[Federal Register Volume 62, Number 209 (Wednesday, October 29, 1997)]
[Rules and Regulations]
[Pages 56075-56082]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-28644]


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ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 180

[OPP-300565; FRL-5750-2]
RIN 2070-AB78


4-(2,2-difluoro-1,3-benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile; 
Pesticide Tolerance

AGENCY: Environmental Protection Agency (EPA).
ACTION: Final rule.

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SUMMARY: This regulation establishes a tolerance for 4-(2,2-difluoro-
1,3-benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile in or on potatoes . The 
Ciba-Geigy Corporation submitted a petition to EPA under the Federal 
Food, Drug and Cosmetic Act (FFDCA), as amended by the Food Quality 
Protection Act of 1996 (Pub. L. 104-170) requesting this tolerance.
DATES: This regulation is effective October 29, 1997. Objections and 
requests for hearings must be received by EPA on or before December 29, 
1997.

ADDRESSES: Written objections and hearing requests, identified by the 
docket control number, [OPP-300565], must be submitted to: Hearing 
Clerk (1900), Environmental Protection Agency, Rm. M3708, 401 M St., 
SW., Washington, DC 20460. Fees accompanying objections and hearing 
requests shall be labeled ``Tolerance Petition Fees'' and forwarded to: 
EPA Headquarters Accounting Operations Branch, OPP (Tolerance Fees), 
P.O. Box 360277M, Pittsburgh, PA 15251. A copy of any objections and 
hearing requests filed with the Hearing Clerk identified by the docket 
control number, [OPP-300565], must also be submitted to: Public 
Information and Records Integrity Branch, Information Resources and 
Services Division (7502C), Office of Pesticide Programs, Environmental 
Protection Agency, 401 M St., SW., Washington, DC 20460. In person, 
bring a copy of objections and hearing requests to Rm. 1132, CM #2, 
1921 Jefferson Davis Hwy., Arlington, VA.
    A copy of objections and hearing requests filed with the Hearing 
Clerk may also be submitted electronically by sending electronic mail 
(e-mail) to: [email protected]. Copies of objections and 
hearing requests must be submitted as an ASCII file avoiding the use of 
special characters and any form of encryption. Copies of objections and 
hearing requests will also be accepted on disks in WordPerfect 5.1 file 
format or ASCII file format. All copies of objections and hearing 
requests in electronic form must be identified by the docket control 
number [OPP-300565]. No Confidential Business Information (CBI) should 
be submitted through e-mail. Electronic copies of objections and 
hearing requests on this rule may be filed online at many Federal 
Depository Libraries.

FOR FURTHER INFORMATION CONTACT: By mail: Mary L. Waller, Registration 
Division 7505C, Office of Pesticide Programs, Environmental Protection 
Agency, 401 M St., SW., Washington, DC 20460. Office location, 
telephone number, and e-mail address: Crystal Mall #2, 1921 Jefferson 
Davis Hwy., Arlington, VA, (703) 308-9354, e-mail: 
[email protected].

SUPPLEMENTARY INFORMATION: In the Federal Register of February 5, 1997 
(62 FR 5403) (FRL-5584-1), EPA, issued a notice pursuant to section 408 
of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(e) 
announcing the filing of a pesticide petition (PP6F4694) for tolerance 
by the Ciba-Geigy Corporation, 410 Swing Road, Greensboro, NC 27401. 
This notice included a summary of the petition prepared by the Ciba-
Geigy Corporation, the registrant. There were no comments received in 
response to the notice of filing.

[[Page 56076]]

    The petition requested that 40 CFR part 180 be amended by 
establishing a tolerance for the fungicide, 4-(2,2-difluoro-1,3-
benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile, in or on potatoes at 0.02 
parts per million (ppm).

I. Risk Assessment and Statutory Findings

    New section 408(b)(2)(A)(i) of the FFDCA allows EPA to establish a 
tolerance (the legal limit for a pesticide chemical residue in or on a 
food) only if EPA determines that the tolerance is ``safe.'' Section 
408(b)(2)(A)(ii) defines ``safe'' to mean that ``there is a reasonable 
certainty that no harm will result from aggregate exposure to the 
pesticide chemical residue, including all anticipated dietary exposures 
and all other exposures for which there is reliable information.'' This 
includes exposure through drinking water and in residential settings, 
but does not include occupational exposure. Section 408(b)(2)(C) 
requires EPA to give special consideration to exposure of infants and 
children to the pesticide chemical residue in establishing a tolerance 
and to ``ensure that there is a reasonable certainty that no harm will 
result to infants and children from aggregate exposure to the pesticide 
chemical residue. . . .''
    EPA performs a number of analyses to determine the risks from 
aggregate exposure to pesticide residues. First, EPA determines the 
toxicity of pesticides based primarily on toxicological studies using 
laboratory animals. These studies address many adverse health effects, 
including (but not limited to) reproductive effects, developmental 
toxicity, toxicity to the nervous system, and carcinogenicity. Second, 
EPA examines exposure to the pesticide through the diet (e.g., food and 
drinking water) and through exposures that occur as a result of 
pesticide use in residential settings.

A. Toxicity

    1. Threshold and non-threshold effects. For many animal studies, a 
dose response relationship can be determined, which provides a dose 
that causes adverse effects (threshold effects) and doses causing no 
observed effects (the ``no-observed effect level'' or ``NOEL'').
    Once a study has been evaluated and the observed effects have been 
determined to be threshold effects, EPA generally divides the NOEL from 
the study with the lowest NOEL by an uncertainty factor (usually 100 or 
more) to determine the Reference Dose (RfD). The RfD is a level at or 
below which daily aggregate exposure over a lifetime will not pose 
appreciable risks to human health. An uncertainty factor (sometimes 
called a ``safety factor'') of 100 is commonly used since it is assumed 
that people may be up to 10 times more sensitive to pesticides than the 
test animals, and that one person or subgroup of the population (such 
as infants and children) could be up to 10 times more sensitive to a 
pesticide than another. In addition, EPA assesses the potential risks 
to infants and children based on the weight of the evidence of the 
toxicology studies and determines whether an additional uncertainty 
factor is warranted. Thus, an aggregate daily exposure to a pesticide 
residue at or below the RfD (expressed as 100% or less of the RfD) is 
generally considered acceptable by EPA. EPA generally uses the RfD to 
evaluate the chronic risks posed by pesticide exposure. For shorter 
term risks, which could occur for residential uses of a pesticide, EPA 
calculates a margin of exposure (MOE) by dividing the estimated human 
exposure into the NOEL from the appropriate animal study. Commonly, EPA 
finds MOEs lower than 100 to be unacceptable. This 100-fold MOE is 
based on the same rationale as the 100-fold uncertainty factor.
    Lifetime feeding studies in two species of laboratory animals are 
conducted to screen pesticides for cancer effects. When evidence of 
increased cancer is noted in these studies, the Agency conducts a 
weight of the evidence review of all relevant toxicological data 
including short-term and mutagenicity studies and structure activity 
relationship. Once a pesticide has been classified as a potential human 
carcinogen, different types of risk assessments (e.g., linear low dose 
extrapolations or MOE calculation based on the appropriate NOEL) will 
be carried out based on the nature of the carcinogenic response and the 
Agency's knowledge of its mode of action.
    2. Differences in toxic effect due to exposure duration. The 
toxicological effects of a pesticide can vary with different exposure 
durations. EPA considers the entire toxicity data base, and based on 
the effects seen for different durations and routes of exposure, 
determines which risk assessments should be done to assure that the 
public is adequately protected from any pesticide exposure scenario. 
Both short and long durations of exposure are always considered. 
Typically, risk assessments include ``acute,'' ``short-term,'' 
``intermediate,'' and ``chronic'' risks. These assessments are defined 
by the Agency as follows.
    Acute risk, by the Agency's definition, results from 1-day 
consumption of food and water, and reflects toxicity which could be 
expressed following a single oral exposure to the pesticide residues. 
High-end exposure to food and water residues are typically assumed.
    Short-term risk results from exposure to the pesticide for a period 
of 1-7 days, and therefore overlaps with the acute risk assessment. 
Historically, this risk assessment was intended to address primarily 
dermal and inhalation exposure which could result, for example, from 
residential pesticide applications. However, since enactment of FQPA 
this risk assessment has been expanded to include both dietary and non-
dietary sources of exposure, and will typically consider exposure from 
food, water, and residential uses when reliable data are available. In 
this assessment, risks from average food and water exposure, and high-
end residential exposure, are aggregated. High-end exposures from all 
three sources are not typically added because of the very low 
probability of this occurring in most cases, and because the other 
conservative assumptions built into the assessment assure adequate 
protection of public health. However, for cases in which high-end 
exposure can reasonably be expected from multiple sources (e.g. 
frequent and widespread homeowner use in a specific geographical area), 
multiple high-end risks will be aggregated and presented as part of the 
comprehensive risk assessment/characterization. Since the toxicological 
endpoint considered in this assessment reflects exposure over a period 
of at least 7 days, an additional degree of conservatism is built into 
the assessment; i.e., the risk assessment nominally covers 1-7 days 
exposure, and the toxicological endpoint/NOEL is selected to be 
adequate for at least 7 days of exposure. (Toxicity results at lower 
levels when the dosing duration is increased.)
    Intermediate-term risk results from exposure for 7 days to several 
months. This assessment is handled in a manner similar to the short-
term risk assessment.
    Chronic risk assessment describes risk which could result from 
several months to a lifetime of exposure. For this assessment, risks 
are aggregated considering average exposure from all sources for 
representative population subgroups including infants and children.

B. Aggregate Exposure

    In examining aggregate exposure, FFDCA section 408 requires that 
EPA take into account available and reliable information concerning 
exposure from the pesticide residue in the food in

[[Page 56077]]

question, residues in other foods for which there are tolerances, 
residues in groundwater or surface water that is consumed as drinking 
water, and other non-occupational exposures through pesticide use in 
gardens, lawns, or buildings (residential and other indoor uses). 
Dietary exposure to residues of a pesticide in a food commodity are 
estimated by multiplying the average daily consumption of the food 
forms of that commodity by the tolerance level or the anticipated 
pesticide residue level. The Theoretical Maximum Residue Contribution 
(TMRC) is an estimate of the level of residues consumed daily if each 
food item contained pesticide residues equal to the tolerance. In 
evaluating food exposures, EPA takes into account varying consumption 
patterns of major identifiable subgroups of consumers, including 
infants and children.The TMRC is a ``worst case'' estimate since it is 
based on the assumptions that food contains pesticide residues at the 
tolerance level and that 100% of the crop is treated by pesticides that 
have established tolerances. If the TMRC exceeds the RfD or poses a 
lifetime cancer risk that is greater than approximately one in a 
million, EPA attempts to derive a more accurate exposure estimate for 
the pesticide by evaluating additional types of information 
(anticipated residue data and/or percent of crop treated data) which 
show, generally, that pesticide residues in most foods when they are 
eaten are well below established tolerances.
    Percent of crop treated estimates are derived from federal and 
private market survey data. Typically, a range of estimates are 
supplied and the upper end of this range is assumed for the exposure 
assessment. By using this upper end estimate of percent of crop 
treated, the Agency is reasonably certain that exposure is not 
understated for any significant subpopulation group. Further, regional 
consumption information is taken into account through EPA's computer-
based model for evaluating the exposure of significant subpopulations 
including several regional groups, to pesticide residues. For this 
pesticide, the most highly exposed population subgroup (non-nursing 
infants <1 year old) was not regionally based.

II. Aggregate Risk Assessment and Determination of Safety

    Consistent with section 408(b)(2)(D), EPA has reviewed the 
available scientific data and other relevant information in support of 
this action, EPA has sufficient data to assess the hazards of 4-(2,2-
difluoro-1,3-benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile and to make a 
determination on aggregate exposure, consistent with section 408(b)(2), 
for a tolerance for 4-(2,2-difluoro-1,3-benzodioxol-4-yl)-1H-pyrrole-3-
carbonitrile on potatoes at 0.02 ppm. EPA's assessment of the dietary 
exposures and risks associated with establishing the tolerance follows.

A. Toxicological Profile

    EPA has evaluated the available toxicity data and considered its 
validity, completeness, and reliability as well as the relationship of 
the results of the studies to human risk. EPA has also considered 
available information concerning the variability of the sensitivities 
of major identifiable subgroups of consumers, including infants and 
children. The nature of the toxic effects caused by 4-(2,2-difluoro-
1,3-benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile are discussed below.
    1. A battery of acute toxicity studies placing technical 
fludioxonil in Toxicity Category III for eye irritation, Category IV 
for oral LD50, Category IV for inhalation LC50 and dermal irritation, 
and Category III for dermal LD50. 4-(2,2-difluoro-1,3-benzodioxol-4-
yl)-1H-pyrrole-3-carbonitrile is a non-sensitizer.
    2. A subchronic oral toxicity study in rats dosed orally with 
technical fludioxonil at levels of 0, 10, 100, 1,000, 7,000, and 20,000 
ppm (0, 0.8, 6.6, 64, 428, and 1,283 mg/kg/day in males; 0, 1.0, 7.1, 
70, 462, and 1,288 mg/kg/day in females) resulted in the Lowest Effect 
Level (LEL) of 428 mg/kg/day in males and 462 mg/kg/day in females, 
based on the increased incidence of microscopic pathology of the kidney 
and liver, and deceased body weight gain. The Noel is 64 mg/kg/day in 
males; 70 mg/kg/day in females.
    3. A subchronic oral toxicity study in dogs administered doses of 
0, 200, 2,000, and 15,000/10,000 ppm (15,000 ppm for 17 days and 10,000 
ppm from day 18 until study termination) for 13 weeks with a LEL of 
2,000 ppm in males and females, based on the observation of diarrhea at 
this dose level. These dose levels correspond to nominal doses of 0, 5, 
50, or 375/250 mg/kg/day, as actual intake data were not provided. The 
NOEL is 5 mg/kg/day in males and females.
    4. A subchronic oral toxicity study in mice administered doses of 
0, 10, 100, 1,000, 3,000, or 7,000 ppm (0, 1.3, 13.9, 144, 445, or 
1,052 mg/kg/day in males; 0, 1.9, 16.8, 178, 559, or 1,307 mg/kg/day in 
females) with a LEL of 1,052 mg/kg/day in males, and 1,307 mg/kg/day in 
females based on decreased body weight gain in female mice, changes in 
serum chemistry in male and female mice, observed increase in liver to 
body weight ratio, and the increased incidence of nephropathy and 
centrilobular hypertrophy of the liver in both sexes. The NOEL is 445 
mg/kg/day in males and 559 mg/kg/day in females.
    5. A dermal toxicity test in rats exposed as a repeated dermal dose 
under occlusive dressing 6 hrs/day, 5 days/week, for 4 weeks at 0, 40, 
200, and 1,000 mg/kg/day. For dermal irritation, the LEL and NOEL are 
both greater than 1,000 mg/kg for males and females. The LEL for 
systemic toxicity for females is 1,000 mg/kg based on increased AST and 
adrenal weight, and 1,000 mg/kg for males based on increased creatinine 
and adrenal weight. The NOEL is 200 mg/kg/day for males and females.
    6. A chronic oral toxicity study in dogs dosed for 52 weeks at 0, 
100, 1,000, and 8,000 ppm in the diet (0, 3.1, 33.1, and 297.8 mg/kg/
day in males; 3.3, 35.5, and 330.7 mg/kg/day in females. The LEL is 
297.8 mg/kg/day for male dogs based on decreased body weight, 
hematology alterations (increase in platelets and fibrin), clinical 
chemistry alterations (increase in cholesterol and alkaline 
phosphatase) and increased liver weight. The LEL is 35.5 mg/kg/day for 
female dogs based on a marked decrease in body weight gain for weeks 1 
- 13 and weeks 1 - 52 of the study. The NOEL is 33.1 mg/kg/day for male 
dogs and 3.3 mg/kg/day in female dogs.
    7. A combined chronic toxicity/carcinogenicity study in rats fed 0, 
10, 30, 100, 1,000 and 3,000 ppm for either 12 or 24 months (males: 0, 
0.37, 1.1, 3.7, 37 and 113 mg/kg/day, respectively; females: 0, 0.44, 
1.3, 4.4, 44 and 141 mg/kg/day respectively). The 3,000 ppm dose level 
is considered adequate for carcinogenicity testing, based on decreased 
body weight and body weight gain in both sexes, slight anemia in 
females at 12 months, and an increased incidence and severity of liver 
histopathology changes in both sexes. Rats from the control and 3,000 
ppm groups were fed the test diets for 12 months and then allowed to 
recover for one month prior to sacrifice. There was no treatment-
related effect on food or water consumption. Males dosed at 1,000 and 
3,000 ppm, and females dosed at 3,000 ppm exhibited a number of effects 
including higher incidence of dark stool and urine, staining (mostly 
blue) around the pelvic region and abdomen, higher frequency of 
diarrhea (males only), and decrease body weight gain. Females dosed at 
3,000 ppm had some evidence of slight anemia at the 12-month 
evaluation. At necropsy,

[[Page 56078]]

males at the 3,000 ppm dose level exhibited an increased incidence of 
enlarged livers, and kidneys with discolored foci or general 
discoloration and an increased severity of progressive nephropathy; 
kidneys with cysts were reported at both the 1,000 and 3,000 ppm dose 
levels. For females in the 1,000 and 3,000 ppm dose levels there was an 
increase incidence of general discoloration of the the kidneys. Males 
and females in the 3,000 ppm group had an increased incidence and more 
severe grade of histopathological changes in the liver. There was an 
increase incidence of hepatocellular tumors in both sexes of the 3,000 
ppm group, however the increase in males was not statistically 
significant. The statistically significant finding in females was an 
increase in combined adenomas and carcinomas (0/70, 1/60, 0/60, 1/60, 
2/60 and 5/70 in the 0, 10, 30, 100, 1,000 and 3,000 ppm groups, 
respectively). Males and females in the 3,000 ppm group had an 
increased incidence of basophilic foci in the liver; males also had an 
increase in hepatocellular hypertrophy. The LEL for males and females 
was 113 and 141 mg/kg/day, respectively (3,000 ppm) based on decreased 
body weight and weight gain, slight anemia in females at 12 months, and 
increased incidence and severity of histopathology changes in the 
liver. The NOEL for males and females was 37 and 44 mg/kg/day, 
respectively. 4-(2,2-difluoro-1,3-benzodioxol-4-yl)-1H-pyrrole-3-
carbonitrile technical was not carcinogenic in male rats. There was a 
statistically significant increase in the incidence of combined 
adenomas and adenocarcinomas of the liver in female rats in the 3,000 
ppm dosed group.
    8. A carcinogenicity study in mice administered in the diet nominal 
dose levels at 0, 10, 100, 1,000, and 3,000 ppm (0, 1.1, 11.3, 112, and 
360 mg/kg/day for male mice; 0, 1.4, 13.5, 133, and 417 mg/kg/day for 
female mice). Male mice at the 3,000 ppm level exhibited clinical 
toxicity in the form of an incidence of male mice which ``convulsed'' 
when handled. No significant effects on body weight, weight gain, food 
consumption, hematology, or microscopic non-neoplastic pathology was 
reported in either sex. Increased liver weight (9%) and spleen weight 
(34%) were observed in male mice at the 3,000 ppm dose level, which 
correlated with the macroscopic observations of enlarged spleen and 
raised foci of their liver. Female mice showed a statistically 
significant increase in liver weight at the 3,000 ppm dose level, and 
this is also supported by the macroscopic observation of enlarged liver 
at the 3,000 ppm dose level in female mice. Other macroscopic changes 
in female mice were an increased incidence of enlarged thymus, spleen, 
mediastinal lymph node, and liver, and an increased incidence of 
lymphoma in these organs. The LEL is 112 mg/kg/day for male mice, based 
on the increased incidence of clinical toxicity in male mice 
(specifically, the increased incidence of mice convulsing when 
handled), and 417 mg/kg/day for female mice, based on the increase in 
liver weight of female mice, and the increase in incidence of 
macroscopic pathology. The NOEL is 11.3 mg/kg/day and 133 mg/kg/day in 
male and female mice, respectively. There was evidence of 
carcinogenicity in female mice based on an increase incidence of 
lymphoas, which contributed to death. This effect was due to the early 
onset and high incidence of lymphoma at the 3,000 ppm dose relative to 
the control group. Total incidence of lymphoma was reported as 11/59, 
10/59, 13/60, 12/60, and 18/60 for the 0, 10, 100, 1,000, and 3,000 ppm 
dose levels in female mice. This increase in total lymphoma was 
significant by a trend test, but not by pair wise comparison. Whether 
an adequate dose level was used in this study to assess the carcinogic 
potential of 4-(2,2-difluoro-1,3-benzodioxol-4-yl)-1H-pyrrole-3-
carbonitrile is complicated by the observation of an increased lymphoma 
incidence at the 3,000 ppm dose level. This dose level produced some 
systemic effects, such as an increased incidence of male mice which 
`convulsed' when handle and macroscopic pathology in both sexes. But 
this dose level produced no significant effects on body weight, weight 
gain, food consumption, hematology, or microscopic non-neoplastic 
pathology in either sex.
    In a second carcinogenicity study in mice, 4-(2,2-difluoro-1,3-
benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile technical was administered 
in the diet at nominal dose levels of 0, 3, 30, 5,000, and 7,000 ppm 
(0, 0.33, 3.3, 590, and 851 mg/kg/ day for male mice; 0, 0.41, 4.1, 
715, and 1,008 mg/kg/day for female mice). In male and female mice, the 
7,000 ppm dose level produced significant systemic effects in addition 
to significant nephropathy. The nephropathy in both sexes of mice dosed 
at 7,000 ppm contributed to death in a majority of the mice. Survival 
in female mice was below 25%, and exceeded the guideline criteria for 
survival in a mouse carcinogenicity study. Changes in liver weights 
were observed in both sexes at the 5,000 and 7,000 ppm dose levels, but 
could not be related to histological alterations in the liver. 
Therefore the LEL is 851 mg/kg/day in males, and 1,008 mg/kg/day in 
females. The NOEL is 590 mg/kg/day in males, and 715 mg/kg/day in 
females. The 7,000 ppm dose is adequate for testing carcinogenic 
potential in male mice, based on the significant systemic effects and 
nephropathy observed at this dose. For female mice, the 7,000 ppm dose 
level is considered excessive, based on the reduction in survival of 
the test animals. There was no evidence of increased incidence of 
tumors in this study for male or female mice.
    9. A developmental toxicity study in rats administered doses of 0, 
10, 100, and 1,000 mg/kg/day by oral gavage in 0.5% 
carboxymethylcellulose to pregnant female rats on gestation days 6 - 15 
inclusive. Maternal Toxicity was evident at 1,000 mg/kg/day, with a 16% 
reduction in corrected body weight gain. Developmental Toxicity was 
evident at the 1,000 mg/kg/day dose level with increased fetal and 
litter incidence of dilated renal pelvis and dilated ureter. Based on 
these observations, the Maternal LEL is 1,000 mg/kg/day and the 
Maternal NOEL is 100 mg/kg/day. The Developmental Toxicity LEL is 1,000 
mg/kg/day, and the Developmental toxicity NOEL is 100 mg/kg/day.
    10. A developmental toxicity (teratology) study in rabbits dosed at 
0, 10, 100, and 300 mg/kg/day in a 0.5% methylcellulose solution in 
distilled water by oral gavage from gestation days 6 through 18, 
inclusive. Maternal toxicity as less body weigh was noted in the mid 
and high dose groups during the dosing period (gestation days 6 through 
18), for the overall dosing plus post dosing periods (gestation days 6 
through 28), and for the entire gestation period; maternal toxicity as 
decreased corrected body weight gains was observed for the dosing plus 
post dosing periods. The high dose group consumed less food than the 
control group during the dosing period (gestation days 6 - 18), the 
post dosing period (gestation days 19 -28), the dosing plus post dosing 
period (gestation days 19 - 28), and for the overall gestation period. 
However, food efficiency was decreased in the mid and high dosed groups 
during the dosing plus post dosing periods, and for the entire 
gestation period. The Maternal Toxicity LEL is 100 mg/kg/day, and the 
Maternal Toxicity NOEL is 10 mg/kg/day based on decreased body weight 
gains and decreased food efficiency. No developmental toxicity was 
noted at the dose levels tested. The Developmental Toxicity LEL is 
greater than 300 mg/kg/day, and the

[[Page 56079]]

Developmental Toxicity NOEL is equal to or greater than 300 mg/kg/day.
    11. A reproduction toxicity study in rats receiving 0, 30, 300, and 
3,000 ppm (equivalent to 0, 2.19, 22.13, and 221.61 mg/kg/day for 
males, and 0, 2.45, 24.24, and 249.67 mg/kg/day for females) 
fludioxonil technical in the diet for 2 generations. The Parental 
Systemic Toxicity LEL is 221.61 mg/kg/day for males, and 249.67 mg/kg/
day for females. The Parental Systemic Toxicity NOEL is 22.13 mg/kg/day 
for males, and 24.24 mg/kg/day for females based on clinical 
observations, reduced body weight and body weight gains, and reduced 
food consumption. Treatment related effects are noted in the high dose 
groups in both the F1 and F2 pups as reduced mean pup body weights 
starting at postnatal day 4 through 21; this was considered a 
developmental toxic effect rather than a true reproductive toxic effect 
, because the reduced mean pup body weights are an effect on the growth 
of the pup. The Reproductive/Developmental Toxicity LEL is 221.61 mg/
kg/day for males, and 249.67 mg/kg/day for females. The Reproductive/
Developmental Toxicity NOEL is 22.13 mg/kg/day for males, and 24.24 mg/
kg/day for females based on reduced pup body weights.
    12. Studies on gene mutation and other genotoxic effects: an Ames 
Salmonella Assay which provided evidence of cytotoxicity at 1,250 
g/plate and 5,000 g/plate concentrations; an 
Unscheduled DNA Synthesis Assay with apparent cytotoxicity at 313 
g/ml; an In Vitro Chromosome Aberrations assay in Chinese 
hamster ovary (CHO) cells, with and without S9-activation which 
provided convincing evidence that technical fludioxonil is a clastogen, 
and a potent inducer of polyploidy in this cultured mammalian cell 
assay; an In Vitro Chromosome Aberrations assay in Chinese hamster bone 
marrow cells with the occurance of hyperploidy in one mid-dose female 
and trisomy in one high dose male; an In Vivo Micronucleus Assay using 
rat hepatocytes, no definitive conclusions were made, and this study 
should be repeated; A Dominant Lethal Assay in mice with no indication 
the test material induced dominant lethal mutations in male mouse 
germinal cells over the entire period of spermatogenesis; a Point 
Mutation Test in CHO cells in vitro, with and without S9-activation, 
with no increase in the number of thioguanine-resistant colonies, 
mutation frequency, or mutation factor with or without S9-activation; 
and a Mouse Micronucleus Assay in a mouse bone morrow micronucleus test 
which was negative.

B. Toxicological Endpoints

    1. Acute toxicity. There is no concern for an acute dietary risk. 
The the available data do not indicate any evidence of significant 
toxicity from one day or single event exposure by oral exposure.

     2. Chronic toxicity. EPA has established the RfD for 4-(2,2-
difluoro-1,3-benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile at 0.03 mg/kg/
day. This RfD is based upon the 1-year toxicity study in dogs with a 
NOEL of 3.3 mg/kg/day in female dogs, and an uncertainty factor of 100 
to account for both interspecies extrapolation and intraspecies 
variability.
     3. Carcinogenicity. This chemical has been classified as a Group D 
- not classifiable as to Human Carcinogenicity. That is, the evidence 
is inadequate and cannot be interpreted as showing either the presence 
or absence of a carcinogenic effect. The Group D classification was 
also based on the increase in liver tumors in female rats that was 
statistically significant for combined adenoma/carcinoma only, the lack 
of a tumorigenic response in male rats or in either sex of the mouse, 
and the need for additional mutagenicity studies.The mutagenicity 
studies will be required as a Condition of Registration for products 
containing 4-(2,2-difluoro-1,3-benzodioxol-4-yl)-1H-pyrrole-3-
carbonitrile, and consists of a repeat of the in vivo rat hepatocyte 
study with a primary interest in determining the mechanism (s) for 
inducing genetic damage and a repeat of the bone marrow micronucleus 
assay using lower doses.

C. Exposures and Risks

    1. From food and feed uses. This is the first tolerance for 
residues of 4-(2,2-difluoro-1,3-benzodioxol-4-yl)-1H-pyrrole-3-
carbonitrile, in or on a raw agricultural commodity. Risk assessments 
were conducted by EPA to assess dietary exposures and risks from 4-
(2,2-difluoro-1,3-benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile as 
follows:
     Chronic exposure and risk. The RfD used for the chronic dietary 
analysis is 0.03 mg/kg/day. A tolerance of 0.02 ppm in/on potatoes was 
used. Tolerances in animal commodities or in potato granules/flakes are 
not required for this seed piece use on potatoes. 4-(2,2-difluoro-1,3-
benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile is currently registered for 
use as a seed treatment on corn and sorghum, and for use in greenhouses 
on nonfood crops. Since the residues were non-quantifiable, no exposure 
was assumed to result for the registered use on corn or sorghum, and 
these uses did not require tolerances. Using the tolerance level 
residue (0.02 ppm) and assuming that 100% of the crop is treated, the 
risk assessment resulted in use of less then 1% of the RfD for the 
general population and all 22 subgroups, including infants under 1 year 
old and children under 13 years of age.
    2. From drinking water.  Because of the requested and currently 
registered use patterns, including the treatment of potato seed pieces 
at a low use rate (approximately 0.06 lbs ai/A), seed treatment of 
field, sweet and popcorn, and sorghum, and ornamental plants grown in 
greenhouses or other enclosed structures, 4-(2,2-difluoro-1,3-
benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile is not expected to impact 
ground or surface waters. Thus the likelihood of residues of 4-(2,2-
difluoro-1,3-benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile in drinking 
water is considered negligible from the above mentioned use patterns. 
Therefore, it is concluded that a drinking water risk assessment is not 
required at this time, and there is no drinking water risk assessment 
to aggregate with the chronic dietary (food sources) risk assessment. 
The aggregate dietary risk is therefore the dietary risk which is less 
than 1% for the general population and all 22 subgroups.
     Acute exposure and risk. There is no concern for an acute dietary 
exposure to fludioxonil from drinking water as stated above, and 
because the available data do not indicate any evidence of significant 
toxicity from a one day or single event exposure by the oral route. 
Therefore, an acute exposure risk assessment is not required for 4-
(2,2-difluoro-1,3-benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile at this 
time.

    3. From non-occupational non-dietary exposure. 4-(2,2-difluoro-1,3-
benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile is currently not registered 
for use on residential non-food sites, therefore no non-occupational 
non-dietary exposure is expected.
    4. Cumulative exposure to substances with common mechanism of 
toxicity. Section 408(b)(2)(D)(v) requires that, when considering 
whether to establish, modify, or revoke a tolerance, the Agency 
consider ``available information'' concerning the cumulative effects of 
a particular pesticide's residues and ``other substances that have a 
common mechanism of toxicity.'' The Agency believes that ``available 
information'' in this context might include not only toxicity, 
chemistry, and exposure data, but also scientific policies and 
methodologies for

[[Page 56080]]

understanding common mechanisms of toxicity and conducting cumulative 
risk assessments. For most pesticides, although the Agency has some 
information in its files that may turn out to be helpful in eventually 
determining whether a pesticide shares a common mechanism of toxicity 
with any other substances, EPA does not at this time have the 
methodologies to resolve the complex scientific issues concerning 
common mechanism of toxicity in a meaningful way. EPA has begun a pilot 
process to study this issue further through the examination of 
particular classes of pesticides. The Agency hopes that the results of 
this pilot process will increase the Agency's scientific understanding 
of this question such that EPA will be able to develop and apply 
scientific principles for better determining which chemicals have a 
common mechanism of toxicity and evaluating the cumulative effects of 
such chemicals. The Agency anticipates, however, that even as its 
understanding of the science of common mechanisms increases, decisions 
on specific classes of chemicals will be heavily dependent on chemical 
specific data, much of which may not be presently available.
    Although at present the Agency does not know how to apply the 
information in its files concerning common mechanism issues to most 
risk assessments, there are pesticides as to which the common mechanism 
issues can be resolved. These pesticides include pesticides that are 
toxicologically dissimilar to existing chemical substances (in which 
case the Agency can conclude that it is unlikely that a pesticide 
shares a common mechanism of activity with other substances) and 
pesticides that produce a common toxic metabolite (in which case common 
mechanism of activity will be assumed).
    EPA does not have, at this time, available data to determine 
whether 4-(2,2-difluoro-1,3-benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile 
has a common mechanism of toxicity with other substances or how to 
include this pesticide in a cumulative risk assessment. Unlike other 
pesticides for which EPA has followed a cumulative risk approach based 
on a common mechanism of toxicity, 4-(2,2-difluoro-1,3-benzodioxol-4-
yl)-1H-pyrrole-3-carbonitrile does not appear to produce a toxic 
metabolite produced by other substances. For the purposes of this 
tolerance action, therefore, EPA has not assumed that 4-(2,2-difluoro-
1,3-benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile has a common mechanism 
of toxicity with other substances.

D. Aggregate Risks and Determination of Safety for U.S. Population

    Chronic risk. Using the Theoretical Maximum Residue Contribution 
(TMRC) exposure assumptions described above, EPA has concluded that 
aggregate exposure to 4-(2,2-difluoro-1,3-benzodioxol-4-yl)-1H-pyrrole-
3-carbonitrile from food will utilize less then 1% of the RfD for the 
U.S. population and the 22 subgroups, including infants and children. 
EPA generally has no concern for exposures below 100% of the RfD 
because the RfD represents the level at or below which daily aggregate 
dietary exposure over a lifetime will not pose appreciable risks to 
human health. EPA concludes that there is a reasonable certainty that 
no harm will result from aggregate exposure to 4-(2,2-difluoro-1,3-
benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile residues.

E. Aggregate Cancer Risk for U.S. Population

    This chemical has been classified as Group D - not classifiable as 
to Human Carcinogenicity. The available carcinogenicity studies in the 
rat and mouse shows some increase in the combined tumors only in the 
female rat above that in the concurrent controls. However, this 
statistical increase in liver tumors in female rats was only at the 
high dose. Some of this significant increase was due to the lack of any 
liver tumors in the concurrent control whereas the historical control 
from the same lab indicated a range of 1.4 to 15% for combined liver 
tumors. Therefore based on available information, a carcinogenic risk 
analysis is not appropriate. EPA believes that this pesticide does not 
pose a significant cancer risk.

F. Aggregate Risks and Determination of Safety for Infants and Children

    1. Safety factor for infants and children-- In general. In 
assessing the potential for additional sensitivity of infants and 
children to residues of 4-(2,2-difluoro-1,3-benzodioxol-4-yl)-1H-
pyrrole-3-carbonitrile, EPA considered data from developmental toxicity 
studies in the rat and rabbit and a two-generation reproduction study 
in the rat. The developmental toxicity studies are designed to evaluate 
adverse effects on the developing organism resulting from pesticide 
exposure during prenatal development to one or both parents. 
Reproduction studies provide information relating to effects from 
exposure to the pesticide on the reproductive capability of mating 
animals and data on systemic toxicity.
    FFDCA section 408 provides that EPA shall apply an additional 
tenfold margin of safety for infants and children in the case of 
threshold effects to account for pre-and post-natal toxicity and the 
completeness of the database unless EPA determines that a different 
margin of safety will be safe for infants and children. The toxicity 
database for fludioxonil includes as acceptable two-generation 
reproduction study in rats and an acceptable prenatal developmental 
toxicity studies in rats and rabbits. The data did not suggest any 
additional sensitivity to the embryo or neonate following in utero or 
early postnatal exposure to fludioxonil. The maternal NOEL, and the 
developmental (fetal and pup) Toxicity NOEL were both 100 mg/kg/day in 
the rat developmental study. In the rabbit developmental study, the 
maternal NOEL was 10 mg/kg/day. No developmental toxicity was noted at 
any dosing level. The developmental NOEL was set equal to or greater 
than 300 mg/kg/day, the highest dose tested. Results from the 2-
generation reproduction study for rats indicated a developmental/
reproduction NOEL of 22.13 mg/kg/day for males and 24.24 mg/kg/day for 
females. The developmental/reproductive NOEL is at least 600 fold 
higher then the RfD (0.03 mg/kg/day), and should be protective for 
infants and children; no additional safety factors are warrented.
    2. Chronic risk. Using the conservative exposure assumptions 
described above, EPA has concluded that aggregate exposure to 4-(2,2-
difluoro-1,3-benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile from food will 
utilize less then 1% of the RfD for infants and children. EPA generally 
has no concern for exposures below 100% of the RfD because the RfD 
represents the level at or below which daily aggregate dietary exposure 
over a lifetime will not pose appreciable risks to human health. EPA 
concludes that there is a reasonable certainty that no harm will result 
to infants and children from aggregate exposure to 4-(2,2-difluoro-1,3-
benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile residues.

III. Other Considerations

A. Metabolism In Plants and Animals

    The metabolism in plants is adequately understood for this potato 
seed piece treatment use. The residue of regulatory concern is the 
parent compound only, 4-(2,2-difluoro-1,3-benzodioxol-4-yl)-1H-pyrrole-
3-carbonitrile. Since it has been determined that secondary residues in 
livestock commodities are not likely to

[[Page 56081]]

result from this use, metabolism of 4-(2,2-difluoro-1,3-benzodioxol-4-
yl)-1H-pyrrole-3-carbonitrile in animals is not relevent to this 
requested use on potato seed treatment.

B. Analytical Enforcement Methodology

    The method accepted by EPA for enforcement of 4-(2,2-difluoro-1,3-
benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile in plants is Ciba-Geigy's 
Method AG-597B. A method, Ciba-Geigy's Method AG-616B (MRID#s 4360412 - 
4360415), is also available for quantifying residues in meat and milk. 
These methods are available from the Docket under docket control number 
[OPP-300565] at the address stated above.

C. Magnitude of Residues

    The submitted residue data indicate that residues of 4-(2,2-
difluoro-1,3-benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile were below the 
level of quantitation (LOQ), <0.01 ppm, in/on immature and mature 
potato tubers grown from seed pieces treated with 0.5% Dust formulation 
of 4-(2,2-difluoro-1,3-benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile at 
1.75 or 2.5 g ai/100 kg seed pieces (0.7X or 1X the labeled rate, 
respectively). Residues of 4-(2,2-difluoro-1,3-benzodioxol-4-yl)-1H-
pyrrole-3-carbonitrile in/on immature and mature tubers treated at a 2X 
application rate ranged from less then 0.01 ppm to 0.04 ppm. Harvest 
times varied from 45 to 143 days after planting treated seed pieces. 
Residue data was also submitted at 6X and 10X the label application 
rate, with reported residues ranging <0.01 - 0.06 ppm and <0.01 - 0.09 
ppm at the 6X rate for immature and mature tubers, respectively; and 
<0.01 - 0.48 ppm amd <0.01 - 0.06 ppm at the 10X rate for immature and 
mature tubers, respectively. Based on the submitted residue data, the 
requested tolerance of 0.02 ppm is adequate for this potato seed piece 
use. Potato processing studies were also submitted to determine whether 
concentration of residues occur in potato chips, granules, and wet 
peels and trimmings from potatoes grown from treated potato seed 
pieces. Based on the submitted processing studies, concentration of the 
pesticide chemical residues of 4-(2,2-difluoro-1,3-benzodioxol-4-yl)-
1H-pyrrole-3-carbonitrile in the processed foods is not expected to be 
greater than the tolerance of 0.02 ppm requested and prescribed in this 
Federal Register document for the pesticide chemical residue in the raw 
agricultural commodity, potatoes. Therefore, the tolerance of 0.02 ppm 
prescribed for potatoes will also cover the residues of fludioxonil up 
to 0.02 ppm resulting in potato processed products from this seed piece 
use.

D. International Residue Limits

    There are currently no CODEX, Canadian, or Mexican listings for 4-
(2,2-difluoro-1,3-benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile residues, 
therefore there are no harmonization issues for this action.

E. Rotational Crop Restrictions

    The submitted confined rotation studies provided adequate results 
to conclude that a 30-day plantback interval is sufficient for all 
crops.

IV. Conclusion

    Therefore, the tolerance is established for 4-(2,2-difluoro-1,3-
benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile in or on potatoes at 0.02 
ppm.

V. Objections and Hearing Requests

    The new FFDCA section 408(g) provides essentially the same process 
for persons to ``object'' to a tolerance regulation issued by EPA under 
new section 408(e) and (l)(6) as was provided in the old section 408 
and in section 409. However, the period for filing objections is 60 
days, rather than 30 days. EPA currently has procedural regulations 
which govern the submission of objections and hearing requests. These 
regulations will require some modification to reflect the new law. 
However, until those modifications can be made, EPA will continue to 
use those procedural regulations with appropriate adjustments to 
reflect the new law.
    Any person may, by December 29, 1997, file written objections to 
any aspect of this regulation and may also request a hearing on those 
objections. Objections and hearing requests must be filed with the 
Hearing Clerk, at the address given above (40 CFR 178.20). A copy of 
the objections and/or hearing requests filed with the Hearing Clerk 
should be submitted to the OPP docket for this rulemaking. The 
objections submitted must specify the provisions of the regulation 
deemed objectionable and the grounds for the objections (40 CFR 
178.25). Each objection must be accompanied by the fee prescribed by 40 
CFR 180.33(i). If a hearing is requested, the objections must include a 
statement of the factual issues on which a hearing is requested, the 
requestor's contentions on such issues, and a summary of any evidence 
relied upon by the requestor (40 CFR 178.27). A request for a hearing 
will be granted if the Administrator determines that the material 
submitted shows the following: There is genuine and substantial issue 
of fact; there is a reasonable possibility that available evidence 
identified by the requestor would, if established, resolve one or more 
of such issues in favor of the requestor, taking into account 
uncontested claims or facts to the contrary; and resolution of the 
factual issues in the manner sought by the requestor would be adequate 
to justify the action requested (40 CFR 178.32). Information submitted 
in connection with an objection or hearing request may be claimed 
confidential by marking any part or all of that information as CBI. 
Information so marked will not be disclosed except in accordance with 
procedures set forth in 40 CFR part 2. A copy of the information 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.

VI. Public Docket

    EPA has established a record for this rulemaking under docket 
control number [OPP-300565] (including any comments and data submitted 
electronically). 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 public 
record is located in Room 1132 of the Public Information and Records 
Integrity Branch, Information Resources and Services Division (7502C), 
Office of Pesticide Programs, Environmental Protection Agency, Crystal 
Mall #2, 1921 Jefferson Davis Hwy., Arlington, VA.

    Electronic comments may be sent directly to EPA at:
    [email protected].

    Electronic comments must be submitted as an ASCII file avoiding the 
use of special characters and any form of encryption.
    The official record for this rulemaking, as well as the public 
version, as described above will be kept in paper form. Accordingly, 
EPA will transfer any copies of objections and hearing requests 
received electronically into printed, paper form as they are received 
and will place the paper copies in the official rulemaking record which 
will also include all comments submitted directly in writing. The 
official rulemaking record is the paper record maintained at the 
Virginia address in ``ADDRESSES'' at the beginning of this document.

[[Page 56082]]

VII. Regulatory Assessment Requirements

    This final rule establishes a tolerance under FFDCA section 408(d) 
in response to a petition submitted to the Agency. The Office of 
Management and Budget (OMB) has exempted these types of actions from 
review under Executive Order 12866, entitled Regulatory Planning and 
Review (58 FR 51735, October 4, 1993). This final rule does not contain 
any information collections subject to OMB approval under the Paperwork 
Reduction Act (PRA), 44 U.S.C. 3501 et seq., or impose any enforceable 
duty or contain any unfunded mandate as described under Title II of the 
Unfunded Mandates Reform Act of 1995 (UMRA) (Pub. L. 104-4). Nor does 
it require any prior consultation as specified by Executive Order 
12875, entitled Enhancing the Intergovernmental Partnership (58 FR 
58093, October 28, 1993), or special considerations as required by 
Executive Order 12898, entitled Federal Actions to Address 
Environmental Justice in Minority Populations and Low-Income 
Populations (59 FR 7629, February 16, 1994), or require OMB review in 
accordance with Executive Order 13045, entitled Protection of Children 
from Environmental Health Risks and Safety Risks (62 FR 19885, April 
23, 1997).
    In addition, since these tolerances and exemptions that are 
established on the basis of a petition under FFDCA section 408(d), such 
as the tolerance in this final rule, do not require the issuance of a 
proposed rule, the requirements of the Regulatory Flexibility Act (RFA) 
(5 U.S.C. 601 et seq.) do not apply. Nevertheless, the Agency has 
previously assessed whether establishing tolerances, exemptions from 
tolerances, raising tolerance levels or expanding exemptions might 
adversely impact small entities and concluded, as a generic matter, 
that there is no adverse economic impact. The factual basis for the 
Agency's generic certification for tolerance actions published on May 
4, 1981 (46 FR 24950) and was provided to the Chief Counsel for 
Advocacy of the Small Business Administration.

VIII. Submission to Congress and the General Accounting Office

    Under 5 U.S.C. 801(a)(1)(A), as added by the Small Business 
Regulatory Enforcement Fairness Act of 1996, the Agency has submitted a 
report containing this rule and other required information to the U.S. 
Senate, the U.S. House of Representatives, and the Comptroller General 
of the General Accounting Office prior to publication of this rule in 
today's Federal Register. This is not a ``major rule'' as defined by 5 
U.S.C. 804(2).

List of Subjects in 40 CFR Part 180

    Environmental protection, Administrative practice and procedure, 
Agricultural commodities, Pesticides and pests, Reporting and 
recordkeeping requirements.

    Dated: October 10, 1997.

Stephen L. Johnson,
Acting Director, Office of Pesticide Programs.
    Therefore, 40 CFR chapter I is amended as follows:

PART 180--[AMENDED]

    1. The authority citation for part 180 continues to read as 
follows:

    Authority: 21 U.S.C. 346a and 371.

    2. Section 180.516 is added to read as follows:


Sec. 180.516  4-(2,2-difluoro-1,3-benzodioxol-4-yl)-1H-pyrrole-3-
carbonitrile ; tolerances for residues.

    (a) General. A tolerance is established for residues of the 
herbicide, 4-(2,2-difluoro-1,3-benzodioxol-4-yl)-1H-pyrrole-3-
carbonitrile, in or on the following food commodity:

------------------------------------------------------------------------
                                                              Parts per 
                         Commodity                             million  
------------------------------------------------------------------------
Potatoes...................................................         0.02
------------------------------------------------------------------------

    (b) Section 18 emergency exemptions. [Reserved]
    (c) Tolerances with regional registrations. [Reserved]
    (d) Indirect or inadvertent residues. [Reserved]

[FR Doc. 97-28644 Filed 10-28-97; 8:45 am]
BILLING CODE 6560-50-F