased bws were 
observed in both male and female rats at the 20,000 ppm dose level; (2) 
clinical chemical effects (i.e., lower potassium, bilirubin, and 
glucose levels) were observed in male and female rats at the 20,000 ppm 
dose level, in the 10,000 ppm dose level, reduced glucose levels were 
only seen in the males, and increased albumin/globulin ratios, sodium, 
chloride and calcium levels were observed only in the females; (3) 
increased urine volumes and lower specific gravity were observed in the 
mid-high and high-dose groups for both male and female rats; (4) minor 
changes in organ weights were noted for animals of the high dose group 
only, which consisted of increased relative liver, adrenal and kidney 
weights, the latter also absolute in females only, at week 26; at the 
end of the study decreased liver weights and increased relative brain 
and testis weights were noted and these changes were considered to be 
associated with the decreased bws; (5) macroscopic findings revealed an 
increase of pituitary nodules in the high dose group for both male and 
female rats which was not confirmed histopathologically and submucosal 
ectopic tissue in the glandular stomach was found in both male and 
female rats in the highest dose levels that was confirmed by 
histopathology which showed an increase of squamous cell hyperplasia in 
males and of basal cell hyperplasia in the forestomach; (6) a higher 
incidence of cellular hyperplasia was observed in the thyroid in the 
mid-high and high dose levels for male and female rats; and (7) no 
increased incidence of neoplasms occurred at any dose levels tested in 
this study.
    In the 24-month B6C3F1 mouse feeding study, conducted at dose 
levels of 0, 400, 2,000, 20,000, and 40,000 ppm with interim sacrifices 
at 52 and 78 weeks, prohexadione calcium was negative for oncogenicity. 
The NOAEL for chronic toxicity was 2,000 ppm for males (279 mg/kg bw) 
and 2,000 ppm for females (351 mg/kg bw). The following effects were 
observed in the 20,000 and 40,000 ppm groups: (1) Statistically 
significant decreases in body weights were observed in male mice at the 
20,000 ppm dose level and in female mice at the 40,000 ppm dose level; 
(2) a variety of changes in hematological parameters were noted in the 
respective investigations at weeks 52, 78, and 104, however, most of 
the changes were not dose related or consistent over time; (3) 
increased absolute and/or relative heart, brain, testes, liver, ovary, 
and kidney weights were observed in the mid-high and highest dose 
groups with a slight progression of severity to the highest dose group; 
(4) a higher incidence of splenomegaly was observed only in the male 
mice of the highest dose group; (5) histopathological examinations 
revealed an ectopic proliferation of the mucosal and glandular 
epithelium in the submucosal layer of the glandular stomach in male and 
female mice in the highest dose group tested, these changes were 
assessed to represent heteroplastic, ectopic proliferative changes 
accompanied by lumen dilatation and cytological degeneration; (6) a 
higher incidence of hyperkeratosis of the forestomach was observed in 
both male and female mice and hyperplasia of the squamous epithelium of 
the forestomach of female male mice was observed in the highest dose 
group tested; (7) vacuolic changes in the exocrine pancreas of the high 
dose female were observed; and (8) no increased incidence of neoplasms 
occurred at any dose levels tested in this study.
    6. Endocrine disruption. No specific tests have been conducted with 
prohexadione calcium to determine whether the chemical may have an 
effect in humans that is similar to an effect produced by a naturally 
occurring estrogen or other endocrine effects. However, there were no 
significant findings in other relevant toxicity studies (i.e., 
subchronic and chronic toxicity, teratology and multi-generation 
reproductive studies) which would suggest that prohexadione calcium 
produces endocrine related effects.

C. Aggregate Exposure

    1. Dietary exposure--i. Food. For purposes of assessing the 
potential dietary exposure, K-I Chemical has estimated aggregate 
exposure based on the Theoretical Maximum Residue Contribution (TMRC) 
from the proposed tolerances for prohexadione calcium in/on peanut 
nutmeat at 1.0 ppm and apples (pome fruit) at 3.0 ppm. A maximum 
residue level of 1.0 ppm was used for pears. The TMRC is a ``worse 
case'' estimate of dietary exposure since it is assumed that 100% of 
all crops for which tolerances are established are treated and that 
pesticide residues are always found at the tolerance levels. The TMRC 
from the proposed use of

[[Page 46196]]

prohexadione calcium on peanuts, pears and apples is 0.002570 mg/kg bw/
day and utilizes 1.3% of the RfD for the overall U.S. population. The 
exposure of the most highly exposed subgroup in the population, non-
nursing infants (< 1 year old), is 0.025758 mg/kg bw/day and utilizes 
12.9% of the RfD.
    Dietary exposure to residues of prohexadione calcium in or on food 
will be limited to residues on peanuts, apples and pears. Apple pomace, 
peanut meal and hay are fed to animals; thus exposure of humans to 
residues in feed items might result if such residues carry through to 
meat, milk, poultry, or eggs. However, K-I Chemical has concluded that 
there is no reasonable expectation that measurable residues of 
prohexadione calcium will occur in meat, milk, poultry, or eggs from 
this use but residues can be expected to be slightly above the limit of 
quantitation for cow kidney. Therefore, K-I Chemical is proposing a 
tolerance in/on cattle meat byproduct (kidney) at 0.1 ppm. There are no 
currently registered uses for prohexadione calcium on food or feed 
crops in the U.S. and thus, there are no established U.S. tolerances.
    The following table summarizes the mean dietary exposures and the 
percents of RfD occupied by these exposures.

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

    ii. Drinking water. Based on studies submitted to EPA for 
assessment of environmental risk, K-I Chemical does not anticipate 
exposure to residues of prohexadione calcium in drinking water. There 
is no established Maximum Concentration Level (MCL) or Health Advisory 
Level (HAL) for prohexadione calcium under the Safe Drinking Water Act 
(SDWA).
    2. Non-dietary exposure. K-I Chemical has not estimated non-
occupational exposure to prohexadione calcium since the only pending 
registration is limited to commercial crop production. Prohexadione 
calcium products are not labeled for any residential uses, therefore 
eliminating the potential for residential exposure. Thus, potential for 
non-occupational exposure of the general population to prohexadione 
calcium is not present.

D. Cumulative Effects

    K-I Chemical is aware of only one other registered compound, 
trinexapac-ethyl [4-(cyclopropyl-a-hydroxymethylene)-3,5-dioxo-
cyclohexanecarboxylic acid ethylester], that has a structure similar to 
prohexadione calcium. However, K-I Chemical has no information that 
would indicate that the two compounds have a common mechanism of 
toxicity. Furthermore, trinexapac is registered for use only on turf. 
Therefore, even if the compounds were considered similar there would be 
no cumulative dietary exposure issue because of the differences in use 
patterns. In summary, dietary exposure to prohexadione calcium should 
not result in cumulative toxicity with other known chemical compounds.

E. Safety Determination

    1. U.S. population. Using the conservative exposure assumptions 
described above and based on the completeness and the reliability of 
the toxicity data, K-I Chemical has estimated that aggregate exposure 
to prohexadione calcium will utilize 1.3% of the RfD for the U.S. 
population. K-I Chemical concludes that there is a reasonable certainty 
that no harm will result from the aggregate exposure to residues of 
prohexadione calcium, including anticipated dietary exposure and non-
occupational exposures.
    2. Infants and children--i. Developmental toxicity in the rat. A 
developmental study was conducted via oral gavage in rats with dosages 
of 0, 100, 300, and 1,000 HDT mg/kg/day with a NOAEL of 1,000 mg/kg/day 
the HDT for developmental and maternal toxicity based on the fact that 
no effects were observed for any test parameter measured in this study. 
Therefore, these NOAEL values are significantly higher than the NOAEL 
from the 1-year feeding study in dogs used to establish the RfD.
    ii. Developmental toxicity in the rabbit. A series of developmental 
studies were conducted via oral gavage in rabbits with dosages ranging 
from 0 to 750 mg/kg/day with a development toxicity NOAEL of 350 mg/kg/
day and a maternal toxicity NOAEL of 100 mg/kg/day based on bw gain 
reductions. These NOAEL values are higher than the NOAEL from the 1-
year feeding study in dogs used to establish the RfD.
    iii. Reproductive toxicity. A 2-generation reproduction study with 
rats fed dosages of 0, 500, 5,000, and 50,000 mg/kg/day resulted in a 
reproductive NOAEL of 50,000 ppm (5,300 mg/kg bw/day), a developmental 
NOAEL of 5,000 ppm (270 mg/kg bw/day), and a maternal toxicity NOAEL of 
500 ppm (50 mg/kg bw/day). The developmental NOAEL was based on a 
slight, transient reduction in offspring growth. The maternal NOAEL is 
similar and the reproductive NOAEL is significantly higher (above the 
limit dose of 1,000 mg/kg/day) than the NOAEL from the 1-year feeding 
study in dogs used to establish the RfD.
    3. Reference dose. Since developmental and reproductive toxicity 
occurs at levels above the levels shown to exhibit parental toxicity 
and since these levels are significantly higher than those used to 
calculate the RfD, K-I Chemical believes the RfD of 0.20 mg/kg/day (20 
mg/kg/day and an Uncertainty Factor of 100) is an appropriate measure 
of safety for infants and children.
    Dietary exposure of the most highly exposed subgroup in the 
population, non-nursing infants (< 1 year old) is 0.025758 mg/kg bw/
day. This accounts for 12.9% of the RfD. There are no residential uses 
of prohexadione calcium and contamination of drinking water is 
extremely unlikely. In addition, there were no significant findings in 
relevant toxicity studies (i.e., subchronic and chronic toxicity, 
teratology and multi-generation reproductive studies) which would 
suggest that prohexadione calcium produces endocrine related effects. 
Therefore, based on the completeness and reliability of the toxicity 
data and the conservative exposure assessment, K-I Chemical concludes 
that there is a

[[Page 46197]]

reasonable certainty that no harm will result to infants and children 
from aggregate exposure to the residues of prohexadione calcium, 
including all anticipated dietary exposure and all other non-
occupational exposures.

F. International Tolerances

    A maximum residue level (MRL) has not been established for 
prohexadione calcium in peanuts, apples or pears by the Codex 
Alimentarius Commission.
[FR Doc. 99-21944 Filed 8-23-99; 8:45 am]
BILLING CODE 6560-50-F