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benoxacor Pesticide Tolerances 2/98

  

[Federal Register: February 13, 1998 (Volume 63, Number 30)]
[Rules and Regulations]               
[Page 7299-7305]
>From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr13fe98-13]

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ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 180

[OPP-300617; FRL-5771-1]
RIN 2070-AB78

 
Benoxacor; Pesticide Tolerances

AGENCY: Environmental Protection Agency (EPA).

ACTION: Final rule.

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SUMMARY: This regulation establishes tolerances for residues of 
benoxacor (4-(dichloroacetyl)-3,4-dihydro-3-methyl-2H-1,4-benzoxazine 
at 0.01 part per million (ppm) when used as an inert ingredient 
(safener) in pesticide formulations containing metolachlor in or on raw 
agricultural commodities for which tolerances have been established for 
metolachlor. It also removes time limitations for residues of benoxacor 
on the same commodities that expire on February 14, 1998. Novartis Crop 
Protection, Incorporated requested this tolerance under the Federal 
Food, Drug and Cosmetic Act (FFDCA), as amended by the Food Quality 
Protection Act of 1996 (Pub. L. 104-170).

DATES: This regulation is effective February 13, 1998. Objections and 
requests for hearings must be received by EPA on or before April 14, 
1998.

ADDRESSES: Written objections and hearing requests, identified by the 
docket control number, [OPP-300617], 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-300617], 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. 119, 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: opp-docket@epamail.epa.gov. 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 5.1/6.1 
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-300617]. 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: Kerry B. Leifer, Registration 
Division (7505W), Office of Pesticide Programs, Environmental 
Protection Agency, 401 M St., SW., Washington, DC 20460. Office 
location, telephone number, and e-mail address: Rm. 4W17, Crystal 
Station #1, 2800 Crystal Drive, Arlington, VA, (703) 308-8811, e-mail: 
leifer.kerry@epamail.epa.gov.

SUPPLEMENTARY INFORMATION: In the Federal Register of June 30, 1992 (57 
FR 29031), EPA established time-limited tolerances under section 408 of 
the FFDCA 21 U.S.C. 346a(d) for residues of benoxacor at 0.01 ppm when 
used as an inert ingredient (safener) in pesticide formulations 
containing metolachlor in or on raw agricultural commodities for which 
tolerances have been established for metolachlor. These time-limited 
tolerances expired on December 1, 1996. In the Federal Register of 
November 5, 1996 (61 FR 56954) (FRL-5572-8), EPA issued a notice 
pursuant to section 408 of FFDCA 21 U.S.C. 346a(e) announcing the 
filing of pesticide petition (PP7E3489) for tolerances by Novartis Crop 
Protection, Incorporated, P.O. Box 18300, Greensboro, NC 27419. This 
notice included a summary of the petition prepared by Novartis, the 
petitioner. There were no comments received in response to the notice 
of filing.
    The petition requested that 40 CFR 180.460 be amended to extend the 
time-limited tolerances for residues of benoxacor at 0.01 ppm when used 
as an inert ingredient (safener) in pesticide formulations containing 
metolachlor in or on raw agricultural commodities for which tolerances 
have been established for metolachlor from December 1, 1996, to 
December 1, 1998. On February 21, 1997 (62 FR 7941) (FRL-5583-4), EPA 
established time-limited tolerances for benoxacor at 0.01 ppm when used 
as an inert ingredient (safener) in pesticide formulations containing 
metolachlor in or on raw agricultural commodities for which tolerances 
have been established for metolachlor with an expiration date of 
February 14, 1998.

[[Page 7300]]

    In the Federal Register of November 21, 1997 (62 FR 62304) (FRL-
5755-4), EPA issued a notice pursuant to section 408 of FFDCA 21 U.S.C. 
346a(e) announcing the filing of pesticide petition (PP7E3489) for 
tolerances by Novartis Crop Protection, Incorporated (formerly Ciba 
Crop Protection), P.O. Box 18300, Greensboro, NC 27419. This notice 
included a summary of the petition prepared by the petitioner. There 
were no comments received in response to the notice of filing.
    The petition requested that the time limitation for tolerances 
established for residues of benoxacor at 0.01 ppm when used as an inert 
ingredient (safener) in pesticide formulations containing metolachlor 
in or on raw agricultural commodities for which tolerances have been 
established for metolachlor be removed based upon the chronic toxicity 
and oncogenicity data submitted as a condition of registration.
    The basis for the time-limited tolerances that expire February 14, 
1998, was given in the February 21, 1997 issue of the Federal Register 
(62 FR 7941). These time-limited tolerances were predicated on the 
expiration of pesticide product registrations that were made 
conditional due to the lack of certain chronic/oncogenicity data. The 
rationale for using time-limited tolerances was to encourage pesticide 
manufacturers to comply with the conditions of registration in a timely 
manner. There is no regulatory requirement to make tolerances time-
limited due to the conditional status of a product under the Federal 
Insecticide, Fungicide, and Rodenticide Act (FIFRA) as amended. It is 
current EPA policy to no longer establish time limitations on 
tolerances if none of the conditions of registration have any bearing 
on human dietary risk. The current petition action meets that condition 
and thus the expiration dates associated with the crop tolerances are 
being deleted.

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, 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 term,'' 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 enaction of FQPA, 
this 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

[[Page 7301]]

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 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 less than one 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 benoxacor 
and to make a determination on aggregate exposure, consistent with 
section 408(b)(2), for a tolerance for residues of benoxacor when used 
as an inert ingredient (safener) in pesticide formulations containing 
metolachlor in or on raw agricultural commodities for which tolerances 
have been established for metolachlor at 0.01 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 benoxacor are 
discussed below.
    1. Acute toxicity. A rat acute oral study with an LD50 
>5,000 milligram/kilogram (mg/kg), a rabbit acute dermal study with an 
LD50 >2,010 mg/kg, a rat inhalation study with an 
LC50 >2,000 mg/liter, a primary eye irritation study in the 
rabbit showing moderate eye irritation, a primary dermal irritation 
study in the rabbit showing benoxacor is not a skin irritant, and a 
skin sensitization study which showed benoxacor to be a skin sensitizer 
in the Guinea pig. Results of a dermal absorption study show a maximum 
of 55.7% of benoxacor is absorbed by the rat following a 24-hour dermal 
exposure.
    2. Genotoxicity. Benoxacor did not induce point mutations in vitro 
at limit (cytotoxic) concentrations in a Salmonella /mammalian 
microsome test or show any mutagenic activity in the Chinese hamster 
V79 mammalian point mutation test and is neither clastogenic nor 
aneugenic in the Chinese hamster at doses up to the limit dose of 5,000 
mg/kg. Benoxacor did not induce unscheduled DNA synthesis in isolated 
rat hepatocytes at cytotoxic concentrations up to 20 micrograms/ml.
    3. Subchronic toxicity--i. Dogs. In a subchronic feeding study in 
dogs (5 dogs/sex/dose), benoxacor was administered at doses of 0, 0.25, 
1, 5, 50, 150, or 400 milligram/kilograms/day (mg/kg/day) for 90 days. 
The NOEL was 5 mg/kg/day and the lowest observed effect level (LOEL) 50 
mg/kg/day based on increased liver and gallbladder weights.
    ii. Mice. In a subchronic feeding study, CD-1 mice were 
administered dietary concentrations of 0, 50, 500, 2,000, and 6,000 ppm 
(approximately 0, 7.14, 70.7, 290, and 1,100 mg/kg/day for males and 0, 
9.53, 99.8, 382, and 1,470 mg/kg/day for females) of benoxacor for 13 
weeks. The systemic toxicity NOEL was 500 ppm (70.7 and 99.8 mg/kg/day 
in males and females respectively) and the systemic toxicity LOEL was 
2,000 ppm (290 and 382 mg/kg/day in males and females respectively) 
based on increased incidence of renal cortex fibrosis and 
calcifications in males, and increases in water consumption, platelet 
counts, and liver and kidney weights in both males and females.
    iii. Rats. In a subchronic feeding study in rats, six groups of 15 
male and 15 female Sprague Dawley rats were fed benoxacor at dietary 
concentrations of approximately 0, 0.5, 5, 15, 50, or 300 mg/kg/day for 
13 weeks. The NOEL was 5 mg/kg/day and the LOEL was 15 mg/kg/day based 
on increased incidence of kidney nephrosis.

[[Page 7302]]

    4. Dermal toxicity study. In a 21-day dermal toxicity study, 
benoxacor was repeatedly applied daily to the shaved skin of 5 male and 
5 female New Zealand white rabbits at dose levels of 0, 1, 500, or 
1,010 mg/kg for 6/hours/day . The NOEL was >1,010 mg/kg/day.
    5. Developmental toxicity study--i. Rabbits. In an oral 
developmental toxicity study, rabbits were administered benoxacor at 
doses of 0, 0.5, 2.5, 12.5,and 62.5 mg/kg/day. The systemic maternal 
NOEL was 12.5 mg/kg/day and the systemic maternal LOEL was 62.5 mg/kg/
day based on decreased consumption values. The developmental toxicity 
NOEL was 12.5 mg/kg/day and the developmental toxicity LOEL was 62.5 
mg/kg/day based on increased frequency of vertebral anomalies with or 
without associated rib anomalies.
    ii. Rats. In an oral developmental toxicity study, rats were 
administered benoxacor at doses of 0, 1, 100, and 400 mg/kg/day. The 
systemic maternal NOEL was 100 mg/kg/day and the systemic maternal LOEL 
was 400 mg/kg/day based on increased maternal gross pathology findings, 
and decreased body weight gain. The developmental toxicity NOEL was 100 
mg/kg/day and the developmental toxicity LOEL was 400 mg/kg/day based 
on decreased fetal weight, number of live fetuses, decreased uterine 
weight and increased early resorptions, and fetal visceral variations, 
malformations, and skeletal variations.
    6. Reproductive toxicity study. In a two-generation reproduction 
study, Sprague-Dawley rats were fed in the diet with benoxacor at doses 
of 0, 10, 50, 100, 500, and 1,000 ppm for two generations. For 
parental/systemic toxicity, the NOEL was 50 ppm (3.55 mg/kg/day in the 
male and 4.51 mg/kg/day in the females) and the LOEL was 500 ppm (34.84 
mg/kg/day in males and 41.21 mg/kg/day in females) based on decreased 
body weight and body weight gain in both sexes and both generations. 
For reproductive toxicity the NOEL was 50 ppm (3.55 mg/kg/day in the 
male and 4.51 mg/kg/day in the female) and the LOEL was 500 ppm (34.84 
mg/kg/day in males and 41.21 mg/kg/day in females) based on decreased 
pup body weight on lactation day 21 in both generations.
    7. Chronic toxicity study. In a 52-week feeding study, benoxacor 
was administered orally to male and female beagle dogs (4/sex/group) at 
doses of 0, 1, 5, 40, or 80 mg/kg/day. The NOEL was 5 mg/kg/day and the 
LOEL was 40 mg/kg/day based upon decreases in mean body weight gain in 
males and increases in adjusted liver and kidney weights and increased 
lipofuscin deposition in the kidney in both sexes.
    8. Carcinogenicity study. In a carcinogenicity study, CD-1 mice 
were fed benoxacor (50/sex/group) at dietary levels of 0, 10, 30, 600, 
and 1,200 ppm (0, 1.2, 3.7, 75, and 167 mg/kg/day for males and 0, 1.6, 
4.7, 93, and 201 mg/kg/day for females) for 18 months. There was 
evidence of carcinogenicity at the two highest doses tested. 
Statistically (p<0.05) significant increases of squamous cell 
papillomas and combined papillomas/carcinomas were seen in the 
nonglandular stomach (forestomach) in both sexes at the highest dose 
tested. There were also statistically significant positive trends for 
carcinomas in male mice and for papillomas and combined papilloma/
carcinoma in both sexes. For chronic toxicity, the NOEL was 30 ppm (3.7 
mg/kg/day and 4.7 mg/kg/day in males and females, respectively) and the 
systemic LOEL was 600 ppm (75 mg/kg/day and 93 mg/kg/day in males and 
females, respectively) based on increased liver/body weight ratios in 
both sexes. The NOEL for mouse forestomach tumors was 3.7 mg/kg/day in 
males and 4.7 mg/kg/day in females with tumors occurring at 75 and 93 
mg/kg/day in males and females. Dosing was considered adequate to 
assess the carcinogenic potential of benoxacor based on body weight 
reduction in males, treatment-related increased liver/body weight 
ratios in both sexes, and other treatment-related increased incidences 
of tumor and nontumor findings in the forestomach.
    9. Chronic/oncogenicity study. In a combined chronic/oncogenicity 
study, Crl:CD BR rats (70 /sex/group) were fed benoxacor dosed at 
dietary levels of 0, 10, 50, 500, and 1,000 ppm (0, 0.4, 2.0, 20.6, and 
41 mg/kg/day for males and 0, 0.6, 2.8, 28.2, and 59 mg/kg/day for 
females) for two years. Statistically significant (p<0.01) increasing 
trends were seen in male rats for forestomach squamous cell papillomas 
and papillomas and/or carcinomas combined. There was also a 
statistically significant (p<0.05) increasing trend for forestomach 
squamous cell carcinomas in male rats. There were significant 
differences in the pair-wise comparisons of the male high-dose group 
with the controls for forestomach squamous cell papillomas (p<0.05) and 
for papillomas and/or carcinomas combined (p<0.01). Statistically 
significant (p<0.01) increasing trends, and differences in the pair-
wise comparisons of the high-dose group with the controls, were seen in 
female rats for forestomach squamous cell papillomas and papillomas 
and/or carcinomas combined. For chronic toxicity, the NOEL was 10 ppm 
(0.4 mg/kg/day and 0.6 mg/kg/day in males and females, respectively) 
and the systemic LOEL is 50 ppm (2.0 mg/kg/day in males) based on 
centrolobular hepatic enlargements with or without hepatocytic 
vacuolation in male rat livers. At a dose level of 2.6 mg/kg/day, 
hyperkeratosis of the forestomach in females was observed. The NOEL for 
rat forestomach tumors was 20.6 mg/kg/day in males and 28.2 in females 
with tumors occurring at 41 and 59 mg/kg/day in males and females.

B. Toxicological Endpoints

    1. Acute toxicity. An acute dietary risk assessment for the general 
population, including infants and children, is not required because no 
treatment-related effects attributable to a single exposure (dose) were 
seen in oral studies conducted with benoxacor.
    2. Short- and intermediate-term toxicity. A short- and 
intermediate-term risk assessment is not required for benoxacor. There 
was no systemic toxicity at 1,010 mg/kg/day (highest dose tested) in a 
21-day dermal toxicity study in rabbits.
    3. Chronic toxicity. EPA has established the RfD for benoxacor at 
0.004 mg/kg/day. This RfD is based on a 2-year feeding study in rats 
with a NOEL of 0.4 mg/kg/day. An uncertainty factor of 100 was used in 
calculating the RfD to account for interspecies extrapolation and 
intra-species variability.
    4. Carcinogenicity. EPA's Health Effects Division Carcinogenicity 
Peer Review Committee (CPRC) has determined that, in accordance with 
the EPA proposed Guidelines for Carcinogenic Risk Assessment (April 23, 
1996), benoxacor's carcinogenic potential be characterized as ``cannot 
be determined, but suggestive'' based on increases in forestomach 
tumors in both sexes of mice and rats. The consensus of the CPRC was 
that these tumors have little or no relevance to humans. For cancer 
risk assessment purposes, the CPRC recommended using a threshold (MOE) 
approach based on the most sensitive precursor forestomach lesions. It 
was further recommended that the NOEL for rat forestomach lesions of 
0.4 mg/kg/day be used as the point of departure for MOE calculations.

C. Exposures and Risks

    1. From food and feed uses. Tolerances have been established (40 
CFR 180.460) for the residues of benoxacor in or on a variety of raw 
agricultural commodities. Risk assessments were conducted by EPA to

[[Page 7303]]

assess dietary exposures and risks from benoxacor as follows:
    i.  Acute exposure and risk. Acute dietary risk assessments are 
performed for a food-use pesticide if a toxicological study has 
indicated the possibility of an effect of concern occurring as a result 
of a one day or single exposure. Since there are no acute toxicological 
concerns for benoxacor, an acute dietary risk assessment was not 
required.
    ii. Chronic exposure and risk. For the purpose of assessing chronic 
dietary exposure from benoxacor, EPA considered the proposed benoxacor 
tolerance of 0.01 ppm and the raw agricultural commodities for which 
tolerances have been established for metolachlor. There are no other 
established U.S. tolerances for benoxacor, and there are no other 
registered uses for benoxacor on food or feed crops in the United 
States. In conducting this exposure assessment, EPA assumed tolerance 
level residues and 100% crop treated, resulting in a large 
overestimation of dietary exposure and protective of any chronic 
dietary exposure scenario. 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. Review of this regional data allows the Agency to be reasonably 
certain that no regional population is exposed to residue levels higher 
than those estimated by the Agency. Based on the chronic dietary 
exposure TMRC's of 0.000205 mg/kg/day for the U.S. population and 
0.000828 mg/kg/day for the most highly exposed population subgroup 
(non-nursing infants less than one year old), this chronic dietary risk 
assessment resulted in the use of 5.13% of the RfD for the U.S. 
population and 20.7% of the RfD for the most highly exposed population 
subgroup. A cancer dietary MOE was calculated to be 1,950.
    2. From drinking water. For the purposes of assessing chronic 
exposure in drinking water, EPA has considered the registered uses and 
the available data on persistence and mobility for benoxacor. The 
Agency has determined through a qualitative risk assessment that the 
physical and chemical characteristics of benoxacor are such that it is 
not expected to impact water resources. While benoxacor is mobile, it 
is not persistent (half-life in soil of 49 days under aerobic 
conditions and 70 days anaerobically). In light of these findings, EPA 
believes that benoxacor's use will not impact ground water or surface 
water resources, and therefore, is not expected to lead to exposure to 
humans through drinking water. If new uses are added in the future, OPP 
will reassess the potential impacts of benoxacor on drinking water as a 
part of the aggregate risk assessment process.
    3. From non-dietary exposure. All registered metolachlor products 
to which benoxacor is added as a safener are commercial agricultural 
products not registered for residential use. The potential for non-
occupational exposure to benoxacor by the general population is 
therefore unlikely except for the potential residues in food crops 
discussed above.
    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 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 benoxacor 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, 
benoxacor 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 benoxacor has a common mechanism of toxicity 
with other substances.

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

    1. Acute risk. Since there are no acute toxicological concerns for 
benoxacor, EPA has no cause for concern for acute aggregate exposure.
    2. Chronic risk. Using the TMRC exposure assumptions described 
above, EPA has concluded that aggregate chronic exposure to benoxacor 
from food and water will utilize 5.13% of the RfD for the U.S. 
population. The major identifiable subgroup with the highest aggregate 
exposure is non-nursing infants less than one year old (utilizing 20.7% 
of the RfD). 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 does not expect the aggregate exposure to 
exceed 100% of the RfD. EPA concludes that there is a reasonable 
certainty that no harm will result from aggregate exposure to benoxacor 
residues.

E. Aggregate Cancer Risk for U.S. Population

    The carcinogenic risk from food uses of benoxacor for the general 
U.S. population was calculated by comparing the dietary exposure from 
benoxacor to the NOEL identified for use with the cancer risk 
assessment. Based on the NOEL selected by the CPRC for cancer risk 
characterization of 0.4 mg/kg/day, the cancer risk was estimated to 
result in a MOE of 1,950 contributed through all the published, pending 
and new uses for benoxacor. Based upon the extreme conservatism of the 
dietary exposure estimates and the fact that tumors were

[[Page 7304]]

observed only at dose levels far in excess of the selected NOEL, this 
MOE is at a level which the Agency does not consider raising a concern 
for excess lifetime cancer.

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

    1. Safety factor for infants and children--i. In general. In 
assessing the potential for additional sensitivity of infants and 
children to residues of benoxacor, EPA considered data from 
developmental toxicity studies in the rat and rabbit and a 2-generation 
reproduction study in the rat. The developmental toxicity studies are 
designed to evaluate adverse effects on the developing organism 
resulting from maternal pesticide exposure gestation. 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. Margins of 
safety are incorporated into EPA risk assessments either directly 
through use of a MOE analysis or through using uncertainty (safety) 
factors in calculating a dose level that poses no appreciable risk to 
humans. In either case, EPA generally defines the level of appreciable 
risk as exposure that is greater than 1/100 of the NOEL in the animal 
study appropriate to the particular risk assessment. This 100-fold 
uncertainty (safety) factor/MOE (safety) is designed to account for 
inter-species extrapolation and intra-species variability. EPA believes 
that reliable data support using the 100-fold uncertainty factor rather 
than the 1,000-fold margin/factor, when EPA has a complete data base 
under existing guidelines and when the severity of the effect in 
infants or children, the potency or unusual toxic properties of a 
compound, or the quality of the exposure data do not raise concerns 
regarding the adequacy of the standard margin/factor.
    ii. Developmental toxicity studies. See Toxicological Profile in 
Unit II.A. of this preamble.
    iii. Reproductive toxicity study. See Toxicological Profile in Unit 
II.A. of this preamble.
    iv. Pre- and post-natal sensitivity. There is no evidence of 
increased sensitivity to young rats or rabbits following pre- or post-
natal exposure to benoxacor.
    v. Conclusion. The toxicological data base for evaluating pre- and 
post-natal toxicity for benoxacor is complete with respect to current 
data requirements. Because both developmental and reproductive effects 
occurred in the presence of parental (systemic) toxicity, these data do 
not suggest an increased pre- or post-natal sensitivity of children and 
infants to benoxacor exposure. Based on the above, EPA concludes that 
reliable data support use of a 100-fold MOE/uncertainty factor, rather 
than the standard 1,000-fold margin/factor to protect infants and 
children. EPA concludes that there is a reasonable certainty that no 
harm will result to infants and children from aggregate exposure to 
benoxacor residues.
    2. Acute risk. Since there are no acute toxicological concerns for 
benoxacor, EPA has no cause for concern for acute aggregate exposure.
    3. Chronic risk. Using the conservative exposure assumptions 
described above, EPA has concluded that aggregate exposure to benoxacor 
from food will range from 3.69% of the RfD for females 13+ years, to 
20.7% of the RfD for non-nursing infants less than one year old. 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 does not expect the aggregate exposure to exceed 100% of 
the RfD. EPA concludes that there is a reasonable certainty that no 
harm will result to infants and children from aggregate exposure to 
benoxacor residues.
    4. Cancer risk. Carcinogenic risk to infants and children from food 
uses of benoxacor is addressed under Aggregate Cancer Risk for U.S. 
Population under Unit II.E. of this preamble.

III. Other Considerations

A. Metabolism In Plants and Animals

    The metabolism of benoxacor in plants and animals is adequately 
understood for purposes of these tolerances.

B. Analytical Enforcement Methodology

     Adequate enforcement methodology, GC/NPD, is available to enforce 
the tolerance expression. An analytical methodology for the 
determination of benoxacor and its metabolites in plant and animal 
commodities (Ciba Analytical Method AG536(C)) is available from: Calvin 
Furlow, 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. 
Office location and telephone number: Rm. 119FF, CM#2, 1921 Jefferson 
Davis Hwy., Arlington, VA 22202, (703) 305-5229.

C. Magnitude of Residues

    The magnitude of the residue in plants is adequately understood for 
the purposes of these tolerances.

D. International Residue Limits

    No Codex Maximum Residue Levels have been established for residues 
of benoxacor on commodities for which a tolerance for metolachlor 
exist.

IV. Conclusion

    Therefore, the tolerances are established for benoxacor (4-
(dichloroacetyl)-3,4-dihydro-3-methyl-2H-1,4-benzoxazine) at 0.01 ppm 
when used as an inert ingredient (safener) in pesticide formulations 
containing metolachlor in or on raw agricultural commodities for which 
tolerances have been established for metolachlor.

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 April 14, 1998, 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

[[Page 7305]]

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 Record and Electronic Submissions

    EPA has established a record for this rulemaking under docket 
control number [OPP-300617] (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 119 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:
    opp-docket@epamail.epa.gov.


    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.

VII. Regulatory Assessment Requirements

    This final rule establishes tolerances 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 tolerances 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 Comptroller General

    The Congressional Review Act, 5 U.S.C. 801 et seq., as added by the 
Small Business Regulatory Enforcement Fairness Act of 1996, generally 
provides that before a rule may take effect, the agency promulgating 
the rule must submit a rule report, which includes a copy of the rule, 
to each House of the Congress and to the Comptroller General of the 
United States. EPA will submit 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 United States prior 
to publication of the rule in the Federal Register. This rule 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: February 10, 1998.

Peter Caulkins,
Acting Director, Registration Division, 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 180.460 is revised to read as follows:


Sec. 180.460  Benoxacor; tolerances for residues.

    (a) General . Tolerances are established for residues of the inert 
ingredient (safener) benoxacor (4-(dichloroacetyl)-3,4-dihydro-3-
methyl-2H-1,4-benzoxazine) at 0.01 ppm when used in pesticide 
formulations containing metolachlor in or on raw agricultural 
commodities for which tolerances have been established for metolachlor.
    (b) Section 18 emergency exemptions. [Reserved]
    (c) Tolerances with regional registrations. [Reserved]
    (d) Indirect or inadvertent residues. [Reserved]

[FR Doc. 98-3750 Filed 2-12-98; 8:45 am]
BILLING CODE 6560-50-F