[Federal Register Volume 62, Number 154 (Monday, August 11, 1997)]
[Notices]
[Pages 42980-42986]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-21147]


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ENVIRONMENTAL PROTECTION AGENCY

[PF-755; FRL-5736-1]


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-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:

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                                   Office location/                     
        Product Manager            telephone number          Address    
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George LaRocca (PM 13)........  Rm. 204, CM #2, 703-    1921 Jefferson  
                                 305-6100, e-mail:       Davis Hwy,     
                                 <a href="/cdn-cgi/l/email-protection" class="__cf_email__" data-cfemail="86eae7f4e9e5e5e7a8e1e3e9f4e1e3c6e3f6e7ebe7ef">[email protected]</a>   Arlington, VA  
                                 l.epa.gov.                             
Mary Waller, Acting (PM 21)...  Rm. 265, CM #2, 703-    Do.             
                                 308-9354, e-mail:                      
                                 <a href="/cdn-cgi/l/email-protection#dea9bfb2b2bbacf0b3bfaca79ebbaebfb3bfb7b2f0bbd4aebff0b9b1a8"><span class="__cf_email__" data-cfemail="81f6e0edede4f3afece0f3f8c1e4f1e0ece0e8edafe4">[email protected]</span>
pa.gov</a>.                                

[[Page 42981]]

                                                                        
James Tompkins, Acting (PM 25)  Rm. 239, CM #2, 703-    Do.             
                                 305-5697, e-mail:                      
                                 <a href="/cdn-cgi/l/email-protection#d5a1bab8a5bebcbba6fbbfbcb895b0a5b4b8b4bcb9fbdfb0a5b4fbb2baa3"><span class="__cf_email__" data-cfemail="3b4f54564b50525548155152567b5e4b5a565a525715">[email protected]</span>
epa.gov</a>.                               
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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-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:
    <a href="/cdn-cgi/l/email-protection#5a352a2a773e3539313f2e1a3f2a3b373b3336743f2a3b743d352c"><span class="__cf_email__" data-cfemail="016e71712c656e626a6475416471606c60686d2f6471602f666e77">[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-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 
requirements.

    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 
item.

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 
to

[[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 
development).

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 
ARC.
    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)

2. DowElanco

PP 5E4571

    EPA has received a pesticide petition (PP 5E4571) from DowElanco, 
9330 Zionsville Road, Indianapolis, IN 46268-1054, 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 the herbicide, tebuthiuron and its related metabolites in 
or on the food commodities refined sugar and molasses at 0.05 parts per 
million (ppm) from treatment of sugarcane outside of the United States 
with tebuthiuron. The proposed analytical method involves 
homogenization, filtration, partition and cleanup with analysis by gas 
liquid chromatography using flame photometric 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 of tebuthiuron has been 
investigated in grasses. The residues of concern are the parent 
compound and its metabolites 103 (OH) N-[5-(2-hydroxy-1,1-
dimethylethyl)-1,3,4-thiazol-2-yl]-N,N'dimethylurea, 104 N-[5-(1,1-
dimethylethyl)-1,3,4-thiazol-2-yl]-N-methylurea, and 109 N-[5-(1,1-
dimethylethyl)-1,3,4-thiazol-2-yl]-N'-hydroxymethyl-N-methylurea. 
Tebuthiuron and its metabolites 104 and 109 have been identified in 
sugarcane.
    2. Analytical method. The method for enforcement of plant 
commodities tolerances is a GLC method with flame photometric 
detection. The stated detection limit for the parent compound and 
metabolites 103 (OH), 104 and 109 is 0.01 ppm.
    Enforcement methods for milk and meat have been developed by 
DowElanco and have been submitted to the Agency as part of 
reregistration. An adequate method (GC/flame photometric detection) 
exists to determine tebuthiuron and some metabolites (104, 106, and 
109) in milk and ruminant tissue. The new enforcement method is needed 
to determine additional metabolites of toxicological concern.
    3. Magnitude of residues. Commercial sugarcane samples were 
collected from two major Brazilian sugarcane growing regions. 
Tebuthiuron had been applied at rates ranging from 750 to 1,500 g ai/
ha. Most of the samples were collected approximately 12 months after 
treatment. Analysis for tebuthiuron and metabolites 104 and 109 
occurred within 60 days of sample collection. No residues of 
tebuthiuron were found above the LOQ (0.01 ppm). In many samples there 
was no detection of metabolites. In samples at one site treated with 
1,250 g ai/ha, however, there were residues of the combined metabolites 
at the LOQ.

B. Toxicological Profile

    1. Acute toxicity. Tebuthiuron is classified as a Moderate 
(Category II) acute toxicant based upon the acute oral LD<INF>50</INF> 
value in the rat (387-477 mg/kg) and rabbit (286 mg/kg. The 
LD<INF>50</INF> for the dermal toxicity in the rabbit was greater than 
the limit dose of 5,000 mg/kg. The acute inhalation LC<INF>50</INF> in 
the rabbit was greater than 3.696 mg/L. Tebuthiuron produced slight 
irritation (slight conjunctival hyperemia at 1 hour post-treatment; 
Category IV) and was not a dermal irritant (Category IV) or dermal 
sensitizer. The following table summarizes the acute toxicity profile 
of tebuthiuron.

                                                                        
------------------------------------------------------------------------
               Test                     Species             Category    
------------------------------------------------------------------------
Oral                              Mouse               III               
                                  Rat, Rabbit         II                
Dermal                            Rabbit              IV                
Inhalation                        Rat                 III               
Eye Irritation                    Rabbit              IV                
Dermal Irritation                 Rabbit              IV                
Dermal Sensitization              Guinea Pig          none              
------------------------------------------------------------------------



[[Page 42984]]

    2. Genotoxicity. Results from a battery of assays in vitro indicate 
that tebuthiuron is not genotoxic. It was inactive in the Ames S. 
typhimurium reverse gene mutation assay with or without metabolic 
activation. In the mouse lymphoma assay, tebuthiuron was negative 
without metabolic activation and slightly positive (mutation index of 
2) with metabolic activation at doses 700 mg/mL. In this assay, 
cytotoxicity was observed at doses 200 mg/mL. In Chinese Hamster Ovary 
cells, there were chromosomal aberrations and cytotoxicity at the 
highest doses tested with (1,550 mg/mL) and without (1,950 mg/mL) 
metabolic activation. There was no Unscheduled DNA Synthesis in primary 
rat hepatocytes at 800 mg/mL, while cytotoxicity was observed at 900 
mg/mL.
    3. Reproductive and developmental toxicity. In a 3-generation 
reproduction study in which rats were fed 28 or 56 mg tebuthiuron/kg/
day, F<INF>1b</INF> weanling pups had reduced mean body weight gains. 
No reproductive no observed effect level (NOEL) could be determined 
from this study.
    In a 2-generation reproduction study, rats were fed tebuthiuron at 
dietary levels of 100, 200 or 400 ppm (7, 14, 28 mg/kg/day). There was 
a reduced rate of body weight gain in the F<INF>1</INF> females during 
the premating period at the 14 and 28 mg/kg/day dose levels. The 
systemic NOEL of this study was 7 mg/kg/day and the reproductive NOEL 
was the highest dose tested (28 mg/kg/day). The RfD for tebuthiuron was 
determined to be 0.07 mg/kg/day based upon the systemic NOEL of this 2-
generation reproduction study with a Safety Factor of 100.
    In a developmental toxicity study in which rats were fed 0, 15, 30, 
or 45 mg tebuthiuron/kg/day, the maternal NOEL was 30 mg/kg/day based 
upon reduced body weight gain and food consumption. There were no 
adverse developmental effects observed in this study. The developmental 
NOEL was the highest dose tested (45 mg/kg/day).
    Rabbits were administered 0, 10, or 25 mg tebuthiuron/kg/day by 
oral gavage on gestation days 6-18. The maternal toxicity NOEL was the 
highest dose tested (25 mg/kg/day). Although there was an apparent 
decrease in fetal weights at the highest dose, this was probably the 
result of an increased number of fetuses per litter in the highest dose 
group (5.7 fetuses/litter versus 4.4 fetuses/litter in controls). 
Therefore, no treatment-related adverse affects were attributed to 
tebuthiuron.
    These studies indicate that tebuthiuron is not a developmental or 
reproductive toxicant.
    4. Subchronic toxicity. Rats were exposed to tebuthiuron in the 
diet at the exposure levels of 0, 20, 50, or 125 mg/kg/day for 90 days. 
The NOEL was determined to be 50 mg/kg/day based upon reduced body 
weight, increased relative liver, kidney, and gonad weights, and slight 
vacuolization of pancreatic acinar cells at 125 mg/kg/day. In addition, 
males also had increased relative spleen and prostate gland weights at 
the highest dose.
    Dogs were exposed to tebuthiuron in the diet for 90 days at 0, 500, 
1,000, or 2,500 ppm. The NOEL was determined to be 500 ppm (12.5 mg/kg/
day) based upon anorexia, weight loss, increases in blood urea nitrogen 
and alkaline phosphatase activity, and increases in spleen and thyroid 
gland weights at the LOEL value of 1,000 ppm (25 mg/kg/day).
    Rabbits were exposed dermally to 1,000 mg tebuthiuron/kg/day for 6 
hours a day for 21 days. Slight erythema occurred in these rabbits and 
resolved by day 7. The NOEL was less than 1,000 mg/kg/day.
    5. Chronic toxicity. Dogs were fed tebuthiuron in capsules at doses 
of 0, 12.5, 25, or 50 mg/kg/day for 1-year. The NOEL was determined to 
be 25 mg/kg/day based upon the clinical signs of anorexia, diarrhea, 
and emesis as well as increased thrombocyte count, alanine transferase, 
and alkaline phosphatase activity, and increased liver, kidney, and 
thyroid weights at the LOEL value of 50 mg/kg/day.
    Tebuthiuron was fed to 40 Harlan (Wistar) rats/sex/group at 
concentrations 400, 800, or 1,600 ppm (20, 40, or 80 mg/kg/day) for 2 
years. There were 60 control rats/sex. The systemic NOEL value was 40 
mg/kg/day and the lowest observed effect level (LOEL) value was 80 mg/
kg/day based upon a reduction in weight gain and elevated kidney 
weights. There were no treatment-related carcinogenic effects.
    In another study, tebuthiuron was fed to 40 Harlan (ICR) mice/sex/
group at 400, 800, or 1,600 ppm (57, 144, or 228 mg/kg/day) for 2 
years. There were 60 control mice/sex. The systemic NOEL value was the 
highest dose tested (228 mg/kg/day). Although there were no compound-
related carcinogenic effects, the dose levels were judged to be 
inadequate for carcinogenic testing. This study was considered to be 
supplemental to the rat study by the Health Effects Division (HED) and 
the Reference Dose (RfD) Committee, and that no additional study would 
be required. The HED RfD Committee has classified tebuthiuron as a 
Group D carcinogen (not classifiable as to human carcinogenicity).
    6. Animal metabolism. The metabolism of tebuthiuron has been 
investigated in ruminants. The residues of concern in milk and meat are 
the parent compound and its metabolites 104, 106 N-[5-(1,1-
dimethylethyl)-1,3,4-thiazol-2-yl]-urea, 108 [2-dimethylethyl)-5-amino-
1,3,4-thiadiazole], and 109.
    The metabolism of radiolabelled tebuthiuron was conducted in four 
laboratory species (rats, rabbits, dogs, and mice) using a single 
administration by gavage of 10 or 160 mg/kg. In all four species, 
tebuthiuron was readily absorbed, metabolized, and excreted. In rats, 
rabbits and dogs, elimination in the urine accounted for 84% to 95% of 
the administered dose (the parent compound accounting for 0.4% to 0.7% 
of the dose). Biliary excretion was demonstrated in the rat. Mice 
excreted less radioactivity in the urine (66%; with 23% as unchanged 
parent compound) and more in the feces (31%) as compared with the other 
species examined. At least seven major metabolites were excreted in the 
urine, and there was no unusual tissue distribution of metabolites.

C. Aggregate Exposure

    Tebuthiuron currently is registered for treatment of forage grasses 
and hay, therefore, potential dietary exposure to humans is from 
secondary residues in milk and meat from livestock which have consumed 
treated grasses. A chronic dietary exposure analysis was conducted for 
tebuthiuron using the existing tolerances of 0.3 ppm in milk and 2.0 
ppm in meat and the proposed tolerance of 0.05 ppm in cane sugar and 
molasses. The exposure assessment included the worst-case assumptions 
that all ruminants and horses were fed treated grasses, and sugar and 
molasses available to consumers came from treated sugarcane. As 
tebuthiuron was detected in ground water at 23 ppb in a small scale 
monitoring study under a high exposure scenario, this value was used in 
all water in the consumption survey. In this estimation, exposure to 
the U.S. population from water sources represented 1.1% of the RfD 
(about 24% of total exposure to tebuthiuron). The following table 
summarizes the results from the chronic aggregate exposure analysis.

[[Page 42985]]



                                                                        
------------------------------------------------------------------------
                                   Dietary Exposure                     
                                    (mg/kg BW/day)         % of Rfd     
------------------------------------------------------------------------
All Infants                        0.004971            7.1%             
Nurs. Infants < 1 yr               0.001859            2.7%             
Non-nurs. Inf. < 1 yr             0.006429             9.2%             
Children 1-6 yrs                   0.005732            8.2%             
Children 7-12 yrs                  0.004376            6.3%             
Females 13-50 yrs                  0.002394            3.4%             
------------------------------------------------------------------------

    As the RfD was based upon decreased body weight gains in the 
reproduction toxicity study, the subpopulations shown above represent 
the groups with the highest potential impact from this endpoint. This 
is a worst-case estimate based upon tolerance values and the assumption 
that all water sources will have the residue concentration that was 
found in the monitoring study. Even with these worst-case estimations, 
aggregate exposure levels were less than 10% of the RfD for any 
subpopulation.

D. Cumulative Effects

    The potential for cumulative effects of tebuthiuron and other 
substances that have a common mechanism of toxicity was considered. The 
mammalian toxicity of tebuthiuron is well defined. However, the 
biochemical mechanism of toxicity of this compound is not well known. 
No reliable information exists to indicate that toxic effects produced 
by tebuthiuron would be cumulative with those of any other chemical 
compounds. Therefore, consideration of a common mechanism of toxicity 
with other compounds is not appropriate. Thus only the potential risks 
of tebuthiuron are considered in the aggregate exposure assessment.

E. Safety Determination

    1. U.S. population. Based upon maximum expected residues in meat, 
milk, and refined sugar and molasses from sugarcane, DowElanco 
concludes that there is a reasonable certainty of no harm resulting 
from aggregate exposure of tebuthiuron to the general population.
    2. Infants and children. The toxicological data indicate that 
tebuthiuron is not a developmental or reproductive toxicant, and that 
infants and children are not sensitive subpopulations. There is a 
reasonable certainty that no harm will result from aggregate exposure 
of tebuthiuron to infants and children.

F. International Tolerances

    No Codex MRLs have been established or proposed for residues of 
tebuthiuron.

G. Endocrine Effects

    An evaluation of the potential effects on the endocrine systems of 
mammals has not been determined; However, no evidence of such effects 
were reported in the chronic or reproductive toxicology studies 
described above. There was no observed pathology of the endocrine 
organs in these studies. There is no evidence at this time that 
tebuthiuron causes endocrine effects. (James Tompkins)

3. Merck Research Laboratories

PP 7F4844

    EPA has received a pesticide petition (PP 7F4844) from Merck 
Research Laboratories, P.O. Box 450, Hillsborough Road, Three Bridges, 
NJ. The petition proposes, pursuant to section 408 of the Federal Food, 
Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d). that EPA amend 40 
CFR part 180 to establish tolerances for pesticide chemical residues 
consisting of the insecticide abamectin (avermectin B<INF>1</INF>) and/
or its delat 8,9- isomers in or on the following food items: grapes, 
raisins, and other grape-derived food items at 0.02 parts per million 
(ppm) and chili peppers at 0.01 ppm. Abamectin has been approved by EPA 
for use on many other food crops, including various tree fruits, nuts, 
and vegetables (including bell peppers), as well as hops and cotton. 
Tolerances corresponding to these uses are in effect for abamectin 
residues (including a tolerance for bell peppers at 0.01 ppm); the most 
recent rule, reissuing tolerances for abamectin on citrus and cotton 
under the FFDCA as amended by the Food Quality Protection Act (FQPA), 
was published in the Federal Register on March 24, 1997 (62 FR 13833). 
A notice of filing with regard to that rulemaking had earlier been 
published on December 10, 1996 (61 FR 65043). The proposed analytical 
method involves homogenization, filtration, partition and cleanup with 
analysis by high performance liquid chromatography using UV 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 of abamectin in plants is 
adequately understood and the residues of concern include the parent 
insecticide, abamectin or avermectin B<INF>1</INF> (which is a mixture 
of a minimum of 80% avermectin B<INF>1a</INF> and a maximum of 20% 
avermectin B<INF>1b</INF>) and the delta 8,9- isomer of the 
B<INF>1a</INF> and of the B<INF>1b</INF> components of the parent 
insecticide. Animal metabolism also has been studied but is not 
relevant to this petition, since the crops involved are not significant 
animal feed items.
    2. Analytical method. Practicable analytical methods (HPLC-
fluorescence methods) are available to detect residues that would 
exceed the proposed tolerances, and for enforcement. The methods are 
sufficiently sensitive to detect residues at or above the tolerances 
proposed. All methods have undergone independent laboratory validation 
as required by PR Notice 88-5.
    3. Magnitude of residues. In residue field trials on grapes, the 
highest residue combined values in day 28 (or later) samples was 6.7 
ppb for abamectin B<INF>1a</INF> plus its delta 8,9- photoisomer; there 
were no detectable levels of abamectin b<INF>1b</INF> residues in any 
of the day 28 (or later) samples. In the two raisin samples the levels 
for abamectin B<INF>1a</INF> ranged from 8.6 to 11.8 ppb. The residues 
did not concentrate in grape juice. These data support the proposed 
tolerance of 0.02 ppm for total toxic residues of abamectin on the RACs 
grapes, grape juice, and raisins and the proposed 28-day PHI.
    For chili peppers the primary B<INF>1a</INF> component and its 
photoisomer, the residues recovered on day 7 were all either 
nonquantifiable (less than 5 ng/g, but equal or greater to 2 ng/g) or 
nondetectable (less than 2 ng/g). These data support the proposed 
tolerance of 0.01 ppm for total toxic residues of

[[Page 42986]]

abamectin on the RAC chili peppers and the proposed 7-day PHI.

B. Toxicological Profile

    All the toxicity data on which this petition is based have 
previously been submitted to EPA in support of other petitions, and 
were summarized in the recent notice of filing (61 FR 65043). In the 
recent final rule (62 FR 13833) EPA concluded that acute dietary 
exposure risk evaluations should be based on a no observed effect level 
(NOEL) of 0.06 mg/kg bw/day (mouse pup NOEL in a developmental toxicity 
study using the delta 8,9-isomer of abamectin) and that a margin of 
exposure of 300 should be required. EPA determined that chronic dietary 
exposure risk evaluations should be based on a reference dose (RfD) of 
0.0004 mg/kg bw/day, derived from a 2-generation rat reproduction study 
with a NOEL of 0.12 mg/kg/day and an uncertainty factor of 300.
    This petition contains a supplemental a document setting forth new 
acute exposure and chronic exposure and risk analyses that corrects 
previously submitted analyses to reflect newly available residue data 
on chili peppers (the previously submitted report used data on bell 
peppers only) and to reflect current Agency preferences regarding the 
handling of blended foods. The results of the old and new analyses are 
substantially similar.

C. Aggregate Exposure

    1. Dietary exposure. The March 1997 rule was based on an exposure 
analysis submitted by Merck that included exposure attributable to 
grapes and peppers. The exposure contribution for chili peppers was 
calculated using data on bell peppers. With the present petition, Merck 
is submitting new residue data on chili peppers and a revised acute and 
chronic risk assessment that incorporates that data; the exposure 
levels have not changed significantly. The chronic exposure for the 
U.S. population at large is estimated to be 0.000006 mg/kg bw/day, and 
for children aged 1-6, the highest exposure group, chronic exposure is 
estimated to be 0.000014 mg/kg bw/day. The estimated acute exposure (at 
the 99.9th percentile level) is for the U.S. population at large, 
0.000025 mg/kg bw/day.
    2. Drinking water. In the final rule EPA also concluded that 
drinking water exposure assumptions were not of concern.
    3. Non-dietary exposure. In the final rule published on March 24, 
1997, EPA concluded that there is no likelihood of significant exposure 
from the registered residential indoor and outdoor nonfat use of 
abamectin. Approval of tolerances for grapes and chili peppers would 
not change that conclusion.

D. Cumulative Effects

    Abamectin is a member of the avermectin family of natural and semi-
synthetic compounds. Ivermectin, another member of that family, is very 
closely similar to abamectin in structural standpoint; it is used as a 
human and animal drug. Emamectin, a proposed new pesticide, is made 
from abamectin but is less similar to abamectin than is avermectin. 
These compounds are all Merck products. Other companies product certain 
other drugs have certain structural similarities. Merck in not aware of 
any information indicating what, if any, cumulative effect would result 
from exposure to two or more of these compounds. The March 1997 rule 
discussed cumulative effects and stated that in view of the lack of 
information on how to evaluate possible common mechanisms, it would not 
assume that abamectin has a common mechanism of toxicity with any other 
substance.

E. Safety Determination

     In the recently issued final rule (62 FR 13833, March 24, 1997) 
EPA discussed analyses of risks from chronic and acute exposure for all 
existing or pending tolerances. Those analyses included exposure to 
grapes and peppers, among other previously-approved and then-pending 
uses. In the final rule, EPA found the risks to be acceptable, with 
regard to both the general U.S. population and with regard to infants 
and children. As noted earlier, Merck now has submitted specific 
residue data on chili peppers, but the exposure analyses are not 
significantly affected thereby.

F. International Tolerances

    Codex has not issued abamectin tolerances for grapes and chili 
peppers. (George LaRocca)
[FR Doc. 97-21147 Filed 8-8-97; 8:45 am]
BILLING CODE 6560-50-F


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