[Federal Register Volume 64, Number 212 (Wednesday, November 3, 1999)]
[Notices]
[Pages 59767-59771]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-28728]


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ENVIRONMENTAL PROTECTION AGENCY

[PF-897; FRL-6389-1]


Notice of Filing a Pesticide Petition To Establish a Tolerance 
for Certain Pesticide Chemicals in or on Food

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

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SUMMARY: This notice announces the initial filing of a pesticide 
petition proposing the establishment of regulations for residues of 
certain pesticide chemicals in or on various food commodities.

DATES: Comments, identified by docket control number PF-897, must be 
received on or before December 3, 1999.

ADDRESSES: Comments may be submitted by mail, electronically, or in 
person. Please follow the detailed instructions for each method as 
provided in Unit I.C. of the ``SUPPLEMENTARY INFORMATION'' section. To 
ensure proper receipt by EPA, it is imperative that you identify docket 
control number PF-897 in the subject line on the first page of your 
response.

FOR FURTHER INFORMATION CONTACT:  By mail: James Tompkins, Registration 
Support Branch, Registration Division (7505C), Office of Pesticide 
Programs, Environmental Protection Agency, 401 M St., SW., Washington, 
DC 20460; telephone number: (703) 305-5697; and e-mail address: 
[email protected].

SUPPLEMENTARY INFORMATION:

I. General Information

A. Does This Action Apply to Me?

    You may be affected by this action if you are an agricultural 
producer, food manufacturer or pesticide manufacturer. Potentially 
affected categories and entities may include, but are not limited to:

 
------------------------------------------------------------------------
                                                          Examples of
           Categories                    NAICS            potentially
                                                       affected entities
------------------------------------------------------------------------
Industry                          111                 Crop production
 
                                  112                 Animal production
 
                                  311                 Food manufacturing
                                  32532               Pesticide
                                                       manufacturing
------------------------------------------------------------------------


    This listing is not intended to be exhaustive, but rather provides 
a guide for readers regarding entities likely to be affected by this 
action. Other types of entities not listed in the table could also be 
affected. The North American Industrial Classification System (NAICS) 
codes have been provided to assist you and others in determining 
whether or not this action might apply to certain entities. If you have 
questions regarding the applicability of this action to a particular 
entity, consult the person listed in the ``FOR FURTHER INFORMATION 
CONTACT'' section.

B. How Can I Get Additional Information, Including Copies of This 
Document and Other Related Documents?

    1. Electronically. You may obtain electronic copies of this 
document, and certain other related documents that might be available 
electronically, from the EPA Internet Home Page at http://www.epa.gov/. 
To access this document, on the Home Page select ``Laws and 
Regulations'' and then look up the entry for this document under the 
``Federal Register--Environmental Documents.'' You can also go directly 
to the Federal Register listings at http://www.epa.gov/fedrgstr/.
    2. In person. The Agency has established an official record for 
this action under docket control number PF-897. The official record 
consists of the documents specifically referenced in this action, any 
public comments received during an applicable comment period, and other 
information related to this action, including any information claimed 
as confidential business information (CBI). This official record 
includes the documents that are physically located in the docket, as 
well as the documents that are referenced in those documents. The 
public version of the official record does not include any information 
claimed as CBI. The public version of the official record, which 
includes printed, paper versions of any electronic comments submitted 
during an applicable comment period, is available for inspection in the 
Public Information and Records Integrity Branch (PIRIB), Rm. 119, 
Crystal Mall #2, 1921 Jefferson Davis Highway,

[[Page 59768]]

Arlington, VA, from 8:30 a.m. to 4 p.m., Monday through Friday, 
excluding legal holidays. The PIRIB telephone number is (703) 305-5805.

C. How and to Whom Do I Submit Comments?

    You may submit comments through the mail, in person, or 
electronically. To ensure proper receipt by EPA, it is imperative that 
you identify docket control number PF-897 in the subject line on the 
first page of your response.
    1. By mail. Submit your comments to: Public Information and Records 
Integrity Branch (PIRIB), Information Resources and Services Division 
(7502C), Office of Pesticide Programs (OPP), Environmental Protection 
Agency, 401 M St., SW., Washington, DC 20460.
    2. In person or by courier. Deliver your comments to: Public 
Information and Records Integrity Branch (PIRIB), Information Resources 
and Services Division (7502C), Office of Pesticide Programs (OPP), 
Environmental Protection Agency, Rm. 119, Crystal Mall #2, 1921 
Jefferson Davis Highway, Arlington, VA. The PIRIB is open from 8:30 
a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The 
PIRIB telephone number is (703) 305-5805.
    3. Electronically. You may submit your comments electronically by 
E-mail to: ``[email protected],'' or you can submit a computer disk as 
described above. Do not submit any information electronically that you 
consider to be CBI. Avoid the use of special characters and any form of 
encryption. Electronic submissions will be accepted in Wordperfect 6.1/
8.0 or ASCII file format. All comments in electronic form must be 
identified by docket control number PF-897. Electronic comments may 
also be filed online at many Federal Depository Libraries.

D. How Should I Handle CBI That I Want To Submit to the Agency?

    Do not submit any information electronically that you consider to 
be CBI. You may claim information that you submit to EPA in response to 
this document as CBI 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. In addition to one complete 
version of the comment that includes any information claimed as CBI, a 
copy of the comment that does not contain the information claimed as 
CBI must be submitted for inclusion in the public version of the 
official record. Information not marked confidential will be included 
in the public version of the official record without prior notice. If 
you have any questions about CBI or the procedures for claiming CBI, 
please consult the person identified in the ``FOR FURTHER INFORMATION 
CONTACT'' section.

E. What Should I Consider as I Prepare My Comments for EPA?

    You may find the following suggestions helpful for preparing your 
comments:
    1. Explain your views as clearly as possible.
    2. Describe any assumptions that you used.
    3. Provide copies of any technical information and/or data you used 
that support your views.
    4. If you estimate potential burden or costs, explain how you 
arrived at the estimate that you provide.
    5. Provide specific examples to illustrate your concerns.
    6. Make sure to submit your comments by the deadline in this 
notice.
    7. To ensure proper receipt by EPA, be sure to identify the docket 
control number assigned to this action in the subject line on the first 
page of your response. You may also provide the name, date, and Federal 
Register citation.

II. What Action Is the Agency Taking?

     EPA has received a pesticide petition as follows proposing the 
establishment and/or amendment of regulations for residues of certain 
pesticide chemical in or on various food commodities under section 408 
of the Federal Food, Drug, and Comestic Act (FFDCA), 21 U.S.C. 346a. 
EPA has determined that this petition contains data or information 
regarding the elements set forth in section 408(d)(2); however, EPA has 
not fully evaluated the sufficiency of the submitted data at this time 
or whether the data supports granting of the petition. Additional data 
may be needed before EPA rules on the petition.

List of Subjects

    Environmental protection, Agricultural commodities, Feed additives, 
Food additives, Pesticides and pests, Reporting and recordkeeping 
requirements.

    Dated: October 26, 1999.

James Jones,

Director, Registration Division, Office of Pesticide Programs.

Summaries of Petitions

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

 E.I. DuPont de Nemours & Company

PP 7F4849 and 9F6039

    EPA has received pesticide petitions (9F6039 and an amended 
petition 7F4849) from E.I. DuPont de Nemours and Company, Barley Mill 
Plaza, P.O. Box 80083, Wilmington, DE 19880-0038 proposing, pursuant to 
section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 
U.S.C. 346a(d), to amend 40 CFR part 180 by establishing a tolerance 
for residues of azafenidin, 2-[2,4-dichloro-5-(2-propynyloxy)phenyl]-
5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridin-3(2H)-one] in or on the 
raw agricultural commodities (RAC) crop groupings of pome fruits at 
0.02 ppm, the crop grouping stone fruits at 0.02 ppm, the crop grouping 
of tree nuts including pistachios at 0.02 ppm, and almond hulls at 0.5 
ppm 9F6039. On December 3, 1997 (62 FR 63942) (FRL-5756-1), EPA issued 
a notice proposing to amend 40 CFR part 180 by establishing tolerances 
for residues of azafendin in or on the raw agricultural commodities 
(RAC) crop grouping citrus, grapes, sugarcane, and sugarcane molasses 
(7F4849). DuPont has amended PP 7F4849 by proposing the amend 40 CFR 
part 180 by establishing tolerances for residues of the herbicide 
azafenidn, 2-[2,4-dichloro-5-(2-propynyloxy)phenyl]-5,6,7,8-tetrahydro-
1,2,4-triazolo[4.3-a]pyridin-3(2H)-one in or on the crop grouping 
citrus at 0.1 ppm, and the RAC citrus oil at 0.50 ppm, grapes at 0.02 
ppm, sugarcane at 0.05 ppm, and sugarcane molasses at 0.5 ppm . EPA has 
determined that the petition contains data or information regarding the 
elements set forth in section 408(d)(2) of the FFDCA; however, EPA has 
not fully evaluated the sufficiency of the submitted data at this time 
or whether the data supports granting of the petition. Additional data 
may be needed before EPA rules on the petition.

A. Residue Chemistry

    1. Plant metabolism. The qualitative nature of the residues of 
azafenidin in pome fruit, stone fruit, and tree nuts is

[[Page 59769]]

adequately understood for the purposes of registration. Similar 
metabolic pathways were previously demonstrated in the three dissimilar 
crops of grapefruit, grapes, and sugarcane. The primary metabolic 
pathway begins with rapid O-dealkylation and production of hydroxyl 
derivatives, with subsequent formation of glucoside conjugates.
    2. Analytical method. There is an independently validated practical 
analytical method available using gas chromatography (GC) and mass 
selective detection (MS) to measure levels of azafenidin in or on pome 
fruits, stone fruits, and tree nuts, with limits of quantitation (LOQ) 
that will allow for monitoring of crop residues at or above tolerance 
levels.
    3. Magnitude of residues. Crop field trial residue data from pome 
fruit, stone fruit and tree nut studies show that the proposed 
tolerances on these commodities will not be exceeded when 
Milestone* is used as directed. Excessive application rates 
made to pome fruit and stone fruit in field trial residue studies 
demonstrated that azafenidin does not concentrate in the processed 
commodities of these crops.

B. Toxicological Profile

    1. Acute toxicity. Technical azafenidin has been placed in acute 
toxicology category III based on overall results from several studies. 
Results from the following studies indicate toxicology category III: 
acute dermal toxicity (LD50 > 2,000 milligrams/kilograms 
(mg/kg); rabbits) and eye irritation (effects reversible within 72 
hours; rabbits). Acute oral toxicity (LD50 > 5,000 mg/kg; 
rats), acute inhalation toxicity (LC50 > 5.4 milligrams per 
liter (mg/L), rats) and skin irritation (slight effects resolved within 
48 hours; rabbits) results were assigned toxicology category IV. 
Technical azafenidin is not a dermal sensitizer.
    An acute neurotoxicity study was conducted in rats administered 
azafenidin via gavage at 0, 100, 300, or 900 mg/kg. Azafenidin was not 
neurotoxic at any dose. The systemic no observed adverse effect level 
(NOAEL) was 100 mg/kg for males and females based on reduced food 
consumption and body weights at 300 mg/kg and above.
    2. Genotoxicity. Technical azafenidin was negative for genotoxicity 
in a battery of in vitro and in vivo tests. These tests included the 
following: mutagenicity in bacterial (Ames test) and mammalian Chinese 
hampster ovary/hypoxanthine guanine phophoribosyl transferase (CHO/
HGPRT assay) cells; in vitro cytogenetics (chromosomal aberration in 
human lymphocytes); in vivo cytogenetics (bone marrow micronucleus 
assay in mice); and unscheduled DNA synthesis (UDS) in rat primary 
hepatocytes.
    3. Reproductive and developmental toxicity--i. A 2-generation 
reproduction study was conducted in rats with dietary technical 
azafenidin concentrations of 0, 5, 30, 180, or 1,080 ppm. The NOAEL was 
30 ppm (1.7 to 2.8 mg/kg/day for P1 and F1 males 
and females and their offspring). This was based on the following 
effects at 180 ppm (10.1 to 17.8 mg/kg/day for P1 and 
F1 males and females and/or their offspring): slight 
reductions in mean body weights for F1 males and females; 
reductions in mean gestation body weight gain and implantation 
efficiency; slightly increased gestation lengths; decreased offspring 
survival, body weights and other indices of offspring health; and 
increased incidence of diarrhea among F1 parental males.
    ii. A developmental study was conducted in rats administered 
technical azafenidin by gavage at 0, 3, 8, 16, or 24 mg/kg/day. 
Azafenidin was not teratogenic. The NOAEL was 16 mg/kg/day based on the 
following observations at 24 mg/kg/day: reduced maternal body weight, 
increased resorptions, reductions in litter size and fetal weights and 
increased sternebral variations. The maternal effects consisted of 
transient body weight reductions; however, the nature of these effects 
suggested that fetal resorptions contributed to weight reductions.
    iii. A developmental study was conducted in rabbits administered 
technical azafenidin by gavage at 0, 12, 36, 100, or 300 mg/kg/day. 
Azafenidin was not teratogenic. The NOAELs for maternal and offspring 
toxicity were 12 and 100 mg/kg/day, respectively. The maternal NOAEL 
was based on reduced body weight at 36 and 100 mg/kg/day and mortality 
at higher doses. Excessive maternal toxicity at 300 mg/kg/day precluded 
assessment of developmental effects at this level. However, the 
developmental NOAEL was considered to be 100 mg/kg/day since there were 
no indications of fetal toxicity up to and including this dose level.
    iv. A dermal pre-natal developmental toxicity study was conducted 
in rats administered technical azafenidin. The dose levels were 0, 5, 
25, 50, and 100 mg/kg/day. The NOAEL was 5 mg/kg/day based on 
postimplantation losses with a corresponding decrease in viable litter 
size and fetal weight, visceral variations and increased skeletal 
malformations at all other dose levels. The maternal effects consisted 
of body weight gain reduction.
    4. Subchronic toxicity--i. A 90-day study in mice was conducted at 
dietary concentrations of 0, 50, 300, 900, or 1,500 ppm. The NOAEL was 
300 ppm (47.2 and 65.8 mg/kg/day for male and female mice, 
respectively). This was based on reduced body weight gain in males and 
microcytic and hypochromic anemia in males and females at 900 ppm (or 
144 and 192 mg/kg/day for males and females, respectively).
    ii. Technical azafenidin was administered in the diets of rats at 
0, 50, 300, 900, or 1,500 ppm for 90 days. The NOAEL was 300 ppm (24.2 
and 28.2 mg/kg/day for male and female rats, respectively). This was 
based on methemoglobinemia and microcytic and hypochromic anemia in 
males and females at 900 ppm (or 71.9 and 83.8 mg/kg/day for male and 
female rats, respectively).
    iii. Dogs were administered technical azafenidin in their diets at 
0, 10, 60, 120, or 240 ppm for 90 days. The NOAEL was 10 ppm (0.34 and 
0.33 mg/kg/day for males and females, respectively). This was based on 
enlarged hepatocytes and increased serum alkaline phosphatase and 
alanine aminotransferase activities at 60 ppm (2.02 and 2.13 mg/kg/day 
for male and female dogs, respectively).
    iv. A 90-day subchronic neurotoxicity study was conducted in rats 
at 0, 50, 750, or 1,500 ppm. There were no neurological effects 
observed in this study. The NOAEL for systemic toxicity was 50 ppm (3.0 
mg/kg/day) and 750 ppm (54.5 mg/kg/day) for male and female rats, 
respectively. These were based on reduced food consumption and body 
weights and increased incidences of clinical signs of toxicity at the 
higher doses.
    v. A 28-day dermal study was conducted in rats at 0, 80, 400, or 
1,000 mg/kg/day. There was no dermal irritation or systemic toxicity 
among males or females at the highest dose tested (HDT). The NOAEL was 
> 1,000 mg/kg/day.
    5. Chronic toxicity--i. An 18-month mouse study was conducted with 
dietary concentrations of 0, 10, 30, 300, or 900 ppm technical 
azafenidin. This product was not oncogenic in mice. The systemic NOAEL 
was 300 ppm (39.8 and 54.1 mg/kg/day for males and females, 
respectively). This was based on hepatotoxicity among males and reduced 
body weights and food efficiency among females at 900 ppm (or 122 and 
163 mg/kg/day for males and females, respectively).
    ii. A 2-year chronic toxicity/oncogenicity study was conducted in 
rats fed diets that contained 0, 5, 15, 30, 300, or 900 ppm technical 
azafenidin.

[[Page 59770]]

 This product was not oncogenic in rats. The systemic NOAEL was 300 ppm 
(12.1 and 16.4 mg/kg/day males and females, respectively). The NOAEL 
was defined by microcytic, hypochromic and hemolytic anemia and 
mortality at 900 (or 35.2 and 50.2 mg/kg/day for male and female rats, 
respectively).
    iii. Technical azafenidin was administered for 1-year to dogs at 
dietary concentrations of 0, 5, 10, 120, and 360 ppm. The NOAEL was 10 
ppm (0.30 mg/kg/day for males and females). This was based on 
observations of altered hepatocyte morphology, hydropic degeneration 
and elevated alanine aminotransferase and alkaline phosphatase at 30 
ppm (0.86 and 0.87 mg/kg/day for male and female dogs, respectively) 
and above.
    6. Animal metabolism. The metabolism of azafenidin in animals (rat 
and goat) is adequately understood and is similar among the species 
evaluated. Azafenidin was readily absorbed following oral 
administration, extensively metabolized and rapidly eliminated in the 
urine and feces. The terminal elimination half-life in plasma was 40 
hours in rats. Less than 1% of the administered dose was present in rat 
tissues at 120 hours. There were no volatile metabolites of azafenidin. 
The major metabolic pathways in the rat and goat consisted of rapid O-
dealkylation and production of hydroxyl derivatives, subsequent 
formation of glucuronide and sulfate conjugates and elimination of 
these conjugates in feces and urine. There was no evidence of 
accumulation of azafenidin or its metabolites in the tissues of either 
species or in the goat's milk.
    7. Metabolite toxicology. There is no evidence that the metabolites 
of azafenidin identified in animal or plant metabolism studies are of 
any toxicological significance. The existing metabolism studies 
indicate that the metabolites formed are unlikely to accumulate in 
humans or in animals that may be exposed to these residues in the diet. 
The fact that no quantifiable residues were found in edible portions of 
treated crops further indicates that exposures to and accumulation of 
metabolites are unlikely.
    8. Endocrine disruption. No special studies investigating potential 
estrogenic or other endocrine effects of azafenidin have been 
conducted. However, the standard battery of toxicology studies required 
to support product registration has been completed. Studies in this 
battery included an evaluation of the potential effects on reproduction 
in the rat over 2-generations and effects on offspring development in 
two species. Evaluations of the pathology of the endocrine organs in 
subchronic and chronic studies at doses that far exceed likely human 
exposures have also been conducted in several species. Based on the 
results of these studies, the potential for azafenidin to impact the 
endocrine system has been adequately defined. There is no evidence to 
suggest that azafenidin has estrogenic properties or mimics the actions 
of other hormones in the endocrine system.

C. Aggregate Exposure

    1. Dietary exposure. It is proposed that azafenidin be defined as 
the residue for enforcement purposes. Monitoring for azafenidin 
residues in field samples will provide an adequate estimate of this 
compound in edible portions of treated crops.
    i. Food--Acute dietary exposure. An acute dietary exposure 
assessment was made using the dietary exposure evaluation model (DEEM) 
computer software (version 6.73, Acute Module, Novigen Sciences, Inc, 
1999). Acute dietary exposure was based upon the following crop uses: 
citrus, grapes, pome fruit, stone fruit, sugarcane, and tree nuts. 
Anticipated residues were estimated based on field trial data and 
assuming that 30% of every crop was treated. The predicted acute 
exposure for the U.S. population subgroup was 0.000158 mg/kg body 
weight day (bw/d). The population subgroup with the highest predicted 
level of acute exposure was the children age 1-6-year subgroup with an 
exposure of 0.000273 mg/kg bw/d (99.9th percentile). Based 
on an acute NOAEL of 16 mg/kg bw/d from an oral developmental toxicity 
study with rats, and a 100-fold safety factor, the acute reference dose 
(aRfD) would be 0.16 mg/kg bw/d. For the U.S. population the predicted 
exposure is equivalent to 0.10% of the aRfD. For the population 
subgroup children age 1-6-year, the exposure would be equivalent to 
0.17% of the aRfD. Because the predicted exposures, expressed as 
percentages of the aRfD, are well below 100%, there is reasonable 
certainty that no acute effects would result from dietary exposure to 
azafenidin.
    ii. Chronic dietary exposure. A chronic dietary exposure assessment 
was made using the DEEM computer software (version 6.74, Chronic 
Module, Novigen Sciences, Inc, 1999). Acute dietary exposure was based 
upon the following crop uses: citrus, grapes, pome fruit, stone fruit, 
sugarcane, and tree nuts. Anticipated residues were estimated based on 
field trial data and assuming that 30% of every crop was treated. The 
predicted chronic exposure for the U.S. population subgroup was 
0.000007 mg/kg bw/d. The population subgroup with the highest predicted 
level of chronic exposure was the children age 1-6-year subgroup with 
an exposure of 0.000021 mg/kg bw/d. Based on a chronic NOAEL of 0.3 mg/
kg bw/d from a 1-year chronic feeding study in dogs, and a 100-fold 
safety factor, the chronic reference dose (cRfD) would be 0.003 mg/kg 
bw/d. For the U.S. population the predicted exposure is equivalent to 
0.2% of the cRfD. For the population subgroup children age 1-6-year, 
the exposure would be equivalent to 0.7% of the cRfD. Because the 
predicted exposures, expressed as percentages of the cRfD, are well 
below 100%, there is reasonable certainty that no chronic effects would 
result from dietary exposure to azafenidin.
    iii. Drinking water. Surface water exposure was estimated using the 
PRZM/EXAMS models. Several USEPA standard scenarios were used (Florida 
citrus, Louisiana sugar cane, and New York grapes) along with standard 
methods for selecting input data. Ground water exposure was estimated 
using SCI-GROW. These are screening level models used for determining 
upper bound concentrations of pesticides in surface and ground water. 
PRZM/EXAMS and SCI-GROW use the soil/water partition coefficient , 
hydrolysis half life, and maximum label rate to estimate surface water 
concentration. The models and accompanying scenarios contain a number 
of very conservative underlying assumptions. Therefore, the 
concentrations derived from PRZM/EXAMS and SCI- GROW for drinking water 
are likely to be great overestimates. The predicted concentration for 
azafenidin in ground water under worst-case conditions was 2 parts per 
billion (ppb). The predicted peak concentration for azafenidin in 
surface water in a small non-flowing pond directly adjacent a treated 
citrus grove at the maximum rate was 24 ppb. The annual average 
concentration predicted for the same pond scenario was 4.72 ppb. EPA 
uses drinking water levels of comparison (DWLOCs) as a surrogate 
measure to capture risk associated with exposure to pesticides in 
drinking water. A DWLOC is the concentration of a pesticide in drinking 
water that would be acceptable as an upper limit in light of total 
aggregate exposure to that pesticide from food, water, and residential 
uses. A DWLOC will vary depending on the residue level in foods, the 
toxicity endpoint and with drinking water consumption patterns and body 
weights for specific subpopulations. The acute DWLOC for

[[Page 59771]]

azafenidin was calculated for the subpopulation of concern, children 
(ages 1-6 years) to be 1.6 parts per million (ppm). The estimated 
maximum concentration of azafenidin in surface water (24 ppb) derived 
from PRZM/EXAMS is much lower than the acute DWLOC. Therefore, one can 
conclude with reasonable certainty that residues of azafenidin in 
drinking water do not contribute significantly to the aggregate acute 
human health risk. The chronic DWLOCs are 0.1 ppm for the U.S. 
population and 0.03 ppm for the most sensitive subgroup, children (1-6 
years). The DWLOCs are substantially higher than the PRZM/EXAMS 
estimated annual environmental concentration of 4.7 ppb for azafenidin 
in surface water. Therefore, one can conclude with reasonable certainty 
that residues of azafenidin in drinking water do not contribute 
significantly to the aggregate chronic human health risk.
    2. Non-dietary exposure. Azafenidin is pending registration for use 
in weed control in selective non-food crop situations including certain 
temperate woody crops, and in non-crop situations including industrial 
sites and unimproved turf areas. Azafenidin is not to be used in on 
residential temperate woody plantings, or on lawns, walkways, 
driveways, tennis courts, golf courses, athletic fields, commercial sod 
operations, or other high maintenance fine turf grass areas, or similar 
areas. Any non-occupational exposure to azafenidin is likely to be 
negligible.

D. Cumulative Effects

    The herbicidal activity of azafenidin is due to its inhibition of 
an enzyme involved with synthesis of the porphyrin precursors of 
chlorophyll, protoporphyrinogen oxidase. Mammals utilize this enzyme in 
the synthesis of heme. Although there are other herbicides that also 
inhibit this enzyme, there is no reliable information that would 
indicate or suggest that azafenidin has any toxic effects on mammals 
that would be cumulative with those of any other chemicals. In addition 
there is no valid methodology for combining the risks of adverse 
effects of overexposures to these compounds.

E. Safety Determination

    1. U.S. population. Based on the completeness and reliability of 
the azafenidin toxicology database and using the conservative aggregate 
exposure assumptions presented earlier, it is concluded that azafenidin 
products may be used with a reasonable certainty of no harm relative to 
exposures from food and drinking water. The TMRC determined for the 
combined pending and proposed uses of azafenidin in citrus, grapes, 
pome fruit, stone fruit, sugar cane and tree nuts utilized only 0.2% of 
the cRfD (an exposure of 0.000007 mg/kg bw/d). The chronic calculated 
drinking water level of comparison DWLOCs of 0.1 ppm for the U.S. 
population is substantially higher than the PRZM/EXAMS estimated annual 
environmental concentration of 4.7 ppb for azafenidin. Therefore, one 
can conclude with reasonable certainty that chronic aggregate exposure 
will not exceed 100% of the cRfD. In a similar analysis of acute risk 
for the U.S. population, a predicted exposure of 0.000158 mg/kg bw/d, 
equivalent to 0.10% of the aRfD is determined. The aRfD For the U.S. 
population is based on an acute NOAEL of 16 mg/kg bw/d from an oral 
developmental toxicity study with rats, and a 100-fold safety factor. 
An acute DWLOC for azafenidin, calculated for the subpopulation of 
children (ages 1-6 yrs), was 1.6 parts per million (ppm). The estimated 
maximum concentration of azafenidin in water (24 ppb) derived from 
PRZM/EXAMS is again, much lower than this acute DWLOC. Therefore, one 
can conclude with reasonable certainty that residues of azafenidin in 
drinking water would not contribute significantly to the aggregate 
acute human health risk. In conclusion, there is a reasonable certainty 
of no harm to the general population resulting from either acute or 
chronic aggregate exposure to azafenidin.
    2. Infants and children. In assessing the potential for additional 
sensitivity of infants and children to residues of azafenidin, data 
from the previously discussed developmental and multigeneration 
reproductive toxicity studies were considered. Developmental studies 
are designed to evaluate adverse effects on the developing organism 
resulting from pesticide exposure during pre-natal development. 
Reproduction studies provide information relating to reproductive and 
other effects on adults and offspring from pre-natal and post-natal 
exposures to the pesticide. The rat reproduction and developmental 
studies indicated developmental effects in this species at exposures 
that produced minimal maternal effects. A clear dose-response and 
developmental NOAEL has been defined for these effects. FFDCA section 
408 provides that EPA may apply an additional uncertainty factor for 
infants and children in the case of threshold effects to account for 
pre-natal and post-natal toxicity and the completeness of the database. 
The additional uncertainty factor may increase the margin of exposure 
(MOE) from the usual 100- up to 1,000-fold. Based on current 
toxicological data requirements, the database for azafenidin relative 
to pre-natal and post-natal effects for children is complete. In 
addition, the NOAEL of 0.3 mg/kg/day in the 1-year dog study and upon 
which the RfD is based is much lower than the NOAELs defined in the 
reproduction and developmental toxicology studies. Conservative 
assumptions utilized to estimate acute and chronic dietary exposures of 
infants and children to azafenidin demonstrated that only 0.17% of the 
aRfD and 0.7% of the cRfD were utilized. Chronic and acute drinking 
water levels of concern (DWLOC's) of 0.03 ppm and 1.6 ppm calculated 
for children age 1-6-years, were significantly greater than predicted 
chronic and acute water concentrations of 4.7 ppb and 24 ppb 
respectively. Based on these exposure estimates it may be concluded 
that there is reasonable certainty that no harm will result to infants 
and children from aggregate exposures to azafenidin.

F. International Tolerances

    There are no established Canadian, Mexican or Codex MRLs for 
azafenidin. Compatibility is not a problem.
[FR Doc. 99-28728 Filed 11-2-99; 8:45 am]
BILLING CODE 6560-50-F