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azafenidin Pesticide Petition Filing 11/97


[Federal Register: December 3, 1997 (Volume 62, Number 232)]
[Notices]               
[Page 63942-63951]
>From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr03de97-74]

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ENVIRONMENTAL PROTECTION AGENCY

[PF-780; FRL-5756-1]

 
Notice of Filing of Pesticide Petitions

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

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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-
docket@epamail.epa.gov. Follow the instructions under ``SUPPLEMENTARY 
INFORMATION.'' No confidential business information should be submitted 
through e-mail.
    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 
table below:

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                                   Office location/                     
        Product Manager            telephone number          Address    
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Joanne Miller (PM 23).........  Rm. 237, CM #2, 703-    1921 Jefferson  
                                 305-6224, e-            Davis Hwy,     
                                 mail:miller.joanne@ep   Arlington, VA  
                                 amail.epa.gov.                         
James Tompkins (PM 25)........  Rm. 239, CM #2, 703-    1921 Jefferson  
                                 305-5697, e-mail:       Davis Hwy,     
                                 tompkins.james@epamai   Arlington, VA. 
                                 l.epa.gov.                             
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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 
petition.
    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:
    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. 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 
requirements.

    Dated: November 21, 1997

Peter Caulkins,
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.

PP 7F4849

    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-
[2,4-dichloro-5-(2-propynyloxy) phenyl]-5,6,7,8-tetrahydro-1,2,4-
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 
sensitizer.
    An acute neurotoxicity study was conducted in rats administered

[[Page 63949]]

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 
and above.
    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 
hepatocytes.
    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 
rats, respectively).
    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/
kg/day.
    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 
rats, respectively).
    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/

[[Page 63950]]

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       
                                         day)                           
------------------------------------------------------------------------
13+/Pregnant; Not Nursing.......  0.000868            86,800            
13+/Nursing.....................  0.001384            11,561            
13 - 19/ Not Pregnant; Not        0.001119            14,561            
 Nursing.                                                               
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 
negligible.

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

[[Page 63951]]

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 
azafenidin].

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