cloquintocet-mexyl Pesticide Petition Filing 4/00
[Federal Register: April 19, 2000 (Volume 65, Number 76)]
>From the Federal Register Online via GPO Access [wais.access.gpo.gov]
ENVIRONMENTAL PROTECTION AGENCY
Notice of Filing a Pesticide Petition to Establish a Tolerance
for Certain Pesticide Chemicals in or on Food
AGENCY: Environmental Protection Agency (EPA).
SUMMARY: This notice announces the amendment of a pesticide petition
(PP7E4920), proposing the establishment of regulations for residues of
a certain pesticide chemical in or on various food commodities.
DATES: Comments, identified by docket control number PF-936, must be
received on or before May 19, 2000.
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. To ensure
proper receipt by EPA, it is imperative that you identify docket
control number PF-936 in the subject line on the first page of your
FOR FURTHER INFORMATION CONTACT: By mail: Treva C. Alston,
Registration Support Branch, Registration Division (7505C), Office of
Pesticide Programs, Environmental Protection Agency, Ariel Rios Bldg.,
1200 Pennsylvania Ave., NW., Washington, DC 20460; telephone number:
(703) 308-8373; e-mail address: email@example.com.
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:
Categories NAICS codes potentially
Industry 111 Crop production
112 Animal production
311 Food 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 under FOR FURTHER INFORMATION
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-936. 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, 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-936 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, Ariel Rios Bldg., 1200 Pennsylvania Ave., NW., Washington, DC
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: ``firstname.lastname@example.org,'' 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-936. 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 under FOR FURTHER INFORMATION
E. What Should I Consider as I Prepare My Comments for EPA?
You may find the following suggestions helpful for preparing your
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
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
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 a 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 support 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
Dated: April 10, 2000.
Director, Registration Division, Office of Pesticide Programs.
Summary of Petition
The petitioner summary of the pesticide petition is 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 view 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.
Novartis Crop Protection, Inc.
Amended Pesticide Petition
On April 15, 1998, EPA published a notice that it had received a
pesticide petition (7E4920) from Novartis Crop Protection, Inc., P.O.
Box 18300, Greensboro, NC 27419, proposing tolerances for the herbicide
safener cloquintocet-mexyl acetic acid, (5-chloro-8-quinolinyl)oxy-,1-
methylhexylester; CGA-185072) in or on raw agricultural commodities
(RACs) of wheat. EPA has received an amendment to PP 7E4920 from
Novartis Crop Protection, Inc., 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 to increase, as requested by EPA, the original
proposed tolerances; thereby establishing tolerances for the combined
residues of cloquintocet-mexyl and its acid metabolite, CGA-153433 (5-
chloro-8-quinolinyl)oxy-acetic acid), in or on the RACs wheat, grain at
0.1 part per million (ppm); wheat, forage at 0.1 ppm; wheat, hay at 0.1
ppm; and wheat, straw at 0.1 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
support granting of the petition. Additional data may be needed before
EPA rules on the petition.
A. Residue Chemistry
1. Plant metabolism. The metabolism of cloquintocet-mexyl 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 cloquintocet-mexyl and its major plant
metabolite CGA-153433 in wheat RACs. Cloquintocet-mexyl is extracted
from crops with acetonitrile, cleaned up by solvent partition and solid
phase extraction and determined by column switching high performance
liquid chromotography (HPLC) with ultra violet (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 cloquintocet-mexyl in forage and
grain, 0.05 ppm for cloquintocet-mexyl in straw, and 0.05 ppm for CGA-
153433 in forage, straw and grain.
3. Magnitude of residues. Both Canadian and United States spring
wheat residue trials were conducted. 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 United States (MT, ND,
SD, MN). Nine trials were conducted in 1989-91 with a tank mix of
clodinafop-propargyl active ingredient (a.i.) and the cloquintocet-
mexyl safener as separate EC formulations and three trials in 1992 were
conducted with clodinafop-propargyl and the cloquintocet-mexyl safener
as a pre-pack EC formulation. All trials had a single post-emergence
application of CGA-185072 at a rate of 20 gram active ingredient/
hectacre (g a.i./ha). In 1998, an additional six spring wheat trials
were conducted in the major growing areas of the United States. In
these trials, cloquintocet-mexyl was applied as a safener in
conjunction with clodinafop-propargyl as a 240EC formulation. The rate
of cloquintocet-mexyl applied was 17 g a.i./ha as a single application.
Samples of 30-day forage and hay, and mature straw and grain treated 60
days prior to harvest were taken for analysis. Grain treated at an
exaggerated rate in one trial was processed under simulated commercial
processing conditions. At pre-harvest intervals (PHIs) of 55-97 days,
no detectable residues of cloquintocet-mexyl or its metabolite CGA-
153433 were found in mature grain or straw from these trials. Separate
decline studies three on green forage showed no detectable residues of
cloquintocet-mexyl or CGA-153433 at 3 days after application. Freezer
storage stability studies indicated reasonable stability of both
analytes for a period of 1 year, with cloquintocet-mexyl declining to
83% in grain and 67% in straw after 2 years, while CGA-153433 was
stable for at least 2 years.
B. Toxicological Profile
1. Acute toxicity. The acute oral and dermal LD50 values
for cloquintocet-mexyl are greater than 2,000 milligrams/kilograms (mg/
kg) for rats of both sexes, respectively. Its acute inhalation
LC50 in the rat is greater than 0.935 milligram/liter (mg/
L), 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 will carry the EPA signal word ``Caution.''
2. Genotoxicity. 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 in vitro; chromosomal aberrations using human
lymphocytes in vitro and the mouse micronucleus test in vivo; and DNA
repair using rat hepatocytes and human fibroblasts in vitro.
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 2 generations at levels as high as 10,000
part per million (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 the kidney in
adults and pups. The treatment had no effect on reproductive organs.
The no observed adverse effect level (NOAEL) for toxicity to the
offspring and parental toxicity was 5,000 ppm, corresponding to a mean
daily intake of 370 to 422 mg/kg/day of cloquintocet-mexyl. The
reproductive NOAEL was > 10,000 ppm (722 mg/kg/day).
In a developmental toxicity study in rats, the highest dose level
of 400 mg/kg bwt day 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 NOAEL for dams and fetuses was 100 mg/kg
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
NOAEL for both dams and fetuses was 60 mg/kg bwt day. EPA's Hazard
Identification Assessment Review Committee (HIARC) suggested the
maternal NOAEL was 60 mg/kg, but the developmental toxicity NOAEL is >
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 NOAEL was 150 ppm (9.66 mg/kg in males and 10.2 mg/kg in
females). EPA's HIARC concluded that the NOAEL in females was 6,000 ppm
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
and 1,000 ppm. The NOAEL 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 NOAEL of 1,500 ppm was
equivalent to a mean daily intake of 43.2 mg/kg in males and 44.8 mg/kg
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 NOAEL of 1,000 ppm was equivalent to a mean daily
dose of 111 mg/kg in males and 102 mg/kg in females.
Rats were fed a top feeding level of 2,000 ppm, based on the 90-day
subchonic study, for a lifetime. This feeding level was well-tolerated,
but produced hyperplasia of the thymus in males at the top dose and
hyperplasia of the thyroid in females at 1,000 and 2,000 ppm. There was
no increase in tumors of any type and the total number of tumor-bearing
animals showed no dose-related trends. The NOAEL of 100 ppm was
equivalent to a mean daily dose of 4.33 mg/kg in females. EPA's HIARC
suggested that the NOAEL in male rats was 1,000 ppm (36.4 mg/kg/day).
6. Carcinogenicity. There is no evidence supporting any oncogenic
potential associated with cloquincet-mexyl. EPA's HIARC classified
cloquintocet-mexyl as a ``not likely'' human carcinogen according to
the proposed guidelines for carcinogen risk assessment.
7. 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. Ninety-five percent 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.
8. Metabolite toxicology. At the present time there is no evidence
which affords an association of the toxicity noted with the highest
feeding levels of cloquintocet-mexyl with its primary metabolite, CGA-
9. 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 a
slight stimulation of the thyroid 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 as a safener
for the postemergence herbicide, clodinafop-propargyl, used on wheat.
The use rate for cloquintocet-mexyl is very low (formulated at a 1:4
ratio of safener to active ingredient and results from plant metabolism
and residue studies show that residues are below the detection limit in
wheat grain and other wheat fractions. The tolerance expression will
include parent cloquintocet-methyl and the corresponding hydrolysis
product, CGA-153433, and tolerances are being proposed at 0.1 ppm in
wheat grain, forage, hay, and straw. No tolerances are proposed for
secondary residues in animal commodities since residues would be far
below the LOQ of existing analytical methodology.
i. Food. Chronic and acute dietary exposure analyses were conducted
using the dietary exposure evaluation model (DEEM) from Novigen
Sciences and the 1994-96 Continuing Survey of Food Intake by
Individuals (CSFII). Chronic and acute tier one dietary assessments
were made assuming tolerance-level residues and treatment of 100% of
all planted wheat.
a. Chronic. Chronic exposure was compared to a reference dose (RfD)
of 0.04 mg/kg/day which was derived from
a NOAEL of 4.3 mg/kg/day in a chronic toxicity/carcinogenicity study in
female rats and a 100x uncertainty factor (UF). Exposure was calculated
assuming that 100% of crop was treated and residues were at the
proposed tolerance levels of 0.1 ppm for wheat grain and associated
fractions. Exposure for the U.S. population was minimal with 0.4% of
the RfD utilized and this result was the same for the U.S. population
through all seasons and all ethnic groups. The most sensitive
subpopulation was children (1-6 years old) with an exposure of 0.9% of
the chronic RfD. These results are extremely conservative since
tolerance values were used and are reflective of the maximum
application rate and minimum PHI. In addition, it was assumed that all
planted acres are treated. Therefore, there is more than a reasonable
certainty of no harm resulting from exposure to residues of
b. Acute. Acute exposure was assessed for the female population
(13+ years) only and was compared to an acute RfD of 1.0 mg/kg/day
based on a NOAEL of 100 mg/kg/day from a developmental toxicity study
in rats and a 100x UF. The resulting assessment revealed that exposures
to all female subpopulations reported in the DEEM were between 0.03%-
0.04% of the RfD at the 95th percentile of exposure. The
95th percentile is the appropriate percentile to consider
since this assessment is based on tolerance-level residues and 100% of
crop treated was assumed. Even at the 99.9th percentile of
exposure, the results show that females (13-50 years old) utilize only
0.07% of the acute RfD. EPA's HIARC concluded that no acute dietary
assessment was necessary for the general population because a suitable
toxicological endpoint (resulting from a single dose exposure) was not
identified in either the rat or rabbit developmental studies.
ii. Drinking water. Another potential route of exposure to residues
of pesticides includes drinking water. Field and laboratory study
results have demonstrated that cloquintocet-mexyl and its degradation
products have minimal potential to reach surface or ground water. Thus,
drinking water exposure to cloquintocet-mexyl and its degradation
products was not included in the aggregate risk assessment. Also, since
cloquintocet-mexyl is not intended for uses other than the agricultural
use on wheat, there is no potential for non-occupational exposure.
The estimated exposures of cloquintocet-mexyl and its main
environmental degradate were combined and the hazards for both
compounds were based on the RfD values determined for cloquintocet-
mexyl alone. The estimated water concentrations for cloquintocet-mexyl
and the degradate were estimated, weighted and combined based on
applications rates adjusted for the maximum concentration of the
degradate present in the aerobic soil metabolism studies.
The GENEEC and SCI-GROW models respectively provided the estimated
surface water and ground water concentrations. The estimated acute
exposures from drinking surface and ground water were 0.04964 part per
billion (ppb) and 0.006166 ppb, respectively. The females 13+ years
sub-population was the only subgroup which was required for the acute
exposure assessment. The acute exposures for females 13+ years were
based on 1.0 mg/kg/day. Based on the 95th percentile acute
dietary assessment, the females (13+/nursing) was the most exposed
female sub-population at 3.71E-6 mg/kg/day. This resulted in an acute
DWLOC of 30,000 ppb. Therefore, the estimated acute surface and ground
water exposures for cloquintocet-mexyl and its degradate did not exceed
the exposure allowed by the risk cup. The chronic dietary exposures for
all sub-populations provided DWLOC values of 224 to 1,396 ppb. The
estimated chronic exposures from drinking surface and ground water were
0.00316 ppb and 0.006166 ppb, respectively. Therefore, the estimated
acute and chronic drinking water exposures of cloquintocet-mexyl and
its degradate did not exceed the exposures allowed by the risk cup.
2. Non-dietary exposure. Exposure to cloquintocet-mexyl for the
mixer/loader/ground-boom/aerial applicator and flagger was calculated
using the pesticide handlers exposure data base. It was assumed that
the product would be applied 6 days per year by ground-boom application
to a maximum of 80 acres per day by the grower, 15 days per year by
ground-boom application to a maximum of 80 acres per day by the
commercial ground-boom applicator, and 15 days per year to a maximum of
350 acres per day by the aerial applicator, at a maximum use rate of
7.1 grams 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. Short-term and intermediate-term dermal and inhalation
risk assessments were performed. Doses and endpoints used for risk
assessments were based on Agency determined toxicological endpoints
recommended by the HIARC. The NOAEL of 200 mg/kg/day from the 28-day
rat dermal toxicity study was used for short-term and intermediate-term
dermal risk assessments. The NOAEL of 100 mg/kg/day from the
developmental toxicity study in rats was used for short-term inhalation
risk assessments. The NOAEL of 4.3 mg/kg/day from the 2-year chronic
toxicity study in rats was used for intermediate-term risk assessments.
Based on the use pattern, no long-term dermal or inhalation exposure is
expected to occur and long-term risk assessments are not required.
Large margins of exposure (MOE) exist for all occupational exposure
scenarios. Short-term dermal exposure MOEs ranged from 6.4E+04 for the
commercial open mixer-loader to 2.8E+06 for the commercial or grower
groundboom enclosed-cab applicator. Intermediate-term dermal exposure
MOEs ranged from 1.6E+06 for the commercial open mixer-loader to
1.7E+08 for the grower ground-boom enclosed-cab applicator. Short-term
inhalation exposure MOEs ranged from 2.8E+06 for the commercial open
mixer-loader to 1.3E+08 for the commercial or grower ground-boom
enclosed-cab applicator. Intermediate-term inhalation exposure MOEs
ranged from 3.0E+06 for the commercial open mixer-loader to 3.4E+08 for
the grower ground-boom enclosed-cab applicator.
Although there are no residential uses of cloquintocet-mexyl, there
is potential for residential exposure to spray drift resulting from
aerial application. No standard operating procedure exists for
performing this risk assessment; however, a very conservative risk
assessment was performed assuming dermal exposure equal to total
deposition to outside clothing for a flagger as well as inhalation
exposure equivalent to a pesticide flagger, as reflected in PHED. A
dermal absorption factor of 100% and offsite drift of 15% were assumed.
The area assumed to be adjacent to the sensitive area was one acre.
Large MOEs exist for this potential exposure scenario. Dermal exposure
MOEs were 2.4E+07 for a 15 kg child and 1.1E+08 for a 70 kg adult.
Inhalation MOEs were 1.8E+09 for a 15 kg child and 8.6E+09 for a 70 kg
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. Acute and chronic dietary exposure is minimal
for cloquintocet-mexyl and corresponding hydrolysis product, CGA-
153433. Both chronic and acute exposure estimates at the 95th
percentile showed that less than 1.0% of the reference dose is utilized
in all populations. These exposure estimates are extremely conservative
and are based on tolerance-level residues and assume all planted acres
Exposure through the consumption of drinking water is minimal from
both surface water and ground water model estimates and in all cases
less than 1% of the risk cup is utilized. The estimated water
concentrations are very conservative since conservative model
parameters were assumed.
There are no residential uses of cloquintocet-mexyl that would
result in non-dietary exposure. However, there is a remote possibility
that spray drift resulting from aerial application could lead to
residential exposure. Since exposure from spray drift would be an
unlikely event, it is not appropriate to include non-dietary exposure
into the aggregate assessment. Therefore, it is concluded that there is
a more than 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
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 NOAEL 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 maternal
NOAEL was 60 mg/kg/day, but the developmental NOAEL was > 300 mg/kg/
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 parental and developmental NOAEL was 5,000
ppm, corresponding to a mean daily intake of 370 to 422 mg/kg/day of
cloquintocet-mexyl. The reproductive NOAEL was > 10,000 ppm (722 mg/kg/
day). 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 prenatal and postnatal toxicity and the completeness of
the data base. Based on the current toxicological data requirements,
the data base relative to prenatal and postnatal effects for children
is complete. EPA's HIARC concluded that there was no concern for an
increased susceptibility for cloquintocet-mexyl based on the
reproduction study in rats and the developmental studies in rat and
rabbit. Further, for cloquintocet-mexyl, the NOAEL of 4.3 mg/kg/day
from the combined chronic/oncogenicity study in rats, which was used to
calculate the RfD, is already lower than the developmental NOAEL of 100
mg/kg/day for the rat developmental toxicity study. Further, the
developmental and parental NOAEL of 370 mg/kg/day from the
cloquintocet-mexyl reproduction study is nearly 100 times greater than
the NOAEL for the combined chronic/oncogenicity rat study. These data
would indicate that there is no additional sensitivity of infants and
children to cloquintocet-mexyl. Therefore, it is concluded that an
additional UF is not warranted to protect the health of infants and
children from the use of cloquintocet-mexyl.
Using conservative exposure assumptions, dietary exposure to the
most sensitive subpopulation, children (1-6 years old), is 0.9% of the
chronic reference dose (RfD). Chronic dietary exposure to infants (non-
nursing, 1-6 years old) is 0.2% of the chronic RfD. EPA's HIARC
concluded that no acute dietary assessment was necessary for the
general population (infants and children) because a suitable
toxicological endpoint (resulting from a single dose exposure) was not
identified in either the rat or rabbit developmental studies.
Although not required, acute dietary exposure to infants and
children was assessed. Acute exposures for all infants and children at
the 95th percentile are less than 1.0% of the acute RfD
(0.08% of the RfD for the most sensitive subpopulation, children 1-6
years). Exposures to drinking water for children (1-6 years old) and
infants utilize less than 1% of the chronic and acute RfD values
(worst-case surface water estimates). These results show that aggregate
exposure to residues of cloquintocet-mexyl in the diet and drinking
water is negligible. Based on the completeness and reliability of the
toxicity data and the conservative nature of the exposure assumptions,
it is concluded that there is a more than reasonable certainty that no
harm will result to infants and children from exposure to residues of
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 RACs.
[FR Doc. 00-9796 Filed 4-18-00; 8:45 am]
BILLING CODE 6560-50-F