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Tolylfluanid (Bayer). August 11, 1997. Petition to Establish Import Tolerances for residues of the fungicide in or on apples and grapes at 5.0 ppm, hops at 30 ppm and tomatoes at 1.0 ppm. Federal Register.


[Federal Register: August 11, 1997 (Volume 62, Number 154)]
[Page 42980-42986]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]



[PF-755; FRL-5736-1]

Notice of Filing of Pesticide Petitions

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.


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-755, must 
be received on or before September 10, 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 
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-mail:       Davis Hwy,     
                                 larocca.george@epamai   Arlington, VA  
Mary Waller, Acting (PM 21)...  Rm. 265, CM #2, 703-    Do.             
                                 308-9354, e-mail:                      

[[Page 42981]]

James Tompkins, Acting (PM 25)  Rm. 239, CM #2, 703-    Do.             
                                 305-5697, e-mail:                      

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 
    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-755] (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:

    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-755] 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 

    Dated: August 1, 1997.

Peter Caulkins,

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. Bayer Corporation

PP 7E4825

    EPA has received a pesticide petition (PP 7E4825) from Bayer 
Corporation, 8400 Hawthorn Road, Kansas City, MO 64120, 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 import 
tolerances for residues of the fungicide Tolylfluanid in or on the raw 
agricultural commodities apples and grapes at 5.0 parts per million 
(ppm), hops at 30 ppm and tomatoes at 1.0 ppm. EPA has determined that 
the petition contains data or information regarding the elements set 
forth in section 408(d)(2) of the FFDCA; however, EPA has not fully 
evaluated the sufficiency of the submitted data at this time or whether 
the data supports granting of the petition. Additional data may be 
needed before EPA rules on the petition.

A. Residue Chemistry

    1. Plant metabolism. Plant metabolism studies were conducted using 
radiolabeled tolylfluanid applied to apples, grapes, and strawberries. 
Unchanged parent tolylfluanid was the major metabolite identified in 
these studies.
    2. Analytical method. Bayer has developed an analytical method for 
the determination of tolylfluanid residues in raw agricultural and 
processed commodities of apples, grapes, tomatoes, and hops. Samples 
are analyzed by gas chromatography using thermionic nitrogen-phosphorus 
detector or flame photometric detector following extraction, 
filtration, and cleanup procedures. The limit of quantitation is 0.02 
mg/kg for all matrices, except it is 0.05 mg/kg for raisins and wet 
apple pomace, 0.5 mg/kg for green hop cones, and 1.0 mg/kg for dried 
hop cones.
    3. Magnitude of residues. Bayer has conducted over 90 residue field 
trials in seven countries on apples, grapes, tomatoes, and hops. 
Residues of tolylfluanid in or on grapes harvested 14, 21 or 35 days 
following treatment according to recommended practices ranged from 0.03 
mg/kg to 3.45 mg/kg, except residues of tolylfluanid were 5.08 mg/kg in 
one sample from a trial conducted in Spain. Residues of tolylfluanid 
ranged from 0.03 mg/kg to 0.66 mg/kg in tomatoes harvested 3 or 7 days 
following multiple applications with tolylfluanid. Residues of 
tolylfluanid ranged from 0.14 to 2.31 mg/kg in or on apples harvested 7 
days after multiple applications with tolylfluanid. Residues of 
tolylfluanid in or on hops harvested 14 days following multiple 
applications ranged from 3.31 mg/kg to 27.0 mg/kg (dried cone) and 
ranged from 3.8 mg/kg to 17.6 mg/kg (green cone).
    Studies have also been conducted to evaluate the potential for 
concentration of tolylfluanid residues during the processing of apples, 
grapes, and tomatoes. Tolylfluanid does not have the potential to 
concentrate in the EPA required processed commodities consumed by 
humans for apples, grapes and tomatoes. Residues of tolylfluanid may 
have the potential to concentrate in wet apple pomace, an animal feed 

B. Toxicological Profile

    1. Acute toxicity. Tolylfluanid exhibits low acute oral, dermal, 
and inhalation toxicity (LD<INF>50s</INF> >5,000 mg/kg b.w.). An acute 
neurotoxicity study showed no specific evidence of neurotoxicity; non-
specific signs of toxicity were observed in this study (in females 
only) at doses at and greater than 150 mg/kg b.w. Tolylfluanid is a 
severe dermal irritant, moderately irritating to the eye, and a skin 
sensitizer. Tolylfluanid showed no systemic toxicity following subacute 
dermal administration, but did cause dermal irritation. Effects seen in 
the acute as well as subacute inhalation

[[Page 42982]]

study indicate tolylfluanid is a strong respiratory irritant.
    2. Genotoxicity. The genotoxic potential of tolylfluanid was 
assessed in several in vivo and in vitro studies. The weight-of-the-
evidence indicates that tolylfluanid is not genotoxic.
    3. Reproductive and developmental toxicity. Tolylfluanid showed no 
evidence of developmental toxicity based on two rat developmental 
toxicity studies. Tolylfluanid showed evidence of developmental effects 
in rabbits but only at a maternally toxic dose level.
    Two complete 2-generation reproductive toxicity studies in rats and 
one supplementary 2-generation reproductive toxicity rat study have 
been conducted on tolylfluanid. Reproductive toxicity (decreased body 
weight development in pups and decreased number of pups born, birth 
weight, litter size, and lactation index) was noted only in the 
presence of parental toxicity (decreased body weight gain, organ weight 
changes, and hyperostosis of the crania).
    4. Subchronic toxicity. Subchronic toxicity studies have been done 
with tolylfluanid in rats and dogs. Decreased body weight gain, 
decreased liver enzymes, slightly increased relative liver weights, and 
thyroid toxicity were noted in a subchronic rat dietary study (no 
correlating histopathological findings). Decreased body weight gain, 
increased liver enzyme activity, slightly increased relative liver 
weights, and increased PAS staining in the liver occurred in a 
subchronic dietary dog study. A subchronic neurotoxicity study in rats 
showed no evidence of neurotoxicity.
    5. Chronic toxicity. Chronic toxicity studies on tolylfluanid were 
done in the rat, mouse and dog. Tolylfluanid was tested in two rat 
chronic dietary studies. Increased growth of the incisors of the upper 
jaw and skeletal changes (hyperostosis in the skull and ribs) resulted 
from the high fluorine content of the compound. Hepatotoxicity and 
renal toxicity were seen in rats, mice, and dogs. Hepatotoxicity was 
evidenced by hepatocellular cytoplasmic changes, vacuolation, and focal 
fatty changes in rats, hepatocellular hypertrophy and single cell 
necrosis in mice, decreased liver enzymes in rats, and increased liver 
enzymes in mice and dogs. Renal toxicity (microscopic kidney lesions, 
increased relative kidney weights, effects on urinalysis parameters) 
was probably attributable to the effects of fluoride on renal tubules. 
A second chronic toxicity study in dogs is currently ongoing (results 
not yet available).
    6. Oncogenicity. Tolylfluanid showed no evidence of direct 
oncogenic activity in rats or mice. In rats tolylfluanid altered 
thyroid hormone levels and an increased incidence of hyperplastic and 
neoplastic lesions of the thyroid (primarily adenomas) in rats was 
observed. The thyroid neoplasia is considered to be a secondary 
(thresholdable) effect to altered thyroidal iodine metabolism and does 
not suggest a direct oncogenic effect. No treatment-related neoplasms 
were seen in the mouse oncogenicity study.
    Based on the chronic toxicity data, Bayer believes the RfD for 
tolylfluanid is 0.08 mg/kg, based on the no observed adverse effect 
level (NOAEL) of 8 mg/kg b.w./day for parental and reproductive 
toxicity identified in the second 2-generation rat reproductive 
toxicity study (Pinckel and Ricke, 1995) and an uncertainty factor of 
100. No unique concern for toxicity to infants and children was 
identified, therefore an additional safety factor is not warranted. 
(Note there is a seven-fold difference between the NOAEL and lowest 
effect level (LEL).
    Using the Guidelines for Carcinogenic Risk Assessment published in 
September 1986, we believe the Agency will classify tolylfluanid as a 
Group C carcinogen (possible human carcinogen) based on benign thyroid 
tumors seen in the chronic rat studies). Mechanistic studies with 
tolylfluanid have shown that these tumors are induced through a 
nonlinear threshold mechanism similar to that discussed in EPA's 
thyroid policy document. Therefore, tolylfluanid should be regulated 
using the margin of exposure approach.
    7. Animal metabolism. Metabolism studies were conducted using hens 
and goats. No residues of parent tolylfluanid were detected in any 
tissues, organs, milk, or eggs. Tolylfluanid is metabolized and 
excreted rapidly and efficiently in mammals.

C. Aggregate Exposure

    1. Dietary exposure. Food and drinking water/non-dietary exposure.
    2. Food. A chronic dietary exposure analysis was conducted for 
tolylfluanid. The reference dose (RfD) was 0.08 mg/kg/day based on a 
NOEL of 8 mg/kg/day and an uncertainty factor of 100. The no observed 
effect level (NOEL) was obtained from the rat reproduction study and 
the effect was decreased pup viability and decreased body weights.
    The RfD could change based on the NOEL from a repeat chronic dog 
toxicity study which is currently ongoing (doses tested: 5, 20, and 80 
mg/kg/day). The final report for this study is expected to be completed 
in the second part of 1997. If necessary, revising the RfD will be 
addressed at that time.
    Tolylfluanid does not have the potential to concentrate in 
processed commodities consumed by humans. The proposed MRLs for the 
respective crops were used for the raw agricultural and processed 
commodities for grapes (5 mg/kg), tomatoes, (1 mg/kg), and hops (30 mg/
kg). The anticipated residue level for fresh apples and apple juice was 
calculated by adjusting the proposed MRL for apples (5 mg/kg) for the 
percentage of fresh apples (4.8%) and apple juice (59.7%) consumed in 
the U.S. that are imported. No adjustments were made for the 
anticipated residue levels for grapes, tomatoes and hops.
    The results of the chronic dietary exposure analysis for the 
overall U.S. population and the three most highly exposed population 
subgroups are summarized as follows.. The exposure estimate was 
compared against the RfD of 0.08 mg/kg. The theoretical maximum residue 
contribution (TMRC) as percentage of the RfD, was 9.53% for the U.S. 
population, 53.36% for non-nursing infants, 38.02% for nursing infants 
(0-1 yr old), and 26.16% for children (1-6 yrs old). The anticipated 
residue contribution (ARC) as percentage of the RfD was 5.97% for the 
U.S. population, 23.29% for non-nursing infants, 15.41% for nursing 
infants and 15.10% for children. As seen above, chronic dietary 
exposure to tolylfluanid is less than 24% of the RfD for even the most 
highly exposed subgroup. In addition, these exposure estimates greatly 
over estimate the anticipated risk for the following reasons: (1) a 
relatively small percentage of these crops will be treated with 
tolylfluanid; (2) a small percentage of the treated crops are imported 
to the U.S.; (3) a small percentage of the total U.S. consumption of 
these crops are imported products; and (4) the actual residues in the 
imported commodities will likely be below the proposed MRLs.
    3. Drinking water. Tolylfluanid residue levels in tap water, non-
tap water, and water in commercially prepared food were assumed to be 
zero because tolylfluanid is not registered for use in the United 
States and therefore, the only exposure is from the importation of 
tolylfluanid-treated commodities.
    4. Non-dietary exposure. Tolylfluanid is not registered in the 
United States, therefore there is no non-occupational, structural or 
residential exposure.

D. Cumulative Effects

    Tolylfluanid is a fungicide that is somewhat structurally similar 

[[Page 42983]]

Captan, and appears to share a common mechanism of fungicidal action 
with this product. However, tolylfluanid does not show a similar 
mammalian toxicity profile to Captan, which has been reported to 
produce mouse gastrointestinal tumors and male rat kidney tumors. No 
significant cumulative toxicity to mammals based on a common mechanism 
of action to that of Captan is anticipated for tolylfluanid.
    Tolylfluanid alters the thyroid hormone balance, but: (1) no data 
exist showing specifically how tolylfluanid causes thyroid changes; (2) 
tolylfluanid is not known to be structurally similar to other thyroid 
tumorigens; (3) no common mechanism has been established or proposed 
and (4) even if it is eventually determined that the mechanism for 
thyroid tumorigenesis may be similar to other classes of pesticides, 
this endpoint is seen with tolylfluanid only at very high exposure 
levels. If an RfD for tolylfluanid were based on dose levels at which 
thyroid hormone levels were altered, a very low impact on a cumulative 
risk cup would be anticipated because the potency of tolylfluanid is 
very low.
    Endocrine effects. Endocrine-related effects of tolylfluanid 
exposure appear to be limited to the thyroid. No evidence of estrogenic 
or anti-estrogenic activity was present in the available animal 
studies. The developmental toxicity and reproductive toxicity studies 
showed no effects suggesting endocrine disruption, (e.g., change in 
fetal sex ratios, change in estrous cycles or mating performance, 
change in fertility, or malformed or altered reproductive organ 

E. Safety Determination

    1. U.S. population. A chronic dietary exposure analysis was 
conducted for tolylfluanid. The chronic dietary exposure to 
tolylfluanid is 5.97% of the RfD for the U.S. population, using the 
    2. Infants and children. A chronic dietary exposure analysis was 
conducted for tolylfluanid. The chronic dietary exposure to 
tolylfluanid is 23.29% of the RfD for non-nursing infants, the most 
highly exposed group, using the ARC.

F. International Tolerances

    The current Codex tolerances for tolylfluanid are based on residues 
of parent only. The Codex tolerances are: 5 mg/kg for currents (black, 
red, and white), 2 mg/kg for Gherkins, 1 mg/kg for head lettuce, 5 mg/
kg for pome fruits, 3 mg/kg for strawberries, and 2 mg/kg for tomatoes. 
(Mary Waller)