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cloquintocet-mexyl Pesticide Petition Filing 4/98


[Federal Register: April 15, 1998 (Volume 63, Number 72)]
[Notices]               
[Page 18411-18420]
>From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr15ap98-90]


[[Page 18411]]

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ENVIRONMENTAL PROTECTION AGENCY

[PF-801; FRL-5781-9]

 
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-801, must 
be received on or before May 15, 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. 119FF, CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
    Comments and data may also be submitted electronically by following 
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    
------------------------------------------------------------------------
Sidney Jackson (PM 5).........  Rm. 268, CM #2, 703-    1921 Jefferson  
                                 305-7610, e-            Davis Hwy,     
                                 mail:jackson.sidney@e   Arlington, VA  
                                 pamail.epa.gov.                        
Bipin Gandhi (PM 5)...........  Rm. 4W53, CS #2, 703-   Do.             
                                 308-8380, e-mail:                      
                                 gandhi.bipin@epamail.                  
                                 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 support 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-801] (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 FRL-5781-9 and appropriate petition 
number. Electronic comments on notice may be filed online at many 
Federal Depository Libraries.

List of Subjects

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

Dated: April 1, 1998

    James Jones,

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. Novartis Crop Protection, Inc.

PP 7E4920

    EPA has received a pesticide petition (PP 7E4920) from Novartis 
Crop Protection, Inc., P.O. Box 18300, Greensboro, NC 27419, 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 inert 
tolerances for residues of cloqiontocet-mexyl (acteic acid, [5-chloro-
8-quinolinyl)oxy]-,1-methylhexylester; CGA-185072) in or on the raw 
agricultural commodities wheat grain at 0.02 ppm and wheat straw at 
0.05 ppm. The proposed analytical method involves homogenization, 
filtration, partition, and cleanup with analysis by high performance 
liquid chromotography using UV 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

[[Page 18418]]

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 metabolism of CGA-185072 in wheat has been 
investigated. Total residues in all crop samples are low. Metabolism 
involves primarily rapid hydrolysis of the parent to the resulting acid 
followed by conjugation.
    2. Analytical method. Novartis has submitted practical analytical 
methods for the determination of CGA-185072 and its major plant 
metabolite CGA-153433 in wheat raw agricultural commodities (RACs). 
CGA-185072 is extracted from crops with acetonitrile, cleaned up by 
solvent partition and solid phase extraction and determined by column 
switching HPLC with UV detection. CGA-153433 is extracted from crops 
with an acetone-buffer (pH=3) solution, cleaned up by solvent partition 
and solid phase extraction, and determined by HPLC with UV detection. 
The limits of quantification (LOQ) for the methods are 0.02 ppm for 
CGA-185072 in forage and grain, 0.05 ppm for CGA-185072 in straw, and 
0.05 ppm for CGA-153433 in forage, straw and grain.
    3. Magnitude of residues. Twelve residue trials were conducted from 
1989-1992 in the major spring wheat growing areas of Manitoba, Alberta 
and Saskatchewan, which share compatible crop zones with the major 
spring wheat growing areas of the U.S. (MT, ND, SD, MN). Nine trials 
were conducted in 1989-91 with a tank mix of CGA-184927 (a.i.) and the 
CGA-185072 safener as separate EC formulations and three trials in 1992 
were conducted with CGA-184927 and the CGA-185072 safener as a pre-pack 
EC formulation. All trials had a single post-emergence application of 
CGA-185072 at a rate of 20 g a.i./Ha. At PHIs of 55-97 days, no 
detectable residues of CGA-185072 or its metabolite CGA-153433 were 
found in mature grain or straw from these trials. Separate decline 
studies (3) on green forage showed no detectable residues of CGA-185072 
or CGA-153433 at 3 days after application. Freezer storage stability 
studies indicated reasonable stability of both analytes for a period of 
one year, with CGA-185072 declining to 83% in grain and 67% in straw 
after two years, while CGA-153433 was stable for at least two years.

B. Toxicological Profile

    1. Acute toxicity. The acute oral and dermal LD<INF>50</INF> values 
for cloquintocet-mexyl are greater than 2,000 mg/kg for rats of both 
sexes, respectively. Its acute inhalation LC<INF>50</INF> in the rat is 
greater than 0.94 mg/liter , the highest attainable concentration. 
Cloquintocet-mexyl is slightly irritating to the eyes, minimally 
irritating to the skin of rabbits, but was found to be sensitizing to 
the skin of the guinea pig. This technical would carry the EPA signal 
word ``Caution''.
    2. Genotoxicty. The mutagenic potential of cloquintocet-mexyl was 
investigated in six independent studies covering different end points 
in eukaryotes and prokaryotes in vivo and in vitro. These tests 
included: Ames reverse mutation with Salmonella typhimurium and Chinese 
hamster V79 cells; chromosomal aberrations using human lymphocytes and 
the mouse micronucleus test; and DNA repair using rat hepatocytes and 
human fibroblasts. Cloquintocet-mexyl was found to be negative in all 
these tests and, therefore, is considered devoid of any genotoxic 
potential at the levels of specific genes, chromosomes or DNA primary 
structure.
    3. Reproductive and developmental toxicity. Dietary administration 
of cloquintocet-mexyl over two generations at levels as high as 10,000 
ppm did not affect mating performance, fertility, or litter sizes, but 
a slightly reduced body weight development of adults and pups was noted 
at this level. The target organ was kidney in adults and pups. The 
treatment had no effect on reproductive organs. The developmental and 
reproductive NOEL was 5,000 ppm, corresponding to a mean daily intake 
of 350 mg/kg cloquintocet-mexyl.
    In a developmental toxicity study in rats, the highest dose level 
of 400 mg/kg resulted in reduced body weight gain of the dams and signs 
of retarded fetal development. No teratogenic activity of the test 
article was detected. The NOEL for dams and fetuses was 100 mg/kg/day.
    In a developmental toxicity study in rabbits, mortality was 
observed in dams at dose levels of 300 mg/kg. No teratogenic effects 
were noted. Fetuses showed signs of slightly retarded development. The 
NOEL for both dams and fetuses was 60 mg/kg/day.
    4. Subchronic toxicity. In a 90-day study, rats fed 6,000 ppm 
exhibited reduced body weight gain and one male died with acute 
nephritis and inflamed urinary bladder. Reduced liver and kidney 
weights were observed in males fed 1,000 and 6,000 and in females fed 
6,000 ppm. Target organs were identified to be kidney and urinary 
bladder. The NOEL was 150 ppm (9.66 mg/kg in males and 10.2 mg/kg in 
females).
    In a 90-day study in beagle dogs, a level of 40,000 ppm resulted in 
deterioration of general condition so that the feeding level was 
reduced in a stepwise fashion to 15,000 ppm. Anemia was noted at 15,000 
ppm and the feeding level of 1,000 ppm. The NOEL of 100 ppm was 
equivalent to a mean daily intake of 2.9 mg/kg in males and females.
    5. Chronic toxicity. In a 12-month feeding study in dogs, 15,000 
ppm resulted in inappetence and body weight loss. As a result, this 
feeding level was adjusted to 10,000 ppm after 2-weeks. Animals fed 
this level exhibited anemia and an elevation in blood urea levels. The 
kidney was considered the target organ. The NOEL of 1,500 ppm was 
equivalent to a mean daily intake of 43.2 mg/kg in males and 44.8 mg/kg 
in females.
    Lifetime dietary administration of cloquintocet-mexyl to mice 
resulted in reduced body weights in both sexes at 5,000 ppm. Overall 
body weight gain was reduced by 17% to 22% in males and females, 
respectively, indicating the MTD was achieved or exceeded. 
Histopathological examination revealed chronic inflammation of the 
urinary bladder. There was no indication of any tumorigenic response 
due to treatment. The NOEL of 1,000 ppm was equivalent to a mean daily 
dose of 111 mg/kg in males and 102 mg/kg in females.
    A top feeding level of 2,000 ppm was selected, based on the 90-day 
study, for the lifetime feeding study in the rat. This feeding level 
was well-accepted, but produced hyperplasia of the thymus in males and 
hyperplasia of the thyroid in females. There was no increase in tumors 
of any type and the total number of tumor- bearing animals showed no 
dose-related trends. The NOEL of 100 ppm was equivalent to a mean daily 
dose of 3.77 mg/kg in males and 4.33 mg/kg in females.
    6. Animal metabolism. In rats, approximately 50% of an oral dose of 
cloquintocet-mexyl was rapidly absorbed through the gastrointestinal 
tract and excreted via urine and bile. The administered dose was 
excreted independent of sex and was essentially complete within 48 
hours. 95% of the excreted dose was associated with one metabolite, an 
acid residue of cloquintocet-mexyl, CGA-153433. Simultaneous 
administration of the cloquintocet-mexyl and clodinafop-propargyl did 
not alter the rate of excretion of cloquintocet-mexyl or its metabolite 
pattern.
    7. Metabolite toxicology. At the present time there is no evidence 
which affords an association of the toxicities noted with the highest 
feeding levels of cloquintocet-mexyl with its primary metabolite, CGA-
153433.

[[Page 18419]]

    8. Endocrine disruption. A special study was conducted to 
investigate a histological finding of hyperplasia of thyroid gland 
epithelium noted in the female rat in the standard lifetime combined 
chronic toxicity and carcinogenicity study. This study was a 28-day 
oral gavage study with a 28-day recovery period at dose levels as high 
as 400 mg/kg/day or approximately 4,000 ppm. No effect was noted on the 
level of thyroid hormones at any of the treatment levels. Although 
thyroid hyperplasia and an accompanying increase in pituitary 
basophilic cells were noted at the end of 28-days, these effects were 
reversible in the recovery period.

C. Aggregate Exposure

    1. Dietary exposure. Cloquintocet-mexyl is intended to be used as a 
safener for the post emergence herbicide, clodinafop-propargyl, used in 
wheat. The use rate is very low (formulated at a 1:4 ratio of safener 
to active ingredient). Results from plant metabolism and residue 
studies show that residues of the safener cloquintocet-mexyl or its 
metabolites are below the detection limit in wheat grains and other 
wheat byproducts including green wheat used for forage. Tolerances in 
wheat and wheat products are being proposed at the detection limit of 
0.02 ppm (LOQ) for the parent active ingredient in wheat grain and 0.05 
ppm (LOQ) in wheat straw. For cloquintocet, similar tolerances will be 
proposed in wheat grain (0.02 ppm) and wheat straw (0.05 ppm).
    i. Chronic. The RfD of 0.0377 mg/kg/day was derived from the male 
NOEL of 3.77 mg/kg/day. Based on the assumption that 100% of all wheat 
used for human consumption would contain residues of cloquintocet-mexyl 
and anticipated residues would be at the level of \1/2\ the LOQ, the 
potential dietary exposure was calculated using the TAS<SUP></SUP> 
exposure program based on the food survey from the year of 1977-1978. 
Calculations were made for anticipated residues using \1/2\ the LOQ or 
0.01 ppm. Calculated on the basis of the assumptions above, the chronic 
dietary exposure of the U.S. population to cloquintocet-mexyl would 
correspond to 0.000014 mg/kg/day or 0.04% of its RfD. MOE against NOEL 
in the most sensitive species is 269,286-fold.
    Using the same conservative exposure assumptions, the percent of 
the RfD that will be utilized is 0.01% for nursing infants less than 1-
year old, 0.03% for non-nursing infants, 0.08% for children 1-6 years 
old and 0.06% for children 7-12 years old. It is concluded that there 
is a reasonable certainty that no harm will result to infants and 
children from exposure to residues of cloquintocet-mexyl.
    ii. Acute. Using the same computer software package used for the 
calculation of chronic dietary exposure, the acute dietary exposure was 
calculated for the general population and several sub-populations 
including children and women of child bearing age. The USDA Food 
Consumption Survey of 1989-1992 was used, however, instead of the 1977-
1978 survey used for the chronic assessment. MOEs were calculated 
against the NOEL of 2.9 mg/kg found in a 90-day dietary toxicity study 
in dogs, which is the lowest NOEL observed in a short term or 
reproductive toxicity study. NOELs from reproductive or developmental 
toxicity studies were significantly higher and there was no evidence 
that cloquintocet-mexyl has any potency to affect these endpoints.
    The exposure model predicted that 99.9% of the general population 
will be exposed to less than 0.000104 mg/kg cloquintocet-mexyl per day, 
which corresponds to a MOE of almost 27,944 when compared to the NOEL 
of 2.9 mg/kg. Children 1-6 years constitute the sub-population with the 
highest predicted exposure. Predicted acute exposure for this subgroup 
is less than 0.000134 mg/kg/day, corresponding to a MOE of at least 
21,721 for 99.9% of the individuals.
    2. Drinking water. Other potential sources of exposure of the 
general population to residues of pesticides are residues in drinking 
water. Results of studies have shown that cloquintocet-mexyl or its 
degradation products do not have any leaching potential. Accordingly, 
there is no risk of groundwater contamination with cloquintocet-mexyl 
or its metabolites. Thus, aggregate risk of exposure to cloquintocet-
mexyl does not include drinking water. Cloquintocet-mexyl is not 
intended for uses other than the agricultural use on wheat. Thus, there 
is no potential for non-occupational exposure.
    The Maximum Contaminant Level Goal (MCLG) calculated for 
cloquintocet-mexyl according to EPA's procedure leads to an exposure 
value substantially above levels that are likely to be found in the 
environment under proposed conditions of use.
    MCLG = RfD x 20% x 70 kg/2 L
    MCLG = 0.0377 mg/kg x 0.2 x 70 kg/2 L
    MCLG = 0.264 ppm = 264 ppb
    3. Non-dietary exposure. Exposure to cloquintocet-mexyl for the 
mixer/loader/ground boom/aerial applicator was calculated using the 
Pesticide Handlers Exposure Database (PHED). It was assumed that the 
product would be applied 10-days per year by ground boom application to 
a maximum of 300 acres per day by the grower, 450 acres per day by the 
commercial groundboom applicator, and 741 acres per day for the aerial 
applicator at a maximum use rate of 28 grams active ingredient (7 grams 
of cloquintocet-mexyl) per acre. For purposes of this assessment, it 
was assumed that an applicator would be wearing a long-sleeved shirt 
and long pants and the mixer/loader would, in addition, wear gloves. 
Daily doses were calculated for a 70 kg person assuming 100% dermal 
penetration.
    The results indicate that large margins of safety exist for the 
proposed experimental use of cloquintocet-mexyl. The use pattern of 
cloquintocet indicates that the NOEL(1,000 mg/kg/day) from the 28-day 
rat dermal study is appropriate for comparison to mixer/loader-
applicator exposure. The chronic NOEL of 3.77 mg/kg/day from the 2-year 
feeding study in rats is used to examine longer term exposure.
    For short-term exposure, MOEs for cloquintocet ranged from 2.4E+05 
for commercial open mixer-loader to 2.5E+06 for commercial groundboom 
enclosed-cab applicator. For chronic exposure, MOEs ranged from 3.2E+04 
for commercial open mixer-loader to 3.5E+05 for commercial groundboom 
enclosed-cab applicator. Aerial application of cloquintocet results in 
short-term MOEs of 1.4E+05 for the mixer-loader and 2.5E+05 for pilots. 
Chronic MOEs are 2.0E+04 for the mixer-loader and 3.4E+04 for the 
pilot. Based on this assessment, occupational exposure to cloquintocet-
mexyl results in acceptable MOEs.
    In reality, the proposed label for the end use product containing 
the active ingredient plus cloquintocet-mexyl will require more 
restrictive personal protective equipment for applicators and other 
handlers, resulting in additional margins of safety.

D. Cumulative Effects

    Novartis has considered the potential for a cumulative exposure 
assessment for effects of cloquintocet-mexyl and other substances with 
the same mechanism of toxicity. It is concluded that such a 
determination would be inappropriate at this time because of the unique 
role of cloquintocet-mexyl as a product specific safener.

E. Safety Determination

    1. U.S. population. Using the same conservative exposure 
assumptions as described for chronic and acute dietary exposure, 
aggregrate exposure of the

[[Page 18420]]

U.S. population to cloquintocet-mexyl would correspond to 0.000014 mg/
kg/day or 0.04% of its RfD. The chronic MOE against the NOEL in the 
most sensitive species is 269,286-fold. EPA generally has no concern 
for exposures below 100% of the RfD because the RfD represents the 
level at or below which daily aggregate dietary exposure over a 
lifetime will not pose appreciable risks to human health. Therefore, it 
is concluded that there is a reasonable certainty that no harm will 
result from aggregate exposure to residues of cloquintocet-mexyl.
    2. Infants and children. In assessing the potential for additional 
sensitivity of infants and children to residues of cloquintocet-mexyl, 
data from developmental toxicity studies in the rat and rabbit and a 2- 
generation reproduction study in the rat have been considered. The 
developmental toxicity studies are designed to evaluate adverse effects 
on the developing organism resulting from chemical exposure during 
prenatal development to one or both parents. Reproduction studies 
provide information relating to effects from exposure to a chemical on 
the reproductive capability of mating animals and data on systemic 
toxicity.
    The highest dose level of 400 mg/kg/day in a developmental toxicity 
study in rats resulted in reduced body weight gain of the dams and 
signs of retarded fetal development. No teratogenic activity due to the 
test article was detected. The NOEL for dams and fetuses was 100 mg/kg/
day. Although mortality was observed in rabbit dams at the dose level 
of 300 mg/kg/day, no teratogenic effects were noted. The NOEL for both 
dams and fetuses was 60 mg/kg/day.
    Dietary administration of cloquintocet-mexyl over 2-generations at 
levels as high as 10,000 ppm did not affect mating performance, 
fertility, or litter sizes in rats, but a slightly reduced body weight 
development of adults and pups was noted at this level. The target 
organ was kidney in adults and pups. The treatment had no effect on 
reproductive organs. The developmental and reproductive NOEL was 5,000 
ppm, corresponding to a mean daily intake of 350 mg/kg cloquintocet-
mexyl.
    FFDCA section 408 provides that EPA may apply an additional safety 
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. Based on the current toxicological data requirements, the 
database relative to pre- and post-natal effects for children is 
complete. Further, for cloquintocet-mexyl, the NOEL of 3.77 mg/kg/day 
from the combined chronic/oncogenicity study in rats, which was used to 
calculate the RfD, is already lower than the NOEL's of 100 and 60 mg/
kg/day for the rat and rabbit developmental toxicity studies, 
respectively. Further, the developmental and reproductive NOEL of 350 
mg/kg/day from the cloquintocet-mexyl reproduction study is nearly 100 
times greater than the NOEL for the combined chronic/oncogenicity rat 
study. These data would indicate there is no additional sensitivity of 
infants and children to cloquintocet-mexyl. Therefore, it is concluded 
that an additional uncertainty factor is not warranted to protect the 
health of infants and children from the use of cloquintocet-mexyl.
    Using the conservative exposure assumptions described above, it is 
concluded that the percentage of the RfD that will utilized by 
aggregate exposure to residues of cloquintocet-mexyl for its proposed 
use as a safener for clodinafop-propargyl on wheat is 0.01% for nursing 
infants less than 1-year old, 0.03% for non-nursing infants, 0.08% for 
children 1-6 years old and 0.06% for children 7-12 years old. 
Therefore, based on the completeness and reliability of the toxicity 
data and the conservative nature of the exposure assessment, it is 
concluded that there is a reasonable certainty that no harm will result 
to infants and children from exposure to residues of cloquintocet-
mexyl.

F. International Tolerances

    Cloquintocet-mexyl is used as a safener for the herbicide, 
clodinafop-propargyl. There are no Codex Alimentarius Commission 
(CODEX) maximum residue levels (MRLs) established for residues of 
cloquintocet-mexyl in or on raw



[FR Doc. 98-9395 Filed 4-14-98; 8:45 am]
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