[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:
tompkins.james@epa.gov.
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: opp-docket@epa.gov,'' 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
