[Federal Register Volume 62, Number 153 (Friday, August 8, 1997)]
[Notices]
[Pages 42785-42791]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-20990]


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ENVIRONMENTAL PROTECTION AGENCY

[PF-752; FRL-5732-6]


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-752, must 
be received on or before September 8, 1997.
ADDRESSES: By mail submit written comments to: Public Information and 
Records Integrity Branch (7506C), Information Resources and Services 
Division, 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

[[Page 42786]]

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:<a href="/cdn-cgi/l/email-protection" class="__cf_email__" data-cfemail="701c11021f1313115e17151f0217153015">[email protected]</a>   Arlington, VA  
                                 pamail.epa.gov.                        
Mary Waller Acting (PM 21)....  Rm. 265, CM #2, 703-    Do.             
                                 308-9354, e-mail:                      
                                 <a href="/cdn-cgi/l/email-protection#fe899f92929b8cd0939f8c87be9b8e9f939f9792d09bf48e9fd0999188"><span class="__cf_email__" data-cfemail="e99e8885858c9bc784889b90a98c998884888085c78c">[email protected]</span>
pa.gov</a>.                                
------------------------------------------------------------------------

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-752] (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:
    <a href="/cdn-cgi/l/email-protection#c5aab5b5e8a1aaa6aea0b185a0b5a4a8a4aca9eba0b5a4eba2aab3"><span class="__cf_email__" data-cfemail="c4abb4b4e9a0aba7afa1b084a1b4a5a9a5ada8eaa1b4a5eaa3abb2">[email protected]</span></a>


    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 [PF-752] 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: July 28, 1997.

Donald R. Stubbs,

Acting Director, Registration Division, Office of Pesticide Programs.

Summaries of Petitions

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

1. E.I. du Pont de Nemours & Co. (Dupont)

PP 4F3023

    EPA has received a request to amend pesticide petition (PP 4F3023) 
from E.I. du Pont de Nemours & Co. (Dupont), P. O. Box 80038, proposing 
pursuant to section 408(d) of the Federal Food, Drug and Cosmetic Act, 
21 U.S.C. 346a(d), to amend 40 CFR part 180 by establishing a tolerance 
for residues of esfenvalerate, (S)-cyano-(3-phenoxyphenyl)methyl (S)-4-
chloro-alpha-(1-methylethyl) benzeneacetate in or on the raw 
agricultural commodity, celery. The enforcement analytical method for 
determining residue is gas chromatography with nitrogen phosphorus 
detection. EPA has determined that the petition contains data or 
information regarding the elements set forth in section 408(d)(2) of 
the FFDCA; however, EPA has not fully evaluated the sufficiency of the 
submitted data at this time or whether the data supports granting of 
the petition. Additional data may be needed before EPA rules on the 
petition.

A. Residue Chemistry

    1. Plant metabolism. The metabolism and chemical nature of residues 
of fenvalerate in plants is adequately understood. The fate of 
fenvalerate has been extensively studied using radioactive tracers in 
plant and animal metabolism/nature of the residue studies previously 
submitted to the Agency. These studies have demonstrated that the 
parent compound is the only residue of toxicological significance.
    2. Analytical method. There is a practical analytical method 
utilizing electron-capture gas chromotography available for enforcement 
with a limit of detection that allows monitoring food with residues at 
or above tolerance levels.
    3. Magnitude of residues. Current tolerances are based on the sum 
of all isomers of fenvalerate. Fenvalerate is a racemic mixture of four 
isomers (about 25% each). This product was registered as Pydrin. 
However since 1992, an S,S-isomer enriched formulation, Asana 
(esfenvalerate), has been the only fenvalerate formulation sold in the 
U.S. Since the S,S-isomer is the insecticidally active isomer, the use 
rate for Asana is four times lower than that for Pydrin. A petition is 
pending (PP 4F4329), to convert tolerances based on the use rates for 
Asana (still to be expressed as the sum of all isomers). Bridging 
studies have shown Asana residues to be 3-4 times lower than Pydrin 
residues.
    Residue trials were conducted on celery at four sites using Asana 
XL and at two sites using Pydrin Insecticides in order to bridge data 
from 14 residue studies previously conducted using Pydrin alone. The 
mean esfenvalerate residue in untrimmed celery samples treated with 
Asana XL was 4.40 ppm (range 1.39 to 6.51 ppm). The mean fenvalerate 
residue in untrimmed celery samples treated with Pydrin was 12.0 ppm 
(range 4.78 to 19.1 ppm). Total fenvalerate residues were approximately 
three times lower after application of Asana XL Insecticide than after 
application of Pydrin Insecticide.
    Since there are no processed commodities of celery, processing 
studies were not conducted. In addition, celery is not an animal feed 
item and, therefore, secondary residues will not be an issue.

[[Page 42787]]

B. Toxicological Profile

    The following studies have been submitted to EPA:
    1. Acute toxicity. A rat acute oral study on esfenvalerate 
technical with an LD<INF>50</INF> of 87.2 mg/kg. A rabbit acute dermal 
study on esfenvalerate with an LD<INF>50</INF> of > 2,000 mg/kg. Acute 
inhalation on technical grade a.i. waived due to negligible vapor 
pressure. A primary eye irritation test using esfenvalerate in the 
rabbit which showed mild irritation (conjunctivitis) that cleared by 
day 7. A primary dermal irritation test using esfenvalerate in the 
rabbit which showed minimal irritation that reversed within 72 hours 
after treatment (MRID 00156510). A dermal sensitization test on 
esfenvalerate in guinea pigs which showed no sensitization (MRID 
41215203).
    2. Genotoxicty. Esfenvalerate was not mutagenic in reverse mutation 
assays in Salmonella and E. Coli or in HGPRT in vitro assay in Chinese 
hamster lung cells. Esfenvalerate did not induce chromosome aberrations 
in an in vitro assay in Chinese hamster ovary cells. Esfenvalerate did 
not induce micronuclei in bone marrow of mice given up to 150 mg/kg 
intraperitoneally. Esfenvalerate did not induce unscheduled DNA 
synthesis in HeLa cells.
    3. Reproductive and developmental toxicity. A pilot developmental 
study in the rat with doses of 0, 1, 2, 3, 4, 5, and 20 mg/kg/day 
esfenvalerate. The maternal NOEL was 3 mg/kg/day based on maternal 
clinical signs of abnormal gait or mobility at 4 mg/kg/day and above. A 
developmental study in the rat with doses of 0, 2.5, 5, 10, and 20 mg/
kg/day esfenvalerate by gavage. There was no maternal NOEL but a 
maternal NOEL was established in the pilot study. Maternal signs 
observed at 2.5 mg/kg/day were erratic jerking and extension of 
forelimbs, rapid side-to-side head movement and excessive grooming. 
There were no fetal or developmental effects in either study at 20 mg/
kg/day, the highest dose tested. Therefore, the fetal/developmental 
NOEL was > 20 mg/kg/day.
    A pilot developmental study in the rabbit with doses of 0, 2, 3, 4, 
4.5, 5, and 20 mg/kg/day esfenvalerate by gavage. The maternal NOEL was 
2 mg/kg/day based on excessive grooming at 3 mg/kg/day and above. A 
developmental study in the rabbit with doses of 0, 3, 10, and 20 mg/kg/
day esfenvalerate by gavage. There was no maternal NOEL but a maternal 
NOEL was established in the pilot study. There were no fetal or 
developmental effects in either study at the highest dose tested. 
Therefore, the fetal/developmental NOEL was > 20 mg/kg/day.
    A 2-generation feeding study with esfenvalerate in the rat at 
dietary levels of 0, 75, 100, or 300 ppm. The high dietary 
concentration was lowered to 150 ppm for the second generation. Very 
mild body weight effects and sores at 75 ppm in both generations were 
considered secondary effects caused by scratching related to skin 
stimulation from dermal exposure. Therefore 75 ppm (4.2 mg/kg/day for 
first generation parental males, 5.6 mg/kg/day for first generation 
parental females, 6.0 mg/kg/day for second generation parental males, 
and 7.3 mg/kg/day for second generation parental females) was 
considered an NOAEL for both adult rats and their offspring. Effects 
were observed in adults and pups of both generations at 100 ppm and 
above. Pups were no more sensitive than adult animals.
    4. Subchronic toxicity. A 90-day feeding study in rats conducted at 
0, 75, 100, 125, and 300 ppm esfenvalerate with a NOEL of 125 ppm (6.3 
mg/kg/day). This study provided intermediate dose levels to supplement 
a 90-day feeding study in rats conducted at 0, 50, 150, 300 and 500 ppm 
esfenvalerate with a NOEL of 50 ppm (2.5 mg/kg/day) based on jerky leg 
movements at 150 ppm (7.5 mg/kg/day) and above.
    A 90-day feeding study in mice conducted at 0, 50, 150, and 500 ppm 
esfenvalerate and 2,000 ppm fenvalerate with a NOEL of 50 ppm 
esfenvalerate (10.5 mg/kg/day) based on lower glucose and triglycerides 
at 150 ppm. Neurologic symptoms were observed with 500 ppm 
esfenvalerate and 2,000 ppm fenvalerate.
    Three-month subchronic study in dogs is satisfied by 1-year oral 
study in dogs, in which the NOEL was 200 ppm esfenvalerate (5 mg/kg/
day). A 21-day dermal study in rabbits with fenvalerate conducted at 
100, 300, and 1,000 mg/kg/day of fenvalerate with an NOAEL of 1,000 mg/
kg/day fenvalerate.
    5. Chronic toxicity. A 1-year study in which dogs were fed 0, 25, 
50, or 200 ppm esfenvalerate with no treatment related effects at any 
dietary level. The NOEL was 200 ppm (5 mg/kg/day). An effect level for 
dietary administration of esfenvalerate for dogs of 300 ppm had been 
established earlier in the 2-week pilot study used to select dose 
levels for the chronic dog study.
    A 20-month study with fenvalerate in mice fed 0, 10, 30, 100, and 
300 ppm fenvalerate. The NOEL was 30 ppm (6mg/kg/day) based on red 
blood cell effects and granulomatous changes at 100 ppm. Fenvalerate 
was not carcinogenic at any concentration.
    An 18-month study with esfenvalerate in mice fed 0, 35, 150, and 
350 ppm esfenvalerate. Mice fed the 350 ppm dose were sacrificed within 
the first 2 months of the study, after excessive morbidity and 
mortality due to self-trauma induced by pharmacological effects on 
dermal sensory nerves. Therefore, data collected from the 350 ppm group 
were not used in the evaluation of the oncogenic potential of 
esfenvalerate. The NOEL was 35 ppm (4.29 and 5.75 mg/kg/day for males 
and females, respectively) based on lower body weight and body weight 
gain at 150 ppm. Esfenvalerate was not carcinogenic at either the 35 
ppm or 150 ppm concentrations.
    A 2-year study with fenvalerate in rats fed 1, 5, 25, and 250 ppm. 
A 1,000 ppm group was added to establish an effect level. The NOEL was 
250 ppm (12.5 mg/kg/day). At 1,000 ppm, hind limb weakness, lower body 
weight, and higher organ-to-body weight ratios were observed. 
Fenvalerate was not carcinogenic at any concentration.
    6. Animal metabolism.After oral dosing, fenvalerate was eliminated 
from rats within 5 days after dosing. The metabolic pathway involved 
cleavage of the ester linkage followed by hydroxylation, oxidation, and 
conjugation of the acid and alcohol moieties.
    7. Metabolite toxicology.The parent molecule is the only moiety of 
toxicological significance which needs regulation in plant and animal 
commodities.
    8. Other potential toxicology considerations - endocrine effects. 
Estrogenic effects have not been observed in any studies conducted on 
fenvalerate or esfenvalerate. In subchronic or chronic studies there 
were no lesions in reproductive systems of males or females. In the 
recent reproduction study with esfenvalerate, full histopathological 
examination of the pituitary and the reproductive systems of males and 
females was conducted. There were no compound-related gross or 
histopathological effects. There were also no compound-related changes 
in any measures of reproductive performance including mating, 
fertility, or gestation indices or gestation length in either 
generation.

C. Aggregate Exposure

    1. Dietary exposure. For purposes of assessing dietary exposure, 
chronic and acute dietary assessments have been conducted using all 
existing and pending tolerances for esfenvalerate. The toxicological 
endpoints used in both dietary assessments are derived from maternal 
NOEL's of 2.0 mg/kg/day

[[Page 42788]]

from rat and rabbit teratology studies. There were no fetal effects.
    2. Food. A chronic dietary exposure assessment using anticipated 
residues and assuming that 100% of all crops are treated, found the 
percentages of the Reference Dose (RfD) utilized by the two most 
sensitive sub-populations to be 44% (Non-Nursing Infants <1 yr.) and 
48% (Children 1-6 yrs.). This assessment also included all food 
tolerances for incidental food handling establishments which were set 
at 0.05 ppm (the limit of quantitation) since there were no detectable 
residues. The results have been adjusted from the study previously 
submitted to reflect the new RfD selected by EPA.
    The Tier 3 acute dietary assessment has been rerun to incorporate 
current EPA thinking on processing studies and secondary residues that 
has arisen since the original study was submitted. The most sensitive 
sub-populations were determined to be: Non-Nursing Infants (< 1 yr.) 
with a Margin of Exposure (MOE) of 914 at the 95th percentile of 
exposure and an MOE of 254 at the 99th percentile of exposure; and 
Children (1-6 yrs.) with an MOE of 698 at the 95th percentile of 
exposure and 321 at the 99th percentile. The MOE's for the general 
population were 1,803 at the 95th percentile of exposure and 676 at the 
99th percentile. This analysis used field trial residue data and market 
share data for the percent of crop treated. It also used Monte Carlo 
sampling and applied appropriate processing factors for apple juice and 
apple juice concentrate. Monte Carlo distribution was also used for 
meat and milk residues. Food handling establishment commodities were 
not included in the analysis because EPA methodology does not include 
them in Tier 3 exposure modeling.
    3. Drinking water. Esfenvalerate is immobile in soil and, 
therefore, will not leach into groundwater. Additionally, due to the 
insolubility and lipophilic nature of esfenvalerate, any residues in 
surface water will rapidly and tightly bind to soil particles and 
remain with sediment, therefore not contributing to potential dietary 
exposure from drinking water. In addition, a screening evaluation of 
leaching potential of esfenvalerate has been conducted using DuPont's 
Tier 1 Ground Water Exposure Model (TIGEM, Version December 30, 1996) 
which is based on results from EPA's Pesticide Root Zone Model (PRZM, 
Version 2.0). Based on this screening assessment, the potential 
concentrations of esfenvalerate in shallow ground water are judged to 
be negligible.
    4. Non-dietary exposure. Dietary exposure is the only significant 
route of chronic non-occupational exposure to esfenvalerate. However, 
esfenvalerate is registered for non-crop uses including spray 
treatments in and around commercial and residential areas, treatments 
for control of ectoparasites on pets, home care products including 
foggers, pressurized sprays, crack and crevice treatments, lawn and 
garden sprays, and pet and pet bedding sprays. For the non-agricultural 
products, the very low amounts of active ingredient they contain, 
combined with the low vapor pressure (1.5 X 10<SUP>-9</SUP> mm Mercury 
at 25 deg. C.) and low dermal penetration, would result in minimal 
inhalation and dermal exposure.

D. Cumulative Effects

    The potential for cumulative effects of esfenvalerate and other 
pyrethroid insecticides that have a common mechanism of toxicity must 
also be considered. While risk assessment methodology has not been 
developed to estimate cumulative exposure to multiple pyrethroids, 
their similar insecticidal efficacy results in the substitution of one 
pyrethroid for another, rather than addition of pyrethroids. Because of 
the breadth of exposures included in the assumptions for esfenvalerate 
risk assessment, it is unlikely that there will be significant additive 
exposure to other pyrethroids.
    These issues are extremely complex and require an extensive 
evaluation of a wealth of proprietary and published data across a broad 
range of pyrethroid insecticides in order to provide a scientifically 
sound interpretation upon which to base any regulatory judgments. The 
Pyrethroid Working Group is currently awaiting guidance from the Agency 
on cumulative effects. They anticipate having some preliminary 
evaluation data available for the Agency by August, 1997. For any 
interim decisions, the Agency should take into consideration the 
relatively benign toxicological profiles of pyrethroid insecticides and 
their long history of safe use.

E. Safety Determination

    1. U.S. population.A chronic dietary exposure assessment using 
anticipated residues and assuming that 100% of all crops are treated, 
found the percentage of the RfD utilized by the General Population to 
be 16%. There is generally 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, there is a reasonable certainty that 
no harm will result from aggregate exposure to esfenvalerate residues.
    A Tier 3 acute dietary exposure assessment found the General 
Population to have MOE's of 1,803 at the 95th percentile of exposure 
and 676 at the 99th percentile of exposure. These values were generated 
using actual field trial residues and market share data for percentage 
of crop treated. These results depict an accurate exposure pattern at 
an exaggerated daily dietary exposure rate. Thus, there is a reasonable 
certainty that no harm will result from aggregate exposure to 
esfenvalerate residues.
    2. Infants and children. The chronic dietary assessment using the 
same assumptions described above, found the two most sensitive sub-
populations to be non-nursing infants (<1 yr.) and children (1-6 yrs.) 
utilizing 44% and 48% of the RfD, respectively. In the Tier 3 acute 
dietary assessment that was rerun using the assumptions described 
above, non-nursing infants were found to have an MOE of 914 at the 95th 
percentile of exposure and an MOE of 254 at the 99th percentile. 
Children (1-6 yrs.) were determined to have an MOE of 698 at the 95th 
percentile and 321 at the 99th percentile. Therefore, there is a 
reasonable certainty that no harm will result from aggregate exposure 
to esfenvalerate residues.

F. International Tolerances

    Codex maximum residue levels (MRL's) have been established for 
residues of fenvalerate on a number of crops that also have U.S. 
tolerances. Several of these MRL's are different than the proposed U.S. 
tolerances for esfenvalerate. Therefore, some harmonization of these 
maximum residue levels is still needed. (George LaRocca)

2. Elf Atochem North America, Inc.

PP 5F4550

    EPA has received a pesticide petition (PP 5F4550) from Elf Atochem 
North America, Inc., 2000 Market Street, Philadelphia, PA 19103-3222, 
proposing pursuant to section 408(d) of the Federal Food, Drug and 
Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 CFR part 180 by 
establishing tolerances for residues of Thiophanate-methyl in or on the 
raw agricultural commodities grapes at 5.0 parts per million (ppm) and 
pears at 7 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

[[Page 42789]]

this time or whether the data supports granting of the petition. 
Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

    1. Plant metabolism. The metabolism of thiophanate-methyl (TM) in 
plants is well understood. Results of testing in wheat, lima beans, 
sugar beets and apples indicate that TM can be converted to methyl 
benzimidazole carbamate (MBC), allophanate (or FH-432), and DX-105 
(sulfonated allophanate). TM, MBC, allophanate, and DX-105 are 
reflected in the tolerance as petitioned.
    2. Analytical method. A proposed enforcement method for crop 
residue was submitted to the Agency in April 1996. The new method 
replaces the acid digestion method currently in widespread use. In 
contrast to the older method which involves acid hydrolysis of TM to 
MBC, the new method is capable of analyzing for TM directly and its 
three metabolites: MBC, allophanate, and DX-105. A proposed enforcement 
method for animal tissue will be submitted to the Agency in July 1997. 
The new method will entirely replace the current enforcement method.
    3. Magnitude of residues--i. Grapes. Elf Atochem North America has 
conducted magnitude of the residue studies on grapes. The petition for 
the addition of a grape tolerance of 5 ppm was submitted June 16, 1995.
    ii. Pears. Elf Atochem North America has conducted magnitude of the 
residue studies on pears. The petition for the addition of a pear 
tolerance of 7 ppm was submitted June 16, 1995.

B. Toxicological Profile

    1. Acute toxicity. Technical thiophanate-methyl is practically non-
toxic (Toxicity Category III) after administration by the oral, dermal 
and respiratory routes. Thiophanate-methyl is a skin sensitizer. 
Exposure to the technical product is not expected to occur to the 
general public or to infants or children.
    2. Genotoxicty. Thiophanate-methyl has been extensively tested for 
genotoxicity and is not genotoxic. This further supports the threshold 
nature of the thyroid and liver effects. MBC has been tested in a wide 
range of genotoxicity assays. It is not a heritable gene mutagen. It 
does not interact with DNA, induce point mutations or result in germ 
cell mutations. Carbendazim (MBC) does cause numerical chromosome 
aberrations in experimental systems in vitro and in vivo as a result of 
interference with cellular tubulin rather than DNA.
    3. Reproductive and developmental toxicity. Thiophanate-methyl 
induced no maternal effects and there were no teratogenic or fetotoxic 
effects in rats at any of the doses tested up to 2,500 ppm thiophanate-
methyl. The maternal No Observable Effect Level, NOEL, is considered to 
be 250 ppm (12.5 mg/kg/day) based on body weight in the initial dosing 
phase of the study. The fetal NOEL was 2,500 ppm (125 mg/kg/day).
    Thiophanate-methyl was also fed to pregnant rabbits at 0, 2, 6, and 
20 mg/kg/day. The NOEL for maternal toxicity is tentatively defined as 
6 mg/kg/day based on minimal body weight and food intake changes and 
the incidence of abortion/total litter loss. The NOEL for developmental 
effects is tentatively defined by EPA as 2 mg/kg/day. The Lowest 
Observable Effect Level, LOEL, was tentatively set at 6 mg/kg/day based 
on non-statistically significant dose-related increases in the 
incidence of asymmetric pelvis. These effects at the high dosage, 20 
mg/kg/day, were well within historical control rates. This effect is 
not considered a harbinger of more significant findings at higher 
dosages. There was no evidence of any major teratogenicity. Based on 
this information, a NOEL of 6 mg/kg/day can be set for developmental 
effects.
    In a 2-generation reproduction study, the thiophanate-methyl NOEL 
for systemic toxicity is <200 ppm based on hepatocellular hypertrophy/
hyperplasia at all dose levels, decreased body weight gain in males, 
and increased liver and thyroid weights in both sexes at the highest 
dose tested. This LOEL is considered to be borderline NOEL/LOEL because 
the effects on the thyroid and liver at 2,100 ppm were minimal. The 
effects were less (fewer animals and less severe) in the succeeding 
generation. The NOEL is 200 ppm based on reduced body weights of the 
F2b pups during lactation at 630 ppm.
    4. Endocrine effects. Thiophanate-methyl has been evaluated in both 
reproductive and developmental studies. No effects were observed that 
would indicate that the endocrine system is disrupted with regard to 
the reproductive system (i.e., anti-estrogenic, estrogenic, androgenic, 
anti-androgenic). TM does alter thyroid function through the thyroid 
stimulating hormone. This effect has been studied further and is 
documented in the rat chronic/oncogenicity study.
    5. Chronic toxicity. Thiophanate-methyl was administered by capsule 
to beagle dogs for one year. Based on the decreased body weight gain in 
both sexes, decreased T4 levels in males and increased thyroid-to-body 
weight ratio and hypertrophic histologic changes in the thyroid gland 
in both sexes, the LOEL for thiophanate-methyl is 40 mg/kg/day and the 
NOEL is 8 mg/kg/day.
    A combined chronic/oncogenicity feeding study was performed in rats 
at dosages of 0, 75, 200, 1,200 and 6,000 ppm TM for 2 years. No 
clinical signs attributable to TM were noted in the first 52 weeks. It 
was concluded that the effects of the treatment with TM included growth 
depression, anemia, morphological and functional changes in the thyroid 
and pituita, hepatocellular hypertrophy with lipofuscin, 
acceleratednephropathy andlipidosis of the adrenal cortex. The MTD was 
determined to be 1,200 ppm for both males and females. At 6,000 ppm, 
approximately five times the MTD, an increase in thyroid follicular 
cell adenomas was observed in males. Thyroid hyperplasia and 
hypertrophy were observed only at or above the MTD. These effects are 
considered to be related to the treatment related changes in hormonal 
homeostasis of the pituitary-thyroid axis. The NOEL is 200 ppm (8.8 mg/
kg/day in males and 10.2 mg/kg/day in females) when fed for 104 weeks.
    6. Carcinogenicity. Thiophanate-methyl was fed to male and female 
CD-1 mice for 18 months. At 3,000 ppm the males showed an increased 
incidence of hepatocellular hypertrophy and a small, but statistically 
significant, decrease in body weight (<8%). Transient increases in 
serum thyroid stimulating hormone (TSH) and in absolute and relative 
thyroid weights were also observed in males. At the highest dose tested 
(7,000 ppm) both males and females showed increased mortality and 
increased liver weight at both weeks 39 and 78. Females at 7,000 ppm 
showed a statistically significant decrease in body weight (<8%), 
decreased serum thyroxine (T4) at week 39, and increased heart weight 
at weeks 39 and 78. A dose-related statistically significant increase 
in the incidence of hepatocellular adenomas was observed in both sexes 
at 3,000 and 7,000 ppm. The systemic NOEL is 150 ppm (23.7 mg/kg/day in 
males and 28.7 mg/kg/day in females). The LOEL is 640 ppm based on an 
increased incidence of hepatocellular hypertrophy in females.
    Mechanistic studies have been performed in rats and mice to 
elucidate the role of TM in the disruption of the thyroid. TSH, T3 and 
T4 are altered by TM treatment. The thyroid effects are alleviated by 
the addition of T4. The effects noted in both the rat, mouse and dog 
studies fit the threshold consideration category outlined by the Agency 
in the document ``Thyroid

[[Page 42790]]

Follicular Carcinogenesis: Mechanistic and Science Policy 
Considerations.''
    7. Animal metabolism. The metabolism of thiophanate-methyl in 
animals is well understood. In animal studies in laying hens and 
lactating goats, some of the metabolites are subsequently hydroxylated. 
Thiophanate-methyl was also orally administered to male and female rats 
at dose levels of 10, 13, and 150 mg/kg. The absorption and excretion 
of the radioactivity was rapid. The maximum concentrations in blood 
were reached after about 1 to 3 hours in the two lower dose groups and 
in 4 to 7 hours in the higher. Less than 0.5% of the administered dose 
was associated with the rat's body. Among the tissues examined, the 
residue level of thiophanate-methyl equivalents was the highest in the 
thyroid and liver. About 70% of the radioactivity was quantitatively 
identified in the urine and feces as TM, 4-OH-TM, 5-OH-MBC and 5-OH-
MBC-S (enzymatic hydrolysis from conjugated material).
    8. Metabolite toxicology. There are three primary plant metabolites 
of thiophanate-methyl: MBC, allophanate, and DX105 (sulfonated 
allophanate). The toxic metabolite, MBC, is well understood and 
documented in the report of the International Programme on Chemical 
Safety (Environmental Health Criteria 149: Carbendazim, World Health 
Organization, 1993). MBC is marketed outside the U. S. under the trade 
name of Carbendazim.
    The NOEL for MBC is 500 mg/kg/day in the rat chronic/oncogenicity 
and 300 mg/kg in the dog chronic studies. Three mouse oncogenicity 
studies were performed in three different strains of mice with mixed 
results. In CD-1 mice, MBC induced hepatocellular adenomas in females 
with a NOEL of 500 mg/kg/day. In SPF mice there was an increase in the 
incidence of combined hepatocellular adenomas and carcinomas. A study 
in NMRKf mice showed no carcinogenic effects up to a dose of 5,000 mg/
kg/day. The rat oncogenicity study showed no carcinogenicity. The 
Agency has categorized MBC (carbendazim) as a C oncogen and assigned a 
Q* of 4.2 x 10<SUP>-3</SUP>.

C. Aggregate Exposure

    1. Dietary exposure. Dietary exposure is the primary route of 
exposure to TM.
    2. Drinking water. Thiophanate-methyl is not expected to be found 
in water. The half-life of TM is very short in soil and water. When 
metabolized or chemically converted to MBC, none is expected to leave 
the soil. Little to no TM exposure is expected in drinking water. In 
the ``EPA Pesticide in Groundwater Database: A Compilation of 
Monitoring Studies: 1971-1991: National Summary'' no TM was detected. 
Based on the environmental fate data, TM or its metabolite MBC is not 
expected to leach into water systems. There are no uses of TM that are 
expected to impact water.
    3. Non-dietary exposure. Thiophanate-methyl has turf use patterns 
which are primarily commercial (golf course, turf farms). Children are 
not primary users of golf courses and would have little opportunity for 
exposure as the result of this use pattern. Homeowner use is expected 
to be low. Based on sales figures use on lawns should not exceed 1%. 
Product is applied by commercial applicators. The dermal exposure 
studies showed no toxicity in a limit test at 2,000 mg/kg. The dermal 
absorption of thiophanate-methyl, and carbendazim is significantly 
lower than the oral route of exposure. The NOEL for a 21-day dermal 
exposure study in rats is 300 mg/kg/day and dermal irritation is 1,000 
mg/kg/day dosage.
    Based on the limited use of the product on lawns and the low dermal 
toxicity, little to no contribution to the TM risk cup is expected 
through non-occupational exposure.

D. Cumulative Effects

    Benomyl, MBC, thiabendazole and TM have been evaluated for similar 
toxicity patterns because of the potential structure-activity 
relationship. TM, although displaying some similarities to each 
benzimidazole, is also very different. These benzimidazoles do not 
share a toxicity profile that would indicate there is common mode of 
action.
    The toxic effects of TM are very different from those published on 
MBC or benomyl. TM toxicity primarily involves the thyroid. In 
contrast, no disruption of the thyroid-pituitary-liver axis is 
documented in either the carbendazim or the benomyl studies. Secondary 
effects on the liver could be seen in common, but these too are very 
different. If driven by MBC alone, TM should have a dose effect much 
higher than MBC. In fact, it is two to three times lower. Reproductive, 
developmental and genetic toxicity are also different between TM and 
MBC. Likewise, thiabendazole is different than TM. It does not 
metabolize to MBC and shows significant differences from TM in the type 
of toxicities observed. Therefore, there is no scientific basis for 
aggregating this class of fungicides, due to a lack of common 
mechanisms of toxicity.

E. Safety Determination

    1. U.S. population. Assessments have been made for chronic, acute, 
and cancer risk. In all assessments, there is a reasonable certainty of 
no harm associated with TM residues on food.
    2. Non-cancer chronic dietary safety determination. For chronic 
assessments other than cancer, the Reference Dose (RfD) is 0.08 mg/kg/
day based on the results of the chronic dog study. Because the data 
base is complete, a 100-fold safety factor can be used. The maximum 
permitted intake (MPI) of TM for a 60 kg human is calculated to be 4.8 
mg/day. The theoretical maximum residue contribution (TMRC) from 
existing tolerances for a 1.5 kg daily diet is calculated to be 0.24002 
mg/day. Based on the Agency's calculations, this represents about 5% 
utilization of the MPI. The addition of grapes would add only 
0.00000895 mg/kg/day and pears would add 0.00000512 mg/kg/day. Using 
anticipated residue rather than tolerances, the actual utilization of 
the MPI will be significantly lower.
    3. Acute dietary safety determination. The acute dietary risk Tier 
3 analysis has been performed using a Monte Carlo analysis. The NOEL 
used was from a developmental study in rabbits (6 mg/kg/day). For the 
total U.S. population, non-nursing infants, children aged 1 to 6, and 
women aged 13 to 50 all margins of exposure (MOE) exceeded 100 at any 
percentile evaluated. At the 95 percentile of per-capita days, the MOE 
for all uses including pending actions for the U.S. population is 
3,468; for non-nursing infants the MOE is 1,123; for all infants the 
MOE is 1,260; children ages 1 to 6 it is 1,620; children ages 7 to 12 
the MOE is 2,911 and for females 13 to 50 the MOE is 7,219. The highest 
exposed sub-population, non-nursing infants, had an MOE of 562 at the 
99th percentile. There is an adequate acute dietary safety margin for 
all current and intended uses of TM.
    4. Cancer risk assessment. Thiophanate-methyl is regulated based on 
the metabolite MBC with a designated Q* of 4.2 x 10<SUP>-3</SUP> based 
on mouse liver tumors. The lifetime cancer dietary risk is calculated 
by summing all sources of MBC that would result from TM use. Residues 
measured as MBC on plants were added to the residues from TM that could 
be converted biologically upon ingestion to MBC. Residue values were 
averaged and adjusted for percent of the crop treated. The bio-
conversion factor was 36.5% based on the rat metabolism study using the 
low dose preconditioned treatment. Using the USDA's Continued Survey of 
Food Intake by Individuals (CSFII) conducted

[[Page 42791]]

from 1989 through 1992 and field trial residue data, MBC exposure was 
calculated. This exposure multiplied by the cancer potency factor (Q*) 
generates the potential cancer risk attributable to MBC at the 95% 
confidence interval. Life-time cancer risk for the total U.S. 
population for all seasons is calculated to be 2.71 x 10<SUP>-7</SUP>. 
With the addition of grape and pear uses the lifetime cancer risk is 
2.89 x 10<SUP>-7</SUP>. The most sensitive sub-population is non-
hispanic other than black or white, with a cancer risk of 4.56 x 
10<SUP>-7</SUP>.
    5. Infants and children. Based on the acute and chronic dietary 
assessments, there is reasonable certainty of no harm to children who 
consume food treated with TM. Potential exposure from water or non-
occupational exposure is minimal. Inhalation and dermal exposure is 
unlikely. The acute MOEs for dietary ingestion are large.
    The potential of TM to induce toxic effects in children at a 
greater sensitivity than the general population has been assessed by 
the rat and rabbit developmental and 2-generation reproduction studies. 
No major teratogenic or fetotoxic effects were present in the absence 
of maternal toxicity. The TM 2-generation reproduction study showed 
thyroid and liver effects in both the parental and first generation 
pups. The effects were greater in the parental animals than in 
subsequent generations. This would indicate that there is no greater 
sensitivity for neo-nates, infants and children to TM than the general 
population. The reproductive and developmental data base is complete. 
There is no need to impose an additional safety factor to protect 
infants and children. Based on the level of potential exposure and 
similar sensitivity to the adult population, infants and children are 
well protected by the current TM regulatory policy.

F. International Tolerances

    The CODEX Maximum Residue Limits (MRL) for thiophanate-methyl are 
expressed as the metabolite MBC. The grape MRL is 10 mg/kg and the pear 
MRL is 5 mg/kg. (Mary Waller)
[FR Doc. 97-20990 Filed 8-7-97; 8:45 am]
BILLING CODE 6560-50-F


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