[Federal Register Volume 62, Number 133 (Friday, July 11, 1997)]
[Notices]
[Pages 37246-37256]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-18085]


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ENVIRONMENTAL PROTECTION AGENCY

[PF-741; FRL-5723-1]


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-741, must 
be received on or before August 11, 1997.

ADDRESSES: By mail submit written comments to: Public Response and 
Program Resources Branch, Field Operations Division (7505C), Office of 
Pesticides Programs, Environmental Protection Agency, 401 M St., SW., 
Washington, DC 20460. In person bring comments to: Rm. 1132, 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    
------------------------------------------------------------------------
George LaRocca (PM 13)........  Rm. 204, CM #2, 703-    1921 Jefferson  
                                 305-6100, e-            Davis Hwy,     
                                 mail:[email protected]   Arlington, VA  
                                 v.                                     
Mary Waller (PM 21)...........  Rm. 265, CM #2, 703-    Do.             
                                 308-9354, e-                           
                                 mail:waller.mary@epam
ail.epa.gov.                           
Cynthia Giles-Parker (PM 22)..  Rm. 229, CM #2, 703-    Do.             
                                 305-5540, 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 raw 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, as well as the public version, 
has been established for this notice of filing under docket control 
number PF-741 (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''.
    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 control number PF-741 and appropriate petition 
number. Electronic comments on this notice may be filed online at many 
Federal Depository Libraries.
    Authority: 21 U.S.C. 346a.

List of Subjects

    Environmental protection, Agricultural commodities, Food

[[Page 37247]]

additives, Feed additives, Pesticides and pests, Reporting and 
recordkeeping requirements.

    Dated: July 2, 1997.

Peter Caulkins,
Acting Director, Registration Division, Office of Pesticide Programs.

Summaries of Petitions

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

1. ISK Biosciences Corporation

PP 6F4611

    EPA has received a pesticide petition (PP 6F4611, (dated 6/25/95) 
from ISK Biosciences Corporation (``ISK''), 5966 Heisley Road, P.O. Box 
8000, Mentor, Ohio 44061-8000 proposing pursuant to section 408(d) of 
the Federal Food, Drug and Cosmetic Act, 21 U.S.C. section 346a(d), to 
amend 40 CFR part 180.275 by establishing tolerances for residues of 4-
hydroxy-2,5,6-trichloroisophthalonitrile (SDS-3701), a metabolite of 
the fungicide chlorothalonil, in/on raw agricultural meat and milk 
commodities as follows:


                                                                        
------------------------------------------------------------------------
                 Commodity                        Parts per million     
------------------------------------------------------------------------
Cattle, fat...............................  0.1                         
Cattle, kidney............................  0.5                         
Cattle, meat..............................  0.03                        
Cattle, mbyp (except kidney)..............  0.05                        
Goats, fat................................  0.1                         
Goats, kidney.............................  0.5                         
Goats, meat...............................  0.03                        
Goats, mbyp (except kidney)...............  0.05                        
Hogs, fat.................................  0.1                         
Hogs, kidney..............................  0.5                         
Hogs, meat................................  0.03                        
Hogs, mbyp (except kidney)................  0.05                        
Horses, fat...............................  0.1                         
Horses, kidney............................  0.5                         
Horses, meat..............................  0.03                        
Horses, mbyp (except kidney)..............  0.05                        
Milk......................................  0.1                         
Sheep, fat................................  0.1                         
Sheep, kidney.............................  0.5                         
Sheep, meat...............................  0.03                        
Sheep, mbyp (except kidney)...............  0.05                        
------------------------------------------------------------------------


A. Residue Chemistry

    1. Plant/Animal metabolism. The nature of the residue of 
chlorothalonil in plants and animals, including ruminants, is 
adequately understood. Chlorothalonil is not systemic in plants. 
Chlorothalonil is rapidly metabolized in the ruminant and is not 
transferred in animals to meat and milk through dietary consumption of 
feedstuffs from crops treated with chlorothalonil products. Analytical 
method development studies and storage stability studies with 
chlorothalonil demonstrated that it is not stable in meat or milk. 
Studies have determined that the chlorothalonil metabolite, 4-hydroxy-
2,5,6-trichloroisophthalonitrile, may be present in meat and milk from 
dietary intake of animal feed items from chlorothalonil treated crops. 
The metabolite, 4-hydroxy-2,5,6-trichloroisophthalonitrile, is stable 
in meat and milk.
    2. Analytical method. The analytical method (electron capture gas 
chromatography) is adequate for analysis of 4-hydroxy-2,5,6-
trichloroisophthalo-nitrile in meat and milk and has been submitted to 
the Agency for inclusion in PAM Vol. II. The method has undergone a 
successful method validation by an independent laboratory.
    3. Magnitude of the residues. Residue studies and metabolism 
studies have shown that residues of chlorothalonil per se are not 
expected to transfer from feed items to meat/milk but residues of 4-
hydroxy-2,5,6-trichloroisophthalonitrile could occur in these 
commodities both from direct transfer of residues of the metabolite 
found on feedstuffs in the diet and from a low percentage conversion of 
chlorothalonil to the metabolite in the animal. Due to the instability 
of chlorothalonil per se in meat and milk tissues, residues would not 
be expected to occur even from misuse of chlorothalonil. The 
chlorothalonil related residue found in meat and milk is 4-hydroxy-
2,5,6-trichloroisophthalonitrile. The submitted lactating dairy cow 
feeding study is adequate to determine appropriate tolerance levels in 
meat and milk. Analytical results are supported by frozen storage 
stability data. No significant losses of 4-hydroxy-2,5,6-
trichloroisophthalonitrile occurred during frozen storage of spiked 
analytical samples. Studies have shown that 4-hydroxy-2,5,6-
trichloroisophthalonitrile does not persist long in animals and that it 
does not bioaccumulate in animal tissues.
    The proposed tolerances are adequate to cover residues of 4-
hydroxy-2,5,6-trichloroisophthalonitrile that might occur in meat and 
milk as a result of chlorothalonil uses on presently-registered crops 
that may involve animal feed items.

B. Toxicological Profile

    The following studies on file with the Agency support this 
petition.
    1. Acute toxicity. Acute toxicity studies include an acute oral rat 
study on technical chlorothalonil with an LD50 >10,000 mg/
kg, an acute dermal toxicity study in the rabbit with an 
LD50 >20,000 mg/kg, a four-hour inhalation study with finely 
ground technical chlorothalonil resulting in a 4-hour LC50 
of 0.092 mg/L (actual airborne concentration), a primary eye irritation 
study with irreversible eye effects in the rabbit at 21 days, a primary 
dermal irritation study showing technical chlorothalonil is not a 
dermal irritant, and a dermal sensitization study showing technical 
chlorothalonil is not a skin sensitizer.
    Acute oral toxicity studies with the 4-hydroxy metabolite, indicate 
the oral LD50s in male and female rats were 332 and 242 mg/
kg respectively.
    2. Genotoxicity. The mutagenic potential of chlorothalonil has been 
evaluated in a large number of studies covering a variety of endpoints. 
The overall conclusion is that chlorothalonil is not mutagenic.
    Mutagenicity studies with chlorothalonil include gene mutation 
assays in bacterial and mammalian cells; in vitro and in vivo 
chromosomal aberration assays; DNA repair assays in bacterial systems; 
and cell transformation assays. All were negative with the following 
two exceptions:
    a. Chlorothalonil was positive in an in vitro chromosomal 
aberration assay in (Chinese Hamster Ovary (CHO) cells without 
metabolic activation but was negative with metabolic activation.
    b. In vivo chromosomal aberration studies in rats and mice were 
negative and one study in the Chinese hamster was equivocal. The 
results of this study could not be confirmed in a subsequent study at 
higher doses. The conclusion was that chlorothalonil does not cause 
chromosome aberrations in bone marrow cells of the Chinese hamster. It 
can be concluded that chlorothalonil

[[Page 37248]]

does not have clastogenic potential in intact mammalian systems.
    In bacterial DNA repair tests, chlorothalonil was negative in 
Bascillus subtilis, but was positive in Salmonella typhimurium. In an 
in vivo DNA binding study in rats with 14C-chlorothalonil, there was no 
covalent binding of the radiolabel to the DNA of the kidney, the target 
organ for chlorothalonil toxicity in rodents.
    c. The mutagenic potential of the 4-hydroxy metabolite has also 
been evaluated for a variety of endpoints and it is concluded that it 
is not mutagenic. The 4-hydroxy metabolite has been tested in gene 
mutations assays in bacterial and mammalian cells; in vivo and in vitro 
chromosome aberration studies; a DNA repair assay in the Salmonella 
typhimurium; and a cell transformation assay.
    The 4-hydroxy metabolite was positive in only one assay, an in 
vitro chromosome aberration assay in CHO cells. In vivo, the 4-hydroxy 
metabolite was negative in a bone marrow chromosome aberration study in 
Chinese hamsters. Dominant lethal studies in rats and mice were clearly 
negative in rats and equivocal in mice. Because it was negative in vivo 
in studies to test for chromosome damage, it can be concluded that the 
4-hydroxy metabolite does not have clastogenic potential in intact 
mammalian systems
    3. Developmental and reproductive toxicity. a. A developmental 
toxicity study with rats given gavage doses of 0, 25, 100, and 400 mg/
kg body weight/day of chlorothalonil from days 6 through 15 of 
gestation resulted in a no observed effect level (NOEL) for maternal 
toxicity of 100 mg/kg/day based on increased mortality, reduced body 
weight, and a slight increase in early resorptions at the highest dose. 
There were no developmental effects observed at any dose in this study.
    b. A developmental toxicity study in rabbits given gavage doses of 
0, 5, 10, or 20 mg/kg/day of chlorothalonil on days 7 through 19 of 
gestation resulted in a maternal NOEL of 10 mg/kg/day. Effects observed 
in the dams in the high-dose group were decreased body weight gain and 
reduced food consumption. There were no developmental effects observed 
in this study.
    c. A two-generation reproduction study in rats fed diets containing 
0, 500, 1,500 and 3,000 ppm of chlorothalonil resulted in a 
reproductive NOEL of 1,500 ppm (equivalent to 115 mg/kg/day) based on 
lower neonatal body weights by day 21.
    There were no effects seen on any reproductive parameter at any 
dose level in this study.
    d. A developmental toxicity study in rabbits receiving gavage doses 
of 0, 1, 2.5 or 5 mg/kg/day of the 4-hydroxy metabolite on days 6 
through 18 of gestation resulted in a maternal NOEL of 2.5 mg/kg/day. 
Effects observed in the dams in the high-dose group were an increase in 
the number of females with dead or resorbed fetuses and in the number 
of aborted fetuses. There were no developmental effects observed in 
this study.
    e. A three-generation reproduction study in rats fed diets 
containing 0, 10, 60 and 125 ppm of the 4-hydroxy metabolite, resulted 
in a NOEL of 10 ppm (equivalent to 0.5 mg/kg/day) based on lower 
neonatal body weights on days 14 and 21 of lactation. The reduction of 
pup growth at the two highest dose levels during the later part of the 
gestation period can be attributed to the direct ingestion of the adult 
diet by the pups which resulted in inordinately high doses (per kg of 
body weight) of the test material for the pups as compared to the 
adults. There were no effects seen on any reproductive parameter at any 
dose level in this study. The reproductive NOEL was the highest dose 
tested.
    f. A one generation reproduction study in rats was conducted to 
further define the NOEL for the reduction in pup growth observed during 
lactation in the three generation reproduction study with the 4-hydroxy 
metabolite. Dietary levels of 0, 10, 20, 30, 60 and 120 ppm of the 4-
hydroxy metabolite were fed to rats. Two litters, F1a and F1b were 
evaluated. The NOEL in this study was determined to be 30 ppm 
(equivalent to 1.5 mg/kg/day).
    4. Subchronic toxicity. a. A subchronic toxicity study (90-days) 
was conducted in rats with chlorothalonil at doses of 0, 1.5, 3.0, 10 
and 40 mg/kg bwt. Treatment-related hyperplasia and hyperkeratosis of 
the forestomach were observed at the two highest dose levels. Although 
the initial histopathological evaluation did not demonstrate any 
nephrotoxicity, a subsequent evaluation observed a treatment-related 
increase in hyperplasia of the proximal tubule epithelium at 40 mg/kg 
bwt. in the male rats but not in the females. The no effect level for 
renal histopathology was 10 mg/kg bwt. in males and 40 mg/kg bwt. in 
females.
    b. A 90-day oral toxicity study was conducted in dogs with dose 
levels of technical chlorothalonil of 15, 150 and 750 mg/kg bwt./day. 
The two highest dosages resulted in lower body weight gain in male 
dogs. The NOAEL was 15 mg/kg/day. There were no macroscopic or 
microscopic tissue alterations related to chlorothalonil and there were 
no signs of renal toxicity.
    c. A subchronic toxicity study (60-days) was conducted in rats with 
the 4-hydroxy metabolite at doses of 0, 10, 20, 40, 75, 125, 250, 500, 
and 750 mg/kg bwt. The NOEL was determined to be 20 mg/kg/day. 
Treatment-related effects observed at higher doses included changes in 
hematopoietic and clinical chemistry parameters, mild hemosiderosis, 
toxic hepatitis, and microscopic degeneration in several organs.
    d. Two 21-day dermal toxicity studies have been conducted with 
technical chlorothalonil. In the initial study doses of 50, 2.5 and 0.1 
mg/kg bwt./day were administered to rabbits. The NOEL for systemic 
effects was greater than 50 mg/kg bwt./day and the NOEL for dermal 
irritation was 0.1 mg/kg bwt./day.
    e. A subsequent 21-day dermal study was conducted in male rats, to 
specifically evaluate the potential for nephrotoxicity in this 
laboratory species following dermal dosing. In this study the doses 
were 60, 100, 250 and 600 mg/kg bwt./day. The NOEL for nephrotoxicity 
was greater than 600 mg/kg bwt./day.
    5. Estrogenic effects. Based upon all of the chronic toxicity, 
teratogenicity, mutagenicity and reproductive studies conducted with 
chlorothalonil and its metabolites, including the 4-hydroxy metabolite, 
there were no results which indicate any potential to cause estrogenic 
effects, or endocrine disruption. These effects would have manifested 
themselves in these studies as reproductive or teratogenic effects, or 
by producing histopathological changes in estrogen sensitive tissues 
such as the uterus, mammary glands or the testes. Thus, it can be 
concluded based upon the in vivo studies, that chlorothalonil does not 
cause estrogenic effects.
    6. Chronic toxicity. a. A 12-month chronic oral toxicity study in 
Beagle dogs was conducted with technical chlorothalonil at dose levels 
of 15, 150 and 500 mg/kg/day. The NOAEL was 150 mg/kg/day based on 
lower blood albumin levels at the highest dose. There was no 
nephrotoxicity observed at any dose in this study. This study replaced 
an old outdated study that was not conducted under current guidelines 
and did not use the current technical material.
    b. A chronic feeding/carcinogenicity study with Fischer 344 rats at 
dose levels of 0, 40, 80 or 175 mg/kg/day of technical chlorothalonil 
for 116 weeks in males or 129 weeks in females, resulted in a 
statistically higher incidence of combined renal adenomas and 
carcinomas. At the high dose,

[[Page 37249]]

which was above the MTD, there was also a statistically significant 
higher incidence of tumors of the forestomach in female rats.
    c. In a second chronic feeding/carcinogenicity study with technical 
chlorothalonil in Fischer 344 rats, designed to define the NOEL for 
tumors and the preneoplastic hyperplasia, animals were fed diets which 
resulted in dose levels of 0, 2, 4, 15 or 175 mg/kg/day. The NOEL in 
this study, based on renal tubular hyperplasia, was a nominal dose of 2 
mg/kg bwt./day. Because of the potential for chlorothalonil to bind to 
diet, the 2 mg/kg bwt./day dose, expressed as unbound chlorothalonil is 
1.8 mg/kg bwt./day. The NOEL for hyperplasia and hyperkeratosis of the 
forestomach was 4 mg/kg bwt./day or a dose of 3.8 mg/kg bwt./day based 
on unbound chlorothalonil.
    d. A 2-year carcinogenicity study, conducted in CD-1 mice with 
technical chlorothalonil at dietary levels of 0, 750 and 1,500 or 3,000 
ppm (equivalent to 0, 107, 214 or 428 mg/kg/day), resulted in a 
statistically higher incidence of squamous cell carcinoma of the 
forestomach in both sexes, and a statistically higher incidence of 
combined renal adenoma/carcinoma in only the male mice receiving the 
low dose. There were no renal tumors in any female mouse in this study.
    e. A 2-year carcinogenicity study in male CD-1 mice for the purpose 
of establishing the no effect level for renal and forestomach effects 
associated with technical chlorothalonil, was conducted at dietary 
levels of 0, 10/15, 40, 175, or 750 ppm (equivalent to 0, 1.4/2.1, 5.7, 
25 or 107 mg/kg/day). The NOEL level for renal effects was 40 ppm and 
the NOEL for forestomach effects was 15 ppm. This study did not 
duplicate the results from the previous study where a statistically 
higher incidence of renal tumors, when compared to controls, was 
observed at 750 ppm. No tumors were observed at this dose level in this 
study.
    f. A chronic feeding/carcinogenicity study with CD rats at doses of 
0, 0.5, 3.0, 15, or 30 mg/kg/day has been conducted with the 4-hydroxy 
metabolite. Because of the severity of the toxicity observed during the 
first six months of the study, the two highest dose levels were reduced 
to 10 and 20 mg/kg/day. The animals receiving the highest dose were 
terminated at 12 months. There were no neoplastic effects at any dose 
level and the NOEL for chronic toxicity was 3 mg/kg/day. At the higher 
dose levels, the treatment related effects included microcytic anemia 
with an increased number of reticulocytes and metarubricytes, 
hypocellular bone marrow, hemosiderin deposition in liver and bone 
marrow and serum biochemistry changes and degenerative tissue changes 
related to hypoxia.
    g. A carcinogenicity study in CD-1 mice was conducted at dietary 
levels of 0, 375, 750 and 1500 ppm of the 4-hydroxy metabolite. The 
mean body weights of the high dose males and females were 4-15% and 5-
18% lower, respectively, when compared to controls. Liver weights were 
also higher at the highest dietary level. There was no increase in the 
incidence of any malignant or benign tumor at any dose in this study.
    In 1987, the Office of Pesticide Programs' Toxicology Branch Peer 
Review Committee classified chlorothalonil as a B2 (probable human 
carcinogen), based on evidence of carcinogenicity in the forestomach 
and kidneys of rats and mice. The Agency currently regulates 
chlorothalonil as a B2 carcinogen although ISK Biosciences Corporation 
has provided a significant amount of mechanistic data indicating that 
the tumors result from a threshold mechanism. A potency factor, 
Q1*, of 0.00766 (mg/kg/day)-1 has been used by the Agency 
when conducting mathematical modeling to estimate carcinogenic risk to 
man. ISK Biosciences Corporation believes that because the 
nephrotoxicity seen in the rat is due to a threshold mechanism, any 
risk associated with chlorothalonil can be managed using the margin of 
safety (exposure) approach.
    Numerous metabolism and toxicology studies indicate that 
chlorothalonil is non-genotoxic, and produces a species specific renal 
toxicity in the rat that eventually may lead to tumor formation through 
an epigenetic mechanism. Studies comparing metabolism and toxicological 
effects in dogs with those in rats demonstrate that the renal effects 
observed in the rat are due to the exposure of the kidney of the rat to 
significant levels of nephrotoxic thiol metabolites of chlorothalonil.
    The 4-hydroxy metabolite was not tumorigenic in either the rat or 
mouse. Reference Dose (RfD): The no effect level for chlorothalonil in 
the rat is 1.8 mg/kg bwt. based on the nephrotoxicity observed in the 
chronic study. The no effect level in the dog was 15 mg/kg bwt. in the 
90-day study and 150 mg/kg bwt. based on the one-year study. No effect 
levels for maternal toxicity from developmental studies are 10 mg/kg 
bwt. in rabbits and 100 mg/kg bwt. in the rat. The no effect level for 
pup growth in the reproduction study was 1,500 mg/kg bwt. which would 
be most conservatively estimated as equating to approximately 75 mg/kg 
bwt. The data indicate that the nephrotoxicity in the rat is produced 
through a mechanism for which there is a clear threshold. In a study 
which measured cell turnover in the rat kidney with BRDU, a NOEL was 
established at 1.5 mg/kg bwt. Other chronic studies have established 
the NOEL for hyperplasia in the kidney to be 1.8 mg/kg bwt. If all the 
available toxicity data in laboratory animals are considered without 
regard to applicability to humans, the lowest NOEL for any adverse 
effect would be 1.5 mg/kg bwt./day. Because the mechanism of toxicity 
which is related to the tumor formation in the kidney has been shown to 
have a threshold, the use of the normal 100-fold safety factor in 
conjunction with the 1.5 mg/kg no observable effect level would produce 
a reference dose which would provide more than adequate safety for all 
of the possible effects seen in any laboratory animal.
    In the two reviews of chlorothalonil by the Joint Meeting of 
Pesticide Residue Experts, and the review by the World Heath 
Organization's International Program For Chemical Safety, these 
esteemed groups concluded that the rat was not the appropriate species 
to use in consideration of the risk assessment for man. They concluded 
that the dog was the more appropriate species for determination of 
subchronic and chronic effects. If the toxicological data for the dog 
were used, the NOEL would be at least 15 mg/kg bwt., based on the most 
recent 90-day study in the dog.
    The NOEL for the 4-hydroxy metabolite based on the reduction of 
weight gain late in the lactation period in a reproduction study would 
be 30 ppm or 1.5 mg/kg/ day. This was not a reproductive effect. The 
NOEL based on chronic toxicity in the rat would be 3.0 mg/kg bwt/day.
    Therefore, under the most conservative scenario, the reference dose 
for chlorothalonil including its 4-hydroxy metabolite would be 1.5 mg/
kg bwt./day divided by a 100-fold safety factor or 0.015 mg/kg bwt./day 
with a threshold model being used for carcinogenic risk assessment. In 
the scenario that uses the toxicological data in the dog, the reference 
dose would be 15 mg/kg bwt./day. divided by a safety factor of 100 or 
0.15 mg/kg bwt./day.

C. Aggregate Exposure

    The following is a description of the likelihood of exposure to 
chlorothalonil from various routes:
    1. Dietary exposure (Food). No residues of chlorothalonil per se 
will be added to the total exposure of chlorothalonil from consumption 
of

[[Page 37250]]

meat or milk from livestock which were fed chlorothalonil-treated 
commodities. Residues of 4-hydroxy-2,5,6-trichloroisophthalo-nitrile on 
crops treated with products containing chlorothalonil are a very low 
percentage of the total crop residue. Although 4-hydroxy-2,5,6-
trichloroisophthalonitrile will transfer to meat and milk, the levels 
present on feedstuffs which are available for transfer are low. 
Presently, there are very few uses of chlorothalonil which involve 
livestock commodities. Meat and milk tolerances for 4-hydroxy-2,5,6-
trichloroisophthalonitrile are needed to support the reregistration of 
chlorothalonil.
    2. Drinking water. Chlorothalonil was included for monitoring in 
the National Survey of Pesticides in Drinking Water Wells conducted by 
EPA. No chlorothalonil residues were detected in any of the 1,300 
community water systems and domestic wells (using methodology for 
chlorothalonil having a limit of detection [LOD] of 0.06 mg/l and limit 
of quantitation of 0.12 mg/l). The absence of chlorothalonil detections 
in the National Survey provides adequate information to conclude that 
chlorothalonil is not a contaminant in drinking water wells and that 
the population is not exposed to chlorothalonil in these water sources. 
These findings are consistent with the known physical/ chemical 
properties of chlorothalonil including low water solubility (0.9 ppm) 
and high affinity for organic matter including soil. It has also been 
demonstrated that chlorothalonil does not leach into groundwater from 
applications made to growing crops.
    Aerobic aquatic metabolism studies with chlorothalonil establish a 
half-life in natural aquatic habitats of less than 10 hours, depending 
on environmental conditions. Considering the short half-life of 
chlorothalonil in natural water/sediment systems and that surface water 
is filtered and treated prior to consumption, chlorothalonil is not 
likely to be present in drinking water obtained from natural surface 
water systems.
    If the exposure estimate is based on the surface water 
concentration recently cited by EPA, it is concluded that the average 
concentration in surface water would be less than 0.002 ppb. Assuming 
that everyone in the US consumed untreated surface water, the exposure 
to chlorothalonil to the general population would be less than 5.8  x  
10-7 mg/kg bwt./day. This would be a worst case scenario.
    The 4-hydroxy metabolite did not leach into ground water in a 
prospective groundwater study, therefore, no intake of this metabolite 
would be anticipated from drinking water.
    3. Non-dietary exposure. Potential non-dietary exposures to 
chlorothalonil may result from the following uses of chlorothalonil. In 
each case, the exposure would be from the dermal route and only for an 
intermittent duration. The two 21-day dermal studies that have been 
conducted in the rabbit and rat indicate that there is no 
nephrotoxicity associated with the dermal exposure to chlorothalonil at 
dose levels up to 600 mg/kg/day. Therefore, the exposures from the uses 
of chlorothalonil listed below, would not be expected to add to the 
carcinogenic risk associated with chlorothalonil.
    Because the 4-hydroxy metabolite is a soil metabolite, no 
significant exposure would be anticipated through non-dietary routes. 
Although some hydrolysis of chlorothalonil to the 4-hydroxy metabolite 
may occur at a basic pH in some paint or wood treatment products, the 
anticipated exposure when the products dry would be negligible.
    a. Golf course uses. Chlorothalonil products are commonly applied 
to golf course tees and greens to control a broad complex of turf 
diseases. Application to golf course fairways is much less common. Golf 
is not a game played by infants or small children, therefore no 
exposure to infants and children would be anticipated.
    b. Residential owner uses. Applications of chlorothalonil products 
to home lawns are rare. Thus, there is very little exposure to 
chlorothalonil related to use on residential turf. Applications to 
roses and other ornamentals in home gardens is also a minor use of 
chlorothalonil.
    c. Paint. Chlorothalonil is used in paints and stains for control 
of mildew and molds on exterior surfaces of buildings. Chlorothalonil 
is also occasionally used for interior paints, but this use represents 
only a small proportion of the chlorothalonil used in paints. About 2% 
of the chlorothalonil used in paint is used in interior paint; however, 
only 0.2% or less of the interior paints in the United States contain 
chlorothalonil. In paints, chlorothalonil is tightly bound within the 
matrices of the paint; thus, effective control of mildew may last for 
several years.
    d. Grouts. Chlorothalonil is used in cement tile grouts for control 
of mildew and molds. Chlorothalonil is bound within the grout matrices 
and very little is available for exposure. This is a minor use of 
chlorothalonil and non-occupational dermal exposure of humans to 
chlorothalonil from this source is extremely low.
    e. Wood treatment. Chlorothalonil is not used for pressure-treating 
wood. It is used for control of sapstain as a surface treatment on 
rough-cut, newly-sawn lumber to protect it from molds and mildews while 
drying. Being a surface residue, it is removed during the finishing 
operations prior to sale of the wood. Chlorothalonil does not occur in 
structural wood used for residential or occupational scenarios.

D. Cumulative Effects

    ISK Biosciences has considered the potential for cumulative effects 
of chlorothalonil and other substances that have a common mechanism of 
toxicity. Chlorothalonil is a halogenated benzonitrile fungicide which 
readily undergoes displacement of the chlorines in the 2, 4 and 6 
positions by glutathione and other thiol containing amino acids and 
proteins. In the rat, the glutathione binding, absorption and 
subsequent metabolism to form the di- and tri-thiol metabolites occur 
at sufficient levels to produce a nephrotoxic effect. In dogs where 
this mechanism does not occur to produce thiol metabolites, 
nephrotoxicity does not occur. ISK Biosciences does not have any 
information to indicate that toxic effects observed in rats occur 
through a mechanism which is common to any other agricultural chemical. 
Thus, consideration of common mechanisms of toxicity is not appropriate 
at this time.
    Chlorothalonil should not be confused with chemicals classified as 
chlorinated hydrocarbon pesticides which have significantly different 
chemical and biological properties.
    There would be no cumulative effects expected between 
chlorothalonil and its 4-hydroxy metabolite because each affects a 
different toxicological endpoint.

E. Safety Determination

    1. U.S. population. The majority of exposure to chlorothalonil and 
its 4-hydroxy metabolite would be expected to occur from the diet. In 
EPA's Dietary Exposure Analysis for the Use of Chlorothalonil in/on 
Meat and Milk Products, dated April 23, 1996, the Agency determined 
that ``Chlorothalonil does not pose a significant chronic or acute 
dietary risk for uses that are currently published or for uses 
recommended by CBRS for registration''. The Agency concluded that 
because of the instability of chlorothalonil in meat and milk, that 
even in misuse, residues of chlorothalonil would not transfer from

[[Page 37251]]

animal feed items to meat and milk. The EPA determined that the 4-
hydroxy metabolite would be a residue in meat and milk and that the 
chronic RfD for chlorothalonil would be sufficient for the metabolite.
    The Agency calculated that the Anticipated Residue Contribution 
when the tolerances for meat and milk are approved, would be 6.8% for 
the general population and 37% for non-nursing infants (<1 yr. old). In 
estimating the carcinogenic risk, the Agency indicated that since the 
4-hydroxy metabolite was not carcinogenic, and that no residues of 
chlorothalonil would transfer to meat and milk, the carcinogenic risk 
calculated for chlorothalonil would not be affected by this tolerance.
    The Agency has used a linearized model to estimate the carcinogenic 
risk associated with chlorothalonil, whereas ISK Biosciences believes 
that a threshold based model is appropriate.
    Because the worst case assumptions for human exposure from drinking 
water indicate that exposure would be only 1% of the dietary exposure, 
the risk assessment is not significantly altered by considering the 
exposure from drinking water.
    2. Infants and children. There is a complete database for 
chlorothalonil which includes pre- and post-natal developmental 
toxicity data as well as mechanistic data related to the rodent 
specific nephrotoxicity observed in subchronic and chronic studies. The 
toxicological effects of chlorothalonil in rodents are well understood. 
Chlorothalonil has a low level of toxicity in dogs.
    In a two-generation reproduction study in rats, all reproductive 
parameters investigated showed no treatment-related effects except pup 
weight gain. Specifically, the weights of pups exposed to 
chlorothalonil were comparable to controls at parturition through day 
four of lactation. It was only after day four of lactation, when the 
pups begin to consume the test diet, that body weight gain lags behind 
controls. This only occurred at the highest dose tested, 3,000 ppm. The 
dose of chlorothalonil the pups would receive would be far in excess of 
the estimated adult dose of 150 mg/kg (3,000 ppm/20). The doses for the 
pups could have easily exceeded 500 mg/kg bwt./day. Dose levels of 375 
mg/kg bwt. and above have been shown to significantly affect body 
weight in the rat. Therefore, the reduction of body weight gain 
observed in the reproduction study is considered to be comparable to 
the effects that have been observed in older rats. The NOEL for this 
effect was 1,500 ppm.
    In a three generation reproduction study and a subsequent one 
generation study with the 4-hydroxy metabolite, there were no 
reproductive effects even at a dose that produced parental toxicity. 
Although a reduction in pup growth was noted at dietary concentrations 
of 60 ppm and higher, it could be attributed to an inordinately high 
dose of the test material received by the pups when compared to adults.
    In developmental toxicity studies conducted in the rat and the 
rabbit, chlorothalonil did not cause any developmental effects even at 
dose levels that produced significant maternal toxicity. In the rabbit 
a dose level of 20 mg/kg caused maternal toxicity, but there were no 
developmental effects, and in the rat a dose level of 400 mg/kg caused 
maternal toxicity without developmental toxicity.
    In a developmental toxicity study conducted with the 4-hydroxy 
metabolite there were no developmental effects even at doses that 
produced significant maternal toxicity. A dose of 5 mg/kg produced 
maternal toxicity but there were no developmental effects.
    The extensive database that is available for chlorothalonil and its 
4-hydroxy metabolite is devoid of any indication that either material 
would represent any unusual or disproportionate hazard to infants or 
children. Therefore, there is no need to impose an additional 10X 
safety factor for infants or children. The standard uncertainty factor 
of 100X should be used for all segments of the human population when 
calculating risks associated with chlorothalonil or its 4-hydroxy 
metabolite.

F. International Tolerances

    A maximum residue level has not been set for the 4-hydroxy 
metabolite of chlorothalonil in milk and meat by the Codex Alimentarius 
Commission. The data indicate that no tolerance would be necessary for 
chlorothalonil on milk and meat since it would not be expected to 
transfer from animal feed items to these commodities.   (PM 22)

2. Novartis

PP 9F3740, PP 5F4424, PP 5F4591, PP 5F4498

    EPA has received pesticide petitions (PP) 9F3740, 5F4424, 5F4591, 
5F4498 from Novartis Crop Protection Inc., PO Box 18300, Greensboro, NC 
27419. The petition proposes, to amend 40 CFR part 180, by establishing 
a tolerance for the residues of the fungicide Propiconazole, which is a 
triazole fungicide registered for use on many crops, including bananas, 
celery, corn, grasses grown for seed, mint (West of the Cascade 
Mountains), pecans, peanuts, rice, small grains (barley, oats, rye, 
wheat), stone fruit, and wild rice. Use rates range from 0.07 to 0.22 
pound (lb.) active ingredient per acre. Petitions currently pending for 
propiconazole include: the tree nuts (PP 9F3740); drybean and soybeans 
(PP 5F4424); berry crop grouping, carrots, and onions (PP 5F4591); and 
alfalfa and sorghum (PP 5F4498).

A. Residue Chemistry

    1. Metabolism. Novartis believes the studies supporting 
propiconazole adequately characterize metabolism in plants and animals. 
The metabolism profile supports the use of an analytical enforcement 
method that accounts for combined residues of propiconazole and its 
metabolites which contain the 2,4-dichlorobenzoic acid (DCBA) moiety.
    2. Analytical methodology. Novartis has submitted a practical 
analytical method involving extraction, filtration, conversion, 
partition, derivitization, and solid phase cleanup with analysis by 
confirmatory gas chromatography using electron capture detection (ECD). 
The total residue method is used for determination of propiconazole and 
its metabolites. The limit of quantitation (LOQ) for the method is 0.05 
part per million (ppm).
    3. Magnitude of residue. Field residue trials have been conducted 
at various rates, timing intervals, and applications methods to 
represent the use patterns which would most likely result in the 
highest residues. For all samples, the total residue method was used 
for determination of the combined residues of parent and its 
metabolites which contain the DCBA moiety.

B. Toxicological Profile

    The following mammalian toxicity studies have been conducted to 
support the tolerances of propiconazole:
    A rat acute oral study with a LD50 of 1,517 mg/kg.
    A rabbit acute dermal study with a LD50 > 6,000 mg/kg.
    A rat inhalation study with a LC50 > 5.8 mg/liter air.
    A primary eye irritation study in rabbits which showed mild 
irritation.
    A primary dermal irritation study in rabbits which showed slight 
irritation.
    A skin sensitization study in guinea pigs which showed no 
sensitization.
    A 21-day dermal study in the rabbit with a No Observed Effect Level 
(NOEL) of 200 mg/kg based on clinical signs of systemic toxicity.

[[Page 37252]]

    A 28-day oral toxicity study in the rat with a No Observed Adverse 
Effect Level (NOAEL) of 50 mg/kg based on increased liver weight.
    A subchronic feeding study in the mouse with a NOEL of 20 ppm (3 
mg/kg) based on liver pathologic changes.
    A 13-week feeding study in the male mouse with a NOEL of 20 ppm (3 
mg/kg) based on liver pathologic changes.
    A 90-day feeding study in the rat with a NOEL of 240 ppm (24 mg/kg) 
based on reduction in body weight gain.
    A 90-day feeding study in the dog with a NOEL of 250 ppm (6.25 mg/
kg) based on reduced food intake and stomach histologic changes.
    A 12-month feeding study in the dog with a NOEL of 50 ppm (1.25 mg/
kg) based on stomach histologic changes.
    A 24-month oncogenicity feeding study in the mouse with a NOEL of 
100 ppm (15 mg/kg). The MTD was exceeded at 2,500 ppm in males based on 
decreased survival and body weight. Increased incidence of liver tumor 
was seen in these males but no evidence of carcinogenicity was seen at 
the next lower dose of 500 ppm in either sex.
    A 24-month chronic feeding/oncogenicity study in the rat with a 
NOEL of 100 ppm (5 mg/kg) based on body weight and blood chemistry. The 
MTD was 2,500 ppm based on reduction in body weight gain and no 
evidence of oncogenicity was seen.
    An oral teratology study in the rabbit with a maternal NOEL of 30 
mg/kg based on reduced food intake but without any fetotoxicity even at 
the top dose of 180 mg/kg.
    An oral teratology study in the rabbit with a maternal NOEL of 100 
mg/kg based on reductions in body weight gain and food consumption and 
a fetal NOEL of 250 mg/kg based on increased skeletal variations at 400 
mg/kg.
    An oral teratology study in the rat with a maternal and fetal NOEL 
of 100 mg/kg based on decreased survival, body weight gain, and food 
consumption in the dams and delayed ossification in the fetuses at 300 
mg/kg.
    A second teratology study in the rat with a maternal and fetal NOEL 
of 30 mg/kg based on reductions in body weight gain and food 
consumption in the dams and delayed development in the fetuses at 90 
and 360/300 mg/kg.
    A supplemental teratology study in the rat involving eight times as 
many animals pergroup as usually required and showing no teratogenic 
potential for the compound.
    A 2-generation reproduction study in the rat showing excessive 
toxicity at 5,000 ppm without any teratogenic effects.
    A 2-generation reproduction study in the rat with no effects on 
reproductive or fetal parameters at any dose level. Postnatal growth 
and survival were affected at the top dose of 2,500 ppm, where parental 
toxicity was also evident. The NOEL for development toxicity is 500 
ppm.
    In vitro gene mutation test: Ames assay - negative; rat hepatocyte 
DNA repair test - negative; human fibroblast DNA repair test - 
negative.
    In vitro chromosome test: human lymphocyte cytogenetic test - 
negative.
    In vivo mutagenicity test: Chinese hamster bone marrow cell nucleus 
aunomaly test -negative; Chinese hamster bone marrow cell micronucleus 
test - negative; mouse dominant lethal test - negative.
    Other mutagenicity test: BALB/3T3 cell transformation assay - 
negative.

C. Threshold Effects

    1. Chronic effects. Based on the available chronic toxicity data, 
Novartis believes the Reference dose (RfD) for propiconazole is 0.0125 
mg/kg/day. This RfD is based on a 1-year feeding study in dogs with a 
No-Observed Effect Level of 1.25 mg/kg/day (50 ppm) and an uncertainly 
factor of 100. No additional modifying factor for the nature of effects 
was judged to be necessary as stomach mucosa hyperemia was the most 
sensitive indicator of toxicity in that study.
    2. Acute toxicity. The risk from acute dietary exposure to 
propiconazole is considered to be very low. The lowest NOEL in a short 
term exposure scenario, identified as 30 mg/kg in the rat teratology 
study, is 24-fold higher than the chronic NOEL (see above). Based on 
worst-case assumptions the chronic exposure assessment (see below) did 
not result in any margin of exposure less than 150 for even the most 
impacted population subgroup. Novartis believes that the margin of 
exposure for acute exposure would be more than one hundred for any 
population groups; margins of exposure of 100 or more are considered 
satisfactory.
    3. Non-threshold effects. Using the Guidelines for Carcinogenic 
Risk Assessment published on September 24, 1986 (51 FR 33992), the 
USEPA has classified propiconazole in group C for carcinogenicity 
(evidence of possible carcinogenicity for humans). The compound was 
tested in 24-month studies with both rats and mice. The only evidence 
of carcinogenicity was an increase in liver tumor incidence in male 
mice at a dose level that exceeded the maximum tolerated dose (MTD). 
Dosage levels in the rat study were appropriate for identifying a 
cancer risk. The Cancer Peer Review Committee recommended the RfD 
approach for quantitation of human risk. Therefore, the RfD is deemed 
protective of all chronic human health effects, including cancer.

D. Aggregate Exposure

    1. Dietary exposure. For the purposes of assessing the potential 
dietary exposure under the existing, pending, and proposed tolerances 
for the residue of propiconazole and its metabolites determined as 2,4-
dichlorobenzoic acid, Novartis has estimated aggregate exposure based 
upon the Theoretical Maximum Residue Concentration (TMRC). The TMRC is 
a ``worst case'' estimate of dietary exposure since it assumes 100 
percent of all crops for which tolerances are established are treated 
and that pesticide residues are at the tolerance levels, resulting in 
an overestimate of human exposure.
    Currently established tolerances range from 0.05 ppm in milk to 60 
ppm in grass seed screenings and include: apricots (1.0 ppm); bananas 
(0.2 ppm); barley grain (0.1 ppm); barley straw (1.5 ppm); cattle 
kidney and liver (2.0 ppm); cattle meat, fat, and meat by products 
except kidney and liver (0.1 ppm); celery (5.0 ppm); corn forage and 
fodder (12.0 ppm); corn grain and sweet (0.1); eggs (0.1 ppm); goat 
kidney and liver (2.0 ppm); goat meat, fat, and meat by products except 
kidney and liver (0.1 ppm); grass forage (0.5 ppm); grass hay/straw 
(40.0 ppm); grass seed screenings (60.0 ppm); hogs kidney and liver 
(2.0 ppm); hog meat, fat, and meat by products except kidney and liver 
(0.1 ppm); horses kidney and liver (2.0 ppm); horse meat, fat, and meat 
by products except kidney and liver (0.1 ppm); milk (0.05 ppm); mint 
tops (0.3 ppm - regional tolerance west of Cascade Mountains); 
mushrooms (0.1 ppm); nectarines (1.0 ppm); oat forage (10.0 ppm); oat 
grain (0.1 ppm); oat hay (30.0 ppm); oat straw (1.0 ppm); peaches (1.0 
ppm); peanut hay (20.0 ppm); peanut hulls (1.0 ppm); peanuts (0.2 
ppm);, pecans (0.1 ppm); pineapple (0.1 ppm); pineapple fodder (0.1 
ppm); plums (1.0 ppm); poultry liver and kidney (0.2 ppm); poultry 
meat, fat, and meat by products except kidney and liver (0.1 ppm); 
prunes, fresh (1.0 ppm); rice grain (0.1 ppm); rice straw (3.0 ppm); 
wild rice (0.5 ppm regional tolerance Minnesota); rye grain (0.1 ppm); 
rye straw (1.5 ppm); sheep kidney and liver (2.0 ppm); sheep meat, fat, 
and meat by products except kidney and liver (0.1 ppm); stone fruit 
crop group 12 (1.0 ppm); wheat grain (0.1 ppm); and wheat straw (1.5 
ppm). In addition, time-limited regional tolerances for

[[Page 37253]]

sorghum grain and stover at 0.1 ppm and 1.5 ppm, respectively were 
established to support a section 18 Crisis exemption in Texas 
(expiration date 10/31/98).
    Additional uses of propiconazole have been requested in several 
pending petitions.
    Proposed tolerances include: PP 5F4424 for use of propiconazole on 
drybean and soybean -- dry bean forage (8.0 ppm); dry bean hay (8.0 
ppm); dry bean vines (0.5 ppm); dry bean (0.5 ppm), soybeans (0.5 ppm); 
soybean fodder (8.0 ppm); soybean forage (8.0 ppm); soybean hay (25.0 
ppm); and soybean straw (0.1 ppm).
    PP 5F4591 for use of propiconazole on berries, carrots and onions -
- berry crop grouping (1.0 ppm); dry bulb onion (0.3 ppm); green onion 
(8.0).
    PP 9F3740 -- tree nut crop grouping (0.1 ppm);
    PP 5F4498 -- inadvertent/rotational crop tolerances for alfalfa 
forage (0.1 ppm), alfalfa hay (0.1 ppm), grain sorghum fodder (0.3 
ppm), grain sorghum forage (0.3 ppm) and grain sorghum grain (0.2 ppm). 
Other potential sources of exposure of the general population to 
residues of propiconazole are residues in drinking water and exposure 
from non-occupational sources. Review of environmental fate data by the 
Environmental Fate and Effects Division of USEPA indicates that 
propiconazole is persistent and moderately mobile to relatively 
immobile in most soil and aqueous environments. No Maximum 
Concentration Level (MCL) currently exists for residues of 
propiconazole in drinking water and no drinking water health advisory 
levels have been established for propiconazole.
    2. Drinking water exposure. The degradation of propiconazole is 
microbially mediated with an aerobic soil metabolism half-life of 70 
days. While propiconazole is hydrolytically and photochemically stable 
(T1/2 >100 days), it binds very rapidly and tightly to soil particles 
following application. Adsorption/desorption and aged leaching data 
indicate that propiconazole and its degradates will primarily remain in 
the top 0-6 inches of the soil. It has been determined that under field 
conditions propiconazole will degrade with a half-life of approximately 
100 days.
    3. Non-dietary exposure. Propiconazole is registered for 
residential use as a preservative treatment for wood and for lawn and 
ornamental uses. At this time, no reliable data exist which would allow 
quantitative incorporation of risk from these uses into a human health 
risk assessment. The exposure to propiconazole from contacting treated 
wood products is anticipated to be very low since the surface of wood 
is usually coated with paint or sealant when used in or around the 
house. The non-occupational exposure from lawn and ornamental 
applications is also considered to be minor. It is estimated that less 
than 0.01 percent of all households nationally use propiconazole in a 
residential setting.
    Consideration of a common mechanism of toxicity is not appropriate 
at this time since there is no reliable information to indicate that 
toxic effects produced by propiconazole would be cumulative with those 
of any other types of chemicals. While other triazoles are available on 
the commercial or consumer market, sufficient structural differences 
exist among these compounds to preclude any categorical grouping for 
cumulative toxicity. Consequently, Novartis is considering only the 
potential risks of propiconazole in its aggregate exposure assessment.

E. Safety Determiniation

    1. U.S. population. Reference dose. Using the conservative exposure 
assumptions described above (100 percent stone fruit acres treated and 
tolerance level residues) and based on the completeness and reliability 
of the toxicity data base for propiconazole, Novartis has calculated 
aggregate exposure levels for this chemical. The calculation shows that 
only 16 percent of the RfD will be utilized for the U.S. population 
based on chronic toxicity endpoints. EPA generally has no concern for 
exposures below 100 percent of the RfD because the RfD represents the 
level at or below which daily aggregate dietary exposure over a 
lifetime will not pose appreciable risks to human health. Novartis 
concludes that there is a reasonable certainty that no harm will result 
from aggregate exposure to propiconazole residues.
    2. Infants and children. Developmental toxicity (e.g., reduced pup 
weight and ossification) was observed in the rat teratology studies and 
2-generation rat reproduction studies at maternally toxic doses. Some 
of these findings are judged to be nonspecific, secondary effects of 
maternal toxicity. The lowest NOEL for developmental toxicity was 
established in the rat teratology study at 30 mg/kg, a level 24-fold 
higher than the NOEL of 1.25 mg/kg on which the RfD is based.
    Reference dose. Using the same conservative exposure assumptions as 
employed for the determination in the general population, Novartis has 
calculated that the percent of the RfD that will be utilized by 
aggregate exposure to residues of propiconazole is 26 percent for 
nursing infants less than 1 year old, 65 percent for non-nursing 
infants less than 1 year old, 35 percent for children 1-6 years old, 
and 23 percent for children 7-12 years old. Therefore, based on the 
completeness and reliability of the toxicity data base and the 
conservative exposure assessment, Novartis concludes that there is a 
reasonable certainty that no harm will result to infants and children 
from aggregate exposure to propiconazole residues.

F. Estrogenic Effects

    Propiconazole does not belong to a class of chemicals known or 
suspected of having adverse effects on the endocrine system.
    Developmental toxicity studies in rats and rabbits and reproduction 
studies in rats gave no indication that propiconazole might have any 
effects on endocrine function related to development and reproduction. 
The subchronic and chronic studies also showed no evidence of a long-
term effect related to the endocrine system.

G. International Tolerances

    International CODEX values are established for almond, animal 
products, bananas, barley, coffee, eggs, grapes, mango, meat, milk, 
oat, peanut-whole, peanut grains, pecans, rape, rye, stone fruit, sugar 
cane, sugar beets, sugar beet tops, and wheat. The U.S. residue 
definition includes both propiconazole and metabolites determined as 
2,4-dichlorobenzoic acid (DCBA), while the CODEX definition is for 
propiconazole, per se, i.e. parent only. This difference results in 
unique tolerance expressions with the U.S. definition resulting in the 
higher tolerance levels.   (PM 21)

3. Novartis Crop Protection, Inc.

PP 5E4450, 6F3332, 5F4546, 5F4576, and 6F4613

    EPA has received pesticide petitions (PP) 5E4450, 6F3332, 5F4546, 
5F4576, and 6F4613) from Novartis Crop Protection, Inc., 410 Swing 
Road, Greensboro, NC 27419, proposing to amend 40 CFR part 180 by 
establishing a tolerance for residues of the insecticide, cyromazine, 
and its metabolite, melamine, in or on the raw agricultural commodities 
of potatoes (potato tubers) at 1.5 ppm, green onions at 3 ppm, dry bulb 
onions at 0.3 ppm, cottonseed at 0.2 ppm, sweet corn (kernels plus cobs 
with husks removed, forage, and fodder) at 0.5 ppm, radishes (roots and 
tops) at 0.5 ppm, and

[[Page 37254]]

mangoes at 0.3 ppm. A tolerance of 0.04 ppm is requested for residues 
of cyromazine in milk; a tolerance of 0.02 ppm is requested for 
residues of melamine in milk.
    Residues of cyromazine and its metabolite, melamine, were 
determined by Analytical Methods AG-408 and AG-417A which, combined, 
are the EPA tolerance enforcement method published in the Pesticide 
Analytical Manual, Volume II. Cyromazine is determined by High 
Performance Liquid Chromatography (HPLC) on a LiChrosorb-NH2 column at 
214 nm. The limit of determination in potatoes is 0.05 ppm.
    Method AG-417A has been validated as reported in report ABR-84069 
and by the EPA method trial reported in the Pesticide Analytical Manual 
(PAM). EPA has accepted AG-408, 417A as the regulatory enforcement 
method for crops.
    Storage stability data for cyromazine have been reported in ABR-
92019 and Special Study 134/93: Interim Report. Stability of field-
incurred residues of cyromazine was demonstrated for 23 months in head 
and leaf lettuce, 24 months in celery, 9\1/2\ months in tomatoes, and 
11 months in mushrooms. In Special Study 134/93: Interim report, no 
degradation of laboratory-spiked cyromazine was observed for 6 months 
in mangoes (the time period required to validate the mango analyses). 
No deterioration of cyromazine residues has been observed in any 
substrate under freezer storage conditions. In this study, the storage 
period for potatoes ranged from 3.5 to 24 months, which is within the 
demonstrated freezer stability period.

A. Chemical Uses

    Cyromazine, the active ingredient in Trigard Insecticide, is a 
synthetic insect growth regulator. Cyromazine is highly efficacious 
against dipterous leafminer larvae developing in the foliage of certain 
agronomic, vegetable, and ornamental crops, and it can be used to 
control flies in mushroom houses. Cyromazine is compatible with 
integrated pest management (IPM) programs.

B. Residue Chemistry

    Six field trials were conducted in three mango production areas of 
Mexico. Residues of cyromazine ranged from less than the detection 
limit (0.03 ppm) to 0.25 ppm. These data support the proposed tolerance 
of 0.3 ppm in mangoes.
    The maximum combined residue of cyromazine and melamine in 
cottonseed from cotton grown as a rotational crop following lettuce 
treated six times at the 1X use rate was 0.18 ppm. These data support 
the proposed tolerance of 0.2 ppm in cottonseed.
    Application of Trigard OMC to onion seed (pelletization) resulted 
in maximum residues in immature whole onion plants of 2.71 ppm. These 
data support the proposed tolerances for combined residues of 
cyromazine and melamine at 3.0 ppm in green onions and 0.3 ppm in dry 
bulb onions.
    Residue data in rotational sweet corn and radishes and potatoes 
have been previously submitted to EPA for review and have been found by 
EPA to support tolerances of 0.5 ppm in sweet corn (kernels & cobs with 
husks removed), sweet corn forage, sweet corn fodder, radish roots and 
radish tops and to support tolerances of 1.5 ppm in/on potatoes. The 
proposed 1.5 ppm for the RAC potatoes will cover any expected residues 
including residues in processed potato wastes.

C. Toxicological Profile

    Novartis has submitted toxicology studies in support of tolerances 
for cyromazine. Cyromazine has low acute toxicity, no indication of 
irritation potential and no sensitization potential. Cyromazine is not 
genotoxic, fetotoxic, embryolethal, or teratogenic. It is not a 
reproductive toxin. High-dose chronic toxicity included bronchiectasis 
in male and female rats, testicular degeneration in dogs, and decreased 
body weights in rats, dogs, and mice. No tumorigenic effects were noted 
in any species tested and EPA has classified cyromazine as Group E, no 
evidence of carcinogenicity in humans. Therefore, Novartis proposes 
that a Margin of Exposure (MOE) or percentage of reference dose (RfD) 
approach be used for characterizing human risk. For cyromazine, 
Novartis concludes that aggregate MOE's are acceptable for the U.S. 
population and all population subgroups for both acute toxicity and 
chronic effects.
    The following mammalian toxicity studies were conducted to support 
proposed tolerances for cyromazine:
    A rat acute oral toxicity study with an LD50 of 
approximately 3,387 mg/kg.
    A rat acute dermal toxicity study with an LD50 >3,100 
mg/kg.
    A rat acute inhalation study with an LC50 >3,600 mg/
m3.
    A primary eye irritation study in the rabbit that showed no eye 
irritation.
    A primary dermal irritation study in the rabbit that showed no 
dermal irritation.
    A dermal sensitization study in the guinea pig that showed no 
sensitization.
    A 21-day dermal study in rabbits demonstrated no target organ 
toxicity at doses up to 2,000 mg/kg/day.
    A 13-week rat feeding study demonstrated no specific target organ 
toxicity and a no observed effect level (NOEL) of 300 ppm (25 mg/kg/
day).
    A 13-week feeding study in dogs demonstrated no specific target 
organ toxicity, although some red blood cell parameters were affected 
in high-dose males. The NOEL was 1,000 ppm (34 mg/kg/day).
    A six-month feeding study in dogs showed reversible red blood cell 
effects and transient changes in clinical parameters in high dose 
males. No specific target organs were identified histologically, 
although changes in some organ to body weight ratios were observed. The 
NOEL was 30 ppm (0.75 mg/kg).
    A 24-month feeding study in rats identified no specific target 
organs. There was no oncogenic effect and the NOEL for the study was 30 
ppm (1.5 mg/kg/day).
    A 24-month mouse feeding study identified no specific target 
organs. There was no oncogenic effect and the NOEL was 50 ppm (7.0 mg/
kg/day).
    A rat teratology study demonstrated no developmental toxicity. The 
maternal NOEL is 100 mg/kg/day and the developmental NOEL was 300 mg/
kg/day.
    Several rabbit teratology studies were conducted. Based on a weight 
of the evidence, no teratogenic effect was demonstrated. The maternal 
NOEL was 10 mg/kg/day, whereas the developmental NOEL was 60 mg/kg/day.
    A multigeneration study in rats demonstrated no impairment of 
reproductive performance or fetal and/or pup effects, although pup body 
weights were slightly decreased at the highest dose. The parental NOEL 
and developmental NOEL's were 1,000 ppm (50 mg/kg/day).
    There was no evidence of induction of point mutations in an Ames 
test.
    There was no indication of a mutagenic effect in a dominant lethal 
test.
    There was no evidence of a mutagenic effect in a nucleus anomaly 
test in Chinese hamsters.

D. Threshold Effects

    1. Chronic effects. EPA has established a reference dose for 
cyromazine at 0.0075 mg/kg/day based on the 6 month dog study using the 
NOEL of 0.75 mg/kg/day (30 ppm) and an uncertainty factor of 100.
    2. Acute toxicity. Based on the low degree of acute toxicity, it 
can be

[[Page 37255]]

concluded that cyromazine does not pose any acute dietary risks.
    Non-threshold effects (Carcinogenicity). Based on the Guidelines 
for Carcinogenic Risk Assessment published by EPA September 24, 1986 
(51 FR 33992), EPA has classified cyromazine as not carcinogenic (Group 
E). This classification was issued by the Health Effects Division 
Carcinogenicity Peer Review Committee on September 14, 1994.

E. Aggregate Exposure

    1. Dietary exposure. For purposes of assessing the potential 
dietary exposure to cyromazine, Novartis has estimated aggregate 
exposure based on the TMRC from the use of cyromazine in or on raw 
agricultural commodities for which tolerances have been established (40 
CFR 180.368) or are pending.
    The TMRC is obtained by multiplying the tolerance level residue for 
all these raw agricultural commodities by the consumption data that 
estimate the amount of these products consumed by various population 
subgroups. Since these raw agricultural commodities (e.g. soybean 
forage and fodder) are fed to animals, the transfer of residues in 
these fed commodities to meat, milk, poultry, or eggs has been 
calculated and tolerances have either been proposed or established.
    In conducting this exposure assessment, Novartis has used either 
EPA's estimate of market share or used best estimates provided by 
Novartis Product Management which assume plateau market share values. 
In addition, the dietary exposure assessment includes residue 
assumptions for meat and milk that provide very conservative estimates.
    2. Drinking Water. The environmental fate database for cyromazine 
indicates that, when used according to label directions, the compound 
is not likely to be found in ground or surface water at biologically 
significant concentrations. To date, cyromazine has never been detected 
in ground or surface water. The primary environmental degradate of 
cyromazine, melamine, has rarely been detected, and melamine detections 
have always been less than 0.3 ppb in water. To evaluate the potential 
impact of exposure to cyromazine in drinking water, Novartis calculated 
a theoretical lifetime Maximum Contaminant Level (MCL). The theoretical 
MCL, 50 ppb, is orders of magnitude greater than levels that are likely 
to be found in the environment under current conditions of use.
    3. Non-dietary exposure. Non-occupational exposure to the general 
population is unlikely since cyromazine is not used in or around the 
home, including home lawns.

F. Cumulative Effects

    Novartis considered the potential for cumulative effects of 
cyromazine and other chemicals in this class that may have a common 
mechanism of toxicity. Consideration of a common mechanism of toxicity 
is not appropriate for cyromazine since the existing data do not 
suggest a common mechanism.

G. Safety Determination

    1. U.S. population. Using the conservative exposure assumptions 
described above, and based on the completeness and reliability of the 
toxicity data, Novartis has concluded that aggregate exposure to 
cyromazine will utilize approximately 35% percent of the RfD for the 
U.S. population based on chronic toxicity endpoints. EPA generally has 
no concern for exposures below 100% of the RfD, because the RfD 
represents the level at or below which daily aggregate dietary exposure 
over a lifetime will not pose appreciable risks to human health. 
Therefore, Novartis concludes that there is reasonable certainty that 
no harm will result from aggregate exposure to cyromazine or residues 
of cyromazine that may appear in raw agricultural commodities.
    2. Infants and children. In assessing the potential for additional 
sensitivity of infants and children to residues of cyromazine, Novartis 
has considered data from developmental toxicity studies in the rat and 
rabbit, and a 2-generation reproduction study in the rat. The 
developmental toxicity studies are designed to evaluate adverse effects 
on the developing organism resulting from chemical exposure during 
prenatal development. Reproduction studies provide information relating 
to effects from exposure to a chemical on the reproductive capability 
of mating animals, on postnatal development, and systemic toxicity, 
particularly to the reproductive system.
    Developmental toxicity (reduced mean fetal body weight and an 
increased incidence of skeletal variations due to delayed ossification) 
was observed in the rat only at the maternally toxic dose of 600 mg/kg/
day. The no observed effect level for developmental toxicity in the rat 
was 300 mg/kg/day, a dose that was still maternally toxic. Similarly, 
the developmental no observed effect level in the rabbit (60 mg/kg/day) 
was higher than the maternal no observed effect level (10 mg/kg/day), 
which suggests that the developmental toxicity associated with high 
doses of cyromazine occurs secondarily to maternal toxicity.
    A 2-generation reproduction study was conducted with cyromazine at 
feeding levels of 0, 30, 1,000, and 3,000 ppm. Reproductive performance 
was unaffected by treatment with cyromazine at feeding levels up to 
3,000 ppm. Evidence of parental toxicity, as indicated by decreased 
body weight gain, was observed in males and females at feeding levels 
>1,000 ppm. Similar effects were noted in the offspring at 3,000 ppm. 
The maternal and developmental no observed effect levels were 
established at 1,000 ppm (50 mg/kg/day).
    FFDCA section 408 provides that EPA may apply an additional safety 
factor for infants and children in the case of threshold effects to 
account for pre- and post-natal toxicity and the completeness of the 
database. Based on the current toxicological data requirements, the 
database relative to pre- and post-natal effects for children is 
complete. Furthermore, the NOEL of 0.75 mg/kg/day from the chronic dog 
study used to calculate the RfD, is approximately 100 fold lower than 
the lowest developmental NOEL in the teratology studies (Rabbit 
Developmental NOEL = 60 mg/kg/day) and the developmental NOEL (50 mg/
kg/day) established in the multigeneration reproduction study. Based on 
these data, Novartis concludes that there is no evidence to suggest 
that developing organisms are more sensitive to the effects of 
cyromazine than are adults.
    The percentage of the RfD utilized by the U.S. population for 48 
states using aggregate exposure estimates is approximately 70%, if 
drinking water intake is assumed to be 100% of the MCL for the 
respective subgroup. It is highly unlikely that concentrations in 
drinking water will approach the MCL for even short periods of time. 
Consequently, this calculation of the percentage of the RfD that would 
be utilized is extremely conservative.
    The percentage of the RfD that is utilized is somewhat higher for 
non-nursing infants if the chronic NOEL is used to estimate exposure 
using the conservative exposure assumptions described above. Novartis 
has determined that the percentage of the lowest developmental NOEL (50 
mg/kg/day from the rat multigeneration study) utilized by aggregate 
exposure to residues of cyromazine is approximately 20% for nursing 
infants less than 1 year old, approximately 21% for non-nursing infants 
and for children 1 to six years old, and 62% for children 7 to 12 years 
old.

[[Page 37256]]

    Therefore, based on the completeness and reliability of the 
toxicity data and the conservative exposure assessment, Novartis 
concludes that there is reasonable certainty that no harm will result 
to infants and children from aggregate exposure to cyromazine residues.

H. Estrogenic Effects

    Cyromazine does not belong to a class of chemicals known to have or 
suspected of having adverse effects on the endocrine system. No adverse 
effects on fertility or reproduction were observed in high dose females 
(3000 ppm) in the rat reproduction study. Although residues of 
cyromazine have been found in raw agricultural commodities, there is no 
evidence that cyromazine bioaccumulates in the environment.

I. Environmental Fate

    Soil metabolism and soil dissipation studies on various soil types 
have shown that cyromazine dissipates moderately over time, while 
melamine is slightly more stable.

J. International Tolerances

    Compatibility problems exist between Codex limits, Mexican limits, 
and the proposed US tolerances. In Codex and Mexican limits, cyromazine 
is the only residue of concern; the metabolite melamine is not included 
in the residue expression. There are no established cyromazine limits 
for the RAC potato, or the processed commodities, potato granules/
flakes, or chips, or the feedstuff, processed potato waste. There is a 
0.01 ppm (at or about the limit of determination) Codex limit in milk.   
 (PM 13)

[FR Doc. 97-18085 Filed 7-10-97; 8:45 am]
BILLING CODE 6560-50-F