azafenidin Pesticide Petition Filing 11/97
[Federal Register: December 3, 1997 (Volume 62, Number 232)]
>From the Federal Register Online via GPO Access [wais.access.gpo.gov]
ENVIRONMENTAL PROTECTION AGENCY
Notice of Filing of Pesticide Petitions
AGENCY: Environmental Protection Agency (EPA).
SUMMARY: This notice announces the initial filing of pesticide
petitions proposing the establishment of regulations for residues of
certain pesticide chemicals in or on various food commodities.
DATES: Comments, identified by the docket control number PF-780, must
be received on or before January 2, 1998.
ADDRESSES: By mail submit written comments to: Public Information and
Records Integrity Branch, Information Resources and Services Division
(7502C), Office of Pesticides Programs, Environmental Protection
Agency, 401 M St., SW., Washington, DC 20460. In person bring comments
to: Rm. 1132, CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
Comments and data may also be submitted electronically to: opp-
firstname.lastname@example.org. Follow the instructions under ``SUPPLEMENTARY
INFORMATION.'' No confidential business information should be submitted
Information submitted as a comment concerning this document may be
claimed confidential by marking any part or all of that information as
``Confidential Business Information'' (CBI). CBI should not be
submitted through e-mail. Information marked as CBI will not be
disclosed except in accordance with procedures set forth in 40 CFR part
2. A copy of the comment that does not contain CBI must be submitted
for inclusion in the public record. Information not marked confidential
may be disclosed publicly by EPA without prior notice. All written
comments will be available for public inspection in Rm. 1132 at the
address given above, from 8:30 a.m. to 4 p.m., Monday through Friday,
excluding legal holidays.
FOR FURTHER INFORMATION CONTACT: The product manager listed in the
Product Manager telephone number Address
Joanne Miller (PM 23)......... Rm. 237, CM #2, 703- 1921 Jefferson
305-6224, e- Davis Hwy,
mail:miller.joanne@ep Arlington, VA
James Tompkins (PM 25)........ Rm. 239, CM #2, 703- 1921 Jefferson
305-5697, e-mail: Davis Hwy,
tompkins.james@epamai Arlington, VA.
SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions as
follows proposing the establishment and/or amendment of regulations for
residues of certain pesticide chemicals in or on various food
commodities under section 408 of the Federal Food, Drug, and Comestic
Act (FFDCA), 21 U.S.C. 346a. EPA has determined that these petitions
contain data or information regarding the elements set forth in section
408(d)(2); however, EPA has not fully evaluated the sufficiency of the
submitted data at this time or whether the data supports granting of
the petition. Additional data may be needed before EPA rules on the
The official record for this notice of filing, as well as the
public version, has been established for this notice of filing under
docket control number [PF-780] (including comments and data submitted
electronically as described below). A public version of this record,
including printed, paper versions of electronic comments, which does
not include any information claimed as CBI, is available for inspection
from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal
holidays. The official record is located at the address in
``ADDRESSES'' at the beginning of this document.
Electronic comments can be sent directly to EPA at:
Electronic comments must be submitted as an ASCII file avoiding the
use of special characters and any form of encryption. Comment and data
will also be accepted on disks in Wordperfect 5.1 file format or ASCII
file format. All comments and data in electronic form must be
identified by the docket number (insert docket number) and appropriate
petition number. Electronic comments on notice may be filed online at
many Federal Depository Libraries.
List of Subjects
Environmental protection, Agricultural commodities, Feed additives,
Food additives, Pesticides and pests, Reporting and recordkeeping
Dated: November 21, 1997
Acting Director, Registration Division, Office of Pesticide Programs.
Summaries of Petitions
Petitioner summaries of the pesticide petitions are printed below
as required by section 408(d)(3) of the FFDCA. The summaries of the
petitions were prepared by the petitioners and represent the views of
the petitioners. EPA is publishing the petition summaries verbatim
without editing them in any way. The petition summary announces the
availability of a description of the analytical methods available to
EPA for the detection and measurement of the pesticide chemical
residues or an explanation of why no such method is needed.
3. E.I. DuPont de Nemours and Co., Inc.
EPA has received a pesticide petition (PP 7F4849) from E.I. DuPont
de Nemours and Co., Inc. (DuPont), 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, 21 U.S.C. 346a(d), to amend 40 CFR
part 180 by establishing a tolerance for residues of for azafenidin, 2-
triazolo [4,3-a] pyridin-3(2H)-1 in or on the raw agricultural
commodities of the crop grouping of citrus, grapes, sugarcane and
sugarcane molasses. The proposed analytical method involves
homogenization, filtration, partition and cleanup with analysis by gas
chromatography using mass selective detection. EPA has determined that
the petition contains data or information regarding the elements set
forth in section 408(d)(2) of the FFDCA; however, EPA has not fully
evaluated the sufficiency of the submitted data at this time or whether
the data supports granting of the petition. Additional data may be
needed before EPA rules on the petition.
A. Residue Chemistry
1. Plant metabolism. The qualitative nature of the residues of
azafenidin in citrus, grapes and sugarcane is adequately understood for
the purposes of registration. Metabolic pathways in grapefruit, grapes
and sugarcane are similar, consisting of rapid O-dealkylation and
production of hydroxyl derivatives, with subsequent formation of
glucuronide and sulfate.
2. Analytical method. The proposed analytical method involves
homogenization, filtration, partition and cleanup with analysis by gas
chromatography using mass selective detection.
3. Magnitude of residues. DuPont proposes establishing tolerances
for residues azafenidin, 2-[2,4-dichloro-5-(2-propynyloxy)phenyl]-
5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridin-3(2H)-1 (Milestone*) in
or on the agricultural commodities of the crop grouping of citrus at
0.1 ppm, grapes at 0.02 ppm, sugarcane at 0.02 ppm and sugarcane
molasses at 0.1 ppm .
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 (LD<INF>50</INF> > 2,000kg; rabbits) and eye
irritation (effects reversible within 72 hours; rabbits). Acute oral
toxicity (LD<INF>50</INF> > 5,000 mg/kg; rats), acute inhalation
toxicity (LC<INF>50</INF> > 5.4 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
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 NOEL was 100 mg/kg for males and
females based on reduced food consumption and body weights at 300 mg/kg
2. Genotoxicty. 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 (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 in rat primary
3. Reproductive and developmental toxicity. A 2-generation
reproduction study was conducted in rats with dietary technical
azafenidin concentrations of 0, 5, 30, 180 or 1,080 ppm. The NOEL was
30 ppm (1.7 to 2.8 mg/kg/day for P<INF></INF><INF>1</INF> and
F<INF></INF><INF>1</INF> 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 P<INF></INF><INF>1</INF> and F<INF></INF><INF>1</INF> males and
females and/or their offspring): slight reductions in mean body weights
for F<INF></INF><INF>1</INF> 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 F<INF></INF><INF>1</INF> parental males.
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 NOEL 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 these weight reductions.
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 NOELs for maternal and offspring
toxicity were 12 and 100 mg/kg/day, respectively. The maternal NOEL 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 a
Crop field trial residue data from citrus, grape and sugarcane studies
show that the proposed tolerances on these commodities will not be
exceeded when Milestone* is used as directed. Assessment of
developmental effects at this level. However, the developmental NOEL
was considered to be 100 mg/kg/day since there were no indications of
fetal toxicity up to and including this dose level.
4. Subchronic toxicity. A 90-day study in mice was conducted at
dietary concentrations of 0, 50, 300, 900 or 1,500 ppm. The NOEL 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).
Technical azafenidin was administered in the diets of rats at 0,
50, 300, 900 or 1,500 ppm for 90 days. The NOEL 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
Dogs were administered technical azafenidin in their diets at 0,
10, 60, 120 or 240 ppm for 90-days. The NOEL 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).
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 NOEL 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.
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. The NOEL was > 1,000 mg/
5. Chronic toxicity. 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 NOEL
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).
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. This product was not oncogenic in rats. The systemic NOEL
was 300 ppm (12.1 and 16.4 mg/kg/day males and females, respectively).
The NOEL 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
Technical azafenidin was administered for 1-year to dogs at dietary
concentrations of 0, 5, 10, 120 and 360 ppm. The NOEL 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.
C. Aggregate Exposure
1. Food--i. Acute dietary exposure. Since there were no acute
affects appropriate for assessment of the general population, the NOEL
of 16 mg/
kg/day from the rat developmental toxicity study was used to assess
acute dietary risk for females 13-years of age and older. Exposures
were estimated using the DEEM computer software (version 5.03b, Novigen
Sciences, Inc, 1997). The proposed azafenidin tolerances for the raw
agricultural commodities and processed fractions that were used in the
calculations included: grapes, 0.02 ppm; citrus, 0.1 ppm; and sugarcane
- 0.02 ppm for cane sugar and 0.1 ppm for molasses. The following
exposures indicate margins of exposure > 11,000 at the 95th percentile
and provides a reasonable certainty that no harm to the individual or
the developing child will occur under these conservative exposure
assumptions (i.e., all labeled crops are treated, residues are present
at the proposed tolerances and there is no reduction of residues prior
to consumption of these food commodities).
Exposure - 95th
Subpopulations Percentile (mg/kg/ MOE<SUP>a
13+/Pregnant; Not Nursing....... 0.000868 86,800
13+/Nursing..................... 0.001384 11,561
13 - 19/ Not Pregnant; Not 0.001119 14,561
20+/Not Pregnant; Not Nursing... 0.000832 0.19,231
13 - 50 Years................... 0.000938 17,056
<SUP>a MOE - Margin of Exposure = NOEL from rat developmental study (16 mg/kg/
day) divided by the 95th percentile exposure.
ii.Chronic dietary exposure. A Reference Dose (RfD) of 0.003 mg/kg/
day has been proposed based on the NOEL from the most sensitive chronic
study (NOEL of 0.3 mg/kg/day from the 1-year dog study) and applying a
100-fold uncertainty factor. General and subpopulation exposures were
estimated using the DEEM computer software (version 5.03b, Novigen
Sciences, Inc, 1997). The following proposed azafenidin tolerances for
the raw agricultural commodities and processed fractions were used in
the calculations: grapes, 0.02 ppm; citrus, 0.1 ppm; and sugarcane -
0.02 ppm for cane sugar and 0.1 ppm for molasses. Exposure assessments
assumed 100% of the crops were treated with azafenidin, that residues
were present at the tolerance level and that no residues were removed
prior to consumption of treated crops. These assessments indicated
adequate margins of exposure for all subpopulations and that only 21%
or less of the RfD was utilized by any group. For example, the TMRCs
were 0.000237 mg/kg/day (7.9% RfD) for the general population and
0.000619 mg/kg/day (20.6% RfD) for the subpopulation with the highest
potential exposure, children ages 1 through 6 years.
2. Drinking water. Other potential dietary sources of exposure of
the general population to pesticides are residues in drinking water.
There is no Maximum Contaminant Level established for residues of
azafendidin. The petitioner is reporting to the Environmental Fate and
Groundwater Branch of EPA (EFGWB) the interim results of a prospective
groundwater monitoring study conducted at a highly vulnerable site.
Based on the preliminary results of this study the petitioner does not
anticipate residues of azafenidin in drinking water and exposure from
this route is unlikely. However, given that less than 21% of the RfD is
attained by the TMRC for the population subgroup with the highest
theoretical dietary exposure (children 1-6 years of age), there is
ample allowance for safe exposure to azafenidin via drinking water
should it ever be detected.
3. Non-dietary exposure. Azafenidin is proposed 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 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
C. 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.
D. Safety Determination
1. U.S. population. Based on the completeness and reliability of
this azafenidin toxicology database and using the conservative
aggregate exposure assumptions presented earlier, it has been concluded
that azafenidin products may be used with a reasonable certainty of no
harm relative to exposures from food and drinking water. A chronic RfD
of 0.003 mg/kg/day has been proposed from the NOEL of the most
sensitive chronic dietary study and the use of a 100-fold uncertainty
factor. The TMRC determined for proposed tolerances in citrus, grapes
and sugar cane utilized only 7.9% of the RfD (an exposure of 0.000237
mg/kg/day). Although there was no data to accurately assess potential
exposures through drinking water, the small fraction of the RfD
utilized for food by the general and subpopulations indicate that is
unlikely that aggregate exposures will exceed acceptable limits. In
addition, the use patterns and physical chemical properties of
azafenidin suggest that the potential for significant concentrations in
drinking water are remote. It has been concluded that the aggregate
exposure for the proposed tolerances on citrus, grapes and sugar cane
provide a reasonable certainty of no harm to the general population.
Because of effects observed in the rat developmental toxicology study,
an acute safety determination based on margins of exposure was
calculated from the NOEL of 16 mg/kg/day. The subpopulation potentially
at risk was considered to be females 13-years of age and older.
However, based on the MOEs presented previously of >11,000 at the 95th
exposure percentile, it was concluded that these potential dietary
exposures represented a reasonable certainty of no harm for this group.
An MOE of 100 or greater is generally considered protective.
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 NOEL 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- and post-natal toxicity and the completeness of the database. The
additional uncertainty factor may increase the MOE from the usual 100-
up to 1,000-fold. Based on current toxicological data requirements, the
database for azafenidin relative to pre- and post-natal effects for
children is complete. In addition, the NOEL of 0.3 mg/kg/day in the 1-
year dog study and upon which the RfD is based is much lower than the
NOELs defined in the reproduction and developmental toxicology studies.
Conservative assumptions utilized to estimate aggregate dietary
exposures of infants and children to azafenidin (0.000619 mg/kg/day)
demonstrated that only 20.6% of the RfD was utilized for the proposed
tolerances. Based on these exposure estimates and the fact that MOEs in
excess of 1,000-fold exist relative to the NOELs in the rat
reproduction study (NOEL = 1.7 mg/kg/day and MOE = 2,746) and the rat
developmental toxicity study (NOEL = 16 mg/kg/day and MOE = 25,848),
the extra 10-fold uncertainty factor is not warranted for these groups.
Therefore, it may be concluded that there is reasonable certainty that
no harm will result to infants and children from aggregate exposures to
E. International Tolerances
There are no established Canadian, Mexican or Codex MRLs for
azafenidin. Compatibility is not a problem.
[FR Doc. 97-31542 Filed 12-2-97; 8:45 am]
BILLING CODE 6560-50-F