[Federal Register Volume 62, Number 119 (Friday, June 20, 1997)]
[Notices]
[Pages 33641-33647]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-16213]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-743; FRL-5723-7]
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-743, must
be received on or before July 21, 1997.
ADDRESSES: By mail submit written comments to: Public Information and
Records Integrity Branch (7506C), Information Resources and Services
Division, Office of Pesticides Programs, Environmental Protection
Agency, 401
[[Page 33642]]
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 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/Regulatory Leader
listed in the table below:
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Product Manager/Regulatory Office location/
Leader telephone number Address
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Marion Johnson (PM 10)........ Rm. 210, CM #2, 703- 1921 Jefferson
305-6788, e- Davis Hwy,
mail:[email protected] Arlington, VA
pamail.epa.gov.
Indira Gairola (Reg. Leader).. 4th floor, CS #1, 703- 2800 Crystal
308-8371, e-mail: Drive,
[email protected] 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-743] (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 [PF-743] and appropriate petition
number. Electronic comments on this 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: June 12,1997
James Jones,
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.
1. Rhone-Poulenc Ag Company
PP-7F4832
EPA has received pesticide petition PP-7F4832 from Rhone-Poulenc Ag
Company, P.O. Box 12014, 2 T.W. Alexander Drive, Research Triangle
Park, NC 27709. This petition proposes, pursuant to section 408(d) of
the Federal Food, Drug and Cosmetic Act (FFDCA), 21 U.S.C.346a, to
amend 40 CFR part 180 by establishing a tolerance for the combined
residues of the insecticide fipronil (5-amino-1-[2,6-dichloro-4-
(trifluoro-methyl)phenyl]-4-[1R, S)-(trifluoromethyl)sulfinyl]-1H-
pyrazole-3-carbonitrile) and its metabolites 5-amino-1-[2,6-dichloro-4-
(trifluoromethyl)phenyl]-4-[(trifluoromethyl) sulfonyl]-1H-pyrazole-3-
carbonitrile; and 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-
[(trifluoromethyl)thio]-1H-pyrazole-3-carbonitrile; and 5-amino-1-[2,6-
dichloro-4-(trifluoromethyl)phenyl]-4-[(1RS)-(trifluoromethyl)]-1H-
pyrazole-3-carbonitrile on or in the following raw agricultural
commodities: potatoes at 0.02 parts per million (ppm), sweet potatoes
at 0.02 ppm, rice grain at 0.02 ppm, rice straw at 0.10 ppm, cottonseed
at 0.05 ppm, and cotton gin trash at 3.0 ppm. The proposed analytical
method is by gas chromatography using a Ni63 electron capture or mass
selective detector. EPA has determined that the petitions contain 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
this petition. Additional data may be needed before EPA rules on the
petition.
A. Residue Chemistry
1. Metabolism. The metabolism of fipronil is adequately
understood. Adequate data on the nature of the residues in both plant
and animals, including identification of major metabolites and
degradates of fipronil, are available. In plants and animal the
metabolism of fipronil proceeds via oxidation of the sulfoxide to yield
sulfone MB 46136 and hydrolysis of nitrile to yield amide RPA 200766. A
limited amount of reduction of sulfoxide to yield sulfide MB 45950
occurs in some cases. In cases where
[[Page 33643]]
fipronil is exposed to light for extended periods of time (i.e., foliar
applications), photo products MB 46513 and RAP 104615 are often
observed. Further transformation of the primary metabolites affords
minor amounts of carboxylic acid RPA 200761, amide RPA 105320 and 4-
protiopyrazole MB 45897.
2. Practical analytical method. Validated analytical methods are
available for detecting and measuring levels of fipronil and its
metabolites in field corn, cotton, potato and rice raw agricultural
commodities and their respective processing fractions and animal
tissues. Residues are extracted from corn grain, fodder and forage with
75:25 acetonitrile: water and from the remaining corn substrates with
acetonitrile. Acetonitrile: water is also used to extract residues from
cottonseed, cotton gin by-products (gin trash), hulls and meal and rice
grain and straw. An aliquot of the extract is partioned against hexane
to remove lipids. After the addition of water and the removal of
acetonitrile, fipronil and its metabolites are then partitioned into
dichloromethane. Column chromatography is utilized for clean up /
removal of coextractive unknowns. For potato tubers, wet peel, dry
peel, flakes and chips and animal tissues, the extraction solvent is a
mixture of acetonitrile:acetone (70:30). Samples clean up is effected
by column chromatography. Quantification of fipronil and its
metabolites is accomplished by gas chromatography using a Ni63 electron
capture or mass selective detector.
B. Toxicology Profile
1. Acute toxicity. The acute oral LD50 in rats is 97 mg/
kg. The dermal LD50 values in rats and rabbits are greater
than 2,000 mg/kg and 354 mg/kg, respectively. The inhalation
LC50 for a 4-hour exposure (nose only) is 0.39 mg/L. Slight
skin and moderate eye irritation are observed in rabbits with complete
clearing within 7 days for skin and 14 days for eye. Fipronil is not a
dermal sensitizer in guinea pigs (Buehler method).
2. Genotoxicity. Fipronil was negative in both in vitro and in vivo
assays conducted to investigate gene mutations, DNA damage, and
chromosomal aberrations.
3. Developmental/reproductive effects. Rat and rabbit
developmental toxicity studies were negative at doses up to 20 mg/kg/
day and 1 mg/kg/day, respectively. In a two-generation rat study, the
NOEL for reproductive toxicity was 30 ppm (2.64 mg/kg/day for both
sexes combined).
4. Subchronic effects. The NOELs in rats and dogs were 5 ppm (0.35
mg/kg/day for both sexes combined) and 2 mg/kg/day, respectively.
5. Chronic effects. The NOELs in 1-year dietary dog and 2-year
dietary rat studies were 0.3 mg/kg/day and 0.5 ppm, respectively, based
on clinical signs. The chronic Reference Dose (RfD) of 0.0002 mg/kg/day
established by EPA is based on the NOEL from the chronic rat study
(equivalent to 0.02 mg/kg/day in male rats and 0.03 mg/kg/day in female
rats) divided by an uncertainty factor of 100 to account for inter- and
intra-species variation.
6. Carcinogenicity. Fipronil was not carcinogenic when
administered to mice at any dose level tested. In rats, thyroid tumors
were observed only at 300 ppm (highest dose tested) (HDT). Mechanistic
data indicate that these tumors are related to an imbalance of thyroid
hormones and are specific to the rat. EPA's Health Effects Division
Carcinogenicity Peer Review Committee classified fipronil in Group C
and recommended that RfD methodology, i.e. non-linear or threshold, be
used for the estimation of human risk.
7. Endocrine effects. No evidence of estrogenic or androgenic
effects were noted in any study with fipronil. No adverse effects on
mating or fertility indices and gestation, live birth, or weaning
indices were noted in a two-generation rat reproduction study. In a
developmental neurotoxicity study, devlopment of pups was delayed only
at a dose producing maternal toxicity which resulted in smaller, less
developed pups. However, even in the presence of maternal toxicity, the
pups developed fully and were comparable to controls by study
termination.
C. Aggregate exposure/cumulative effects
1. Dietary exposure. A chronic dietary assessment for fipronil use
in/on corn demonstrates that the most realistic scenario, i.e.
anticipated residues with estimated market share, results in exposures
of less than 32% of the RfD for all subgroups including the most
sensitive subgroup, children 1 to 6 years of age. Therefore, chronic
dietary exposure to fipronil residues from both primary and secondary
sources, as a result of its use on field corn, potatoes, rice, and
cotton does not represent a significant risk to any segment of the
population.
An acute dietary analysis using tolerances, 100% market share, and
a NOAEL of 5.0 mg/kg from the acute neurotoxicity study results in
Margins of Exposure (MOEs) for all segments of the population of over
2,000 for the 95th percentile and over 1,000 for both the 99th and
99.9th percentile. A more realistic assessment using anticipated
residues would result in considerably higher MOEs. However, even with
extremely conservative assumptions, sufficient MOEs exist for acute
dietary exposure to fipronil residues from both primary and secondary
sources. Therefore, fipronil use on field corn, potatoes, rice, and
cotton does not represent a significant acute dietary risk to any
segment of the population.
2. Drinking water exposure. The combined factors of low mobility,
moderate persistence, and low application rates result in fipronil and
its metabolites having little potential to reach groundwater as a
result of movement through the soil profile or of surface run-off.
Thus, the potential for ground water and/or surface water contamination
by fipronil and its degradates is expected to be very low.
3. Non-occupational exposure . Fipronil is currently registered
for use on golf and commercial turfgrass under the brand name CHIPCO
CHOICETM and for treatment of cats and dogs for fleas and ticks under
the brand name FRONTLINE. These uses are not expected to contribute
significantly to overall exposure. Fipronil has an extremely low vapor
pressure and low dermal penetration. These properties minimize the
amount of actual exposure that might occur. The application of fipronil
on golf and commercial turf using a slit applicator which places the
granule well into or below the thatch reduces the likelihood of post
application exposure. Further, as these areas have only limited human
activity involving minimal dermal contact with treated turf, potential
exposure is expected to be negligible. Exposure due to the application
of FRONTLINE is also expected to be low. The particle size
characteristics of the spray product result in negligible inhalation
exposure while the use of gloves, as required on the label in
conjunction with the low dermal penetration rate of fipronil, result in
minimal exposure via the dermal route. The affinity of fipronil for the
sebum and hair of animals and its one to three month efficacy indicate
that the material remains on the pet and is not bioavailable to those
coming in contact with the pet. Pending uses which include use of
fipronil as a termiticide and use in ant/roach baits are also
anticipated to present negligible exposure.
4. Cumulative risk. Fipronil belongs to a novel chemical class of
insecticides known as phenylpyrazoles. It is the only compound from
this class of chemistry registered for use as an insecticide.
[[Page 33644]]
Fipronil exhibits a mode of action different from traditional
organophosphate, carbamate, or pyrethroid insecticides. Fipronil acts
by binding within the chloride channel of the GABA receptor. There is
no indication that effects from fipronil would be cumulative with any
other pesticide.
D. Safety Determinations
1. U.S General population. Both aggregate and dietary exposure
assessments demonstrate that all current and pending uses of fipronil
do not pose any significant risk to the general population. Therefore,
based on a very complete database, there is reasonable certainty that
no harm will result from aggregate exposure to the chemical residue
including all anticipated dietary exposures and all other exposures for
which there is reliable information.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of fipronil, the
available developmental and reproductive toxicity studies were
considered. Developmental toxicity studies in two species indicate that
fipronil has no teratogenic potential at any dose level. Further, no
adverse effects on fetal development were observed in rats or rabbits
even in the presence of maternal toxicity. In a two-generation rat
reproduction study, effects on pups were seen only at the highest dose
tested in the presence of parental toxicity. In a developmental
neurotoxicity study, development of pups was delayed only at a dose
producing maternal toxicity which resulted in smaller, less developed
pups. However, even in the presence of maternal toxicity, the pups
developed fully and were comparable to controls by study termination.
Thus, maternal and developmental NOELs and LELs were comparable in all
studies indicating no increase susceptibility of developing organisms.
Further, the NOEL of 0.02 mg/kg/day from the 2-year rat study, which
was used to calculate the RfD for fipronil, is already lower than the
NOELs from developmental studies by a factor of 45 to 1,000 times. As a
hundredfold uncertainty factor is already used to calculate the RfD
which is based on a NOEL significantly lower than NOELs from all
developmental and reproductive studies, an additional uncertainty
factor is not warranted and the RfD of 0.0002 mg/kg/day is appropriate
for assessing risk to infants and children.
E. International Tolerances
There are no Codex maximum residue levels established for fipronil.
(Marion Johnson)
2. Rhone-Poulenc Ag Company
PP-5F4426
EPA has received pesticide petition (PP) 5F4426 from Rhone-Poulenc
Ag Company, P.O. Box 12014, 2 T.W. Alexander Drive, Research Triangle
Park, NC 27709. This petition proposes, pursuant to section 408(d) of
the Federal Food, Drug and Cosmetic Act (FFDCA), 21 U.S.C. 346a, to
amend 40 CFR part 180 by establishing a tolerance for the combined
residues of the insecticide fipronil (5-amino-1-[2,6-dichloro-4-
(trifluoromethyl)phenyl]-4-[1R, S)-(trifluoromethyl)sulfinyl]-1H-
pyrazole-3-carbonitrile) and its metabolites 5-amino-1-[2,6-dichloro-4-
(trifluoromethyl)phenyl]-4-[(trifluor omethyl) sulfonyl]-1H-pyrazole-3-
carbonitrile; and 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-
[(trifluoromethyl)thio]-1H-pyrazole-3-carbonitrile on or in the
following raw agricultural commodities: corn grain at 0.02 parts per
million (ppm), corn forage at 0.15 ppm and corn stover at 0.15 ppm; in
the animal product commodities of cattle, goats, horses and sheep: fat
at 0.40 ppm, liver at 0.10 ppm, meat at 0.04 ppm, meat by-products
(except liver) at 0.04 ppm, beef kidney at 0.03 ppm, and milk fat at
0.70 ppm; in the animal product commodities of hogs: fat at 0.04 ppm,
liver at 0.02 ppm, meat at 0.01 ppm and meat by-products (except liver)
at 0.01 ppm; in the animal product commodities of poultry: eggs at 0.03
ppm, fat at 0.05 ppm and meat at 0.02 ppm. The proposed analytical
method is by gas chromatography using a Ni63 electron capture or mass
selective detector. EPA has determined that the petitions contain 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 this petition. Additional data may be needed before EPA rules on the
petition.
As required by section 408(d) of the FFDCA, as recently amended by
the Food Quality protection Act (FQPA), Rhone-Poulenc Ag Company
included in the petition a summary of the petition and authorization
for the summary to be published in the Federal Register in a notice of
receipt of the petition. The summary represents the views of Rhone-
Poulenc Ag Company; EPA is in the process of evaluating the petition.
As required by section 408 (d)(3), EPA is including the summary as a
part of this notice of filing. EPA may have made minor edits to the
summary for the purpose of clarity.
A. Residue Chemistry
1. Metabolism. The metabolism of fipronil is adequately understood.
Adequate data on the nature of the residues in both plant and animals,
including identification of major metabolites and degradates of
fipronil, are available. In plants and animal the metabolism of
fipronil proceeds via oxidation of the sulfoxide to yield sulfone and
hydrolysis of nitrile to yield the amide. Fipronil and its sulfone and
amide constitute greater than 75% of the identified residues in all
studies. A limited amount of reduction of sulfoxide to yield the
sulfide occurs in some cases. Further transformation of the primary
metabolites affords minor amounts of the carboxylic acid, the amide and
the 4-protiopyrazole.
2. Practical analytical method. A validated analytical method is
available for detecting and measuring levels of fipronil and its
metabolites in field corn raw agricultural commodities (grain, forage
and fodder) and its processing fractions (oil and starch). Residues are
extracted from corn grain, fodder and forage with 75:25
acetonitrile:water and from the remaining corn substrates with
acetonitrile. An aliquot of the extract is partitioned against hexane
to remove lipids. After the addition of water and the removal of
acetonitrile, fipronil and its metabolites are partitioned into
dichloromethane. Column chromatography is utilized for clean up /
removal of coextractive unknowns. Quantification of fipronil and its
metabolites is accomplished by gas chromatography using a Ni63 electron
capture or mass selective detector.
B. Toxicology Profile
1. Acute toxicity. The acute oral LD50 in rats is 97 mg/
kg. The dermal LD50 values in rats and rabbits are greater
than 2,000 mg/kg and 354 mg/kg, respectively. The inhalation
LC50 for a 2-hour exposure (nose only) is 0.39 mg/L. Slight
skin and moderate eye irritation are observed in rabbits with complete
clearing within 7 days for skin and 14 days for eye. Fipronil is not a
dermal sensitizer in guinea pigs (Buehler method).
2. Genotoxicity. Fipronil was negative in both in vitro and in vivo
assays conducted to investigate gene mutations, DNA damage, and
chromosomal aberrations.
3. Developmental/reproductive effects. Rat and rabbit developmental
[[Page 33645]]
toxicity studies were negative at doses up to 20 mg/kg/day and 1 mg/kg/
day, respectively. In a 2-generation rat study, the NOEL for
reproductive toxicity was 30 ppm (2.64 mg/kg/day for both sexes
combined).
4. Subchronic effects. The NOELs in rats and dogs were 5 ppm (0.35
mg/kg/day for both sexes combined) and 2 mg/kg/day, respectively.
5. Chronic effects. The NOELs in 1-year dietary dog and 2-year
dietary rat studies were 0.3 mg/kg/day and 0.5 ppm, respectively, based
on clinical signs. The chronic Reference Dose (RfD) of 0.0002 mg/kg/day
established by EPA is based on the NOEL from the chronic rat study
(equivalent to 0.02 mg/kg/day in male rats and 0.03 mg/kg/day in female
rats) divided by an uncertainty factor of 100 to account for inter- and
intra-species variation.
6. Carcinogenicity. Fipronil was not carcinogenic when administered
to mice at any dose level tested. In rats, thyroid tumors were observed
only at 300 ppm (HDT). Mechanistic data indicate that these tumors are
related to an imbalance of thyroid hormones and are specific to the
rat. EPA's Health Effects Division Carcinogenicity Peer Review
Committee classified fipronil in Group C and recommended that RfD
methodology, i.e. non-linear or threshold, be used for the estimation
of human risk.
7. Endocrine effects. No evidence of estrogenic or androgenic
effects were noted in any study with fipronil. No adverse effects on
mating or fertility indices and gestation, live birth, or weaning
indices were noted in a two-generation rat reproduction study. In a
developmental neurotoxicity study, development of pups was delayed only
at a dose producing maternal toxicity which resulted in smaller, less
developed pups. However, even in the presence of maternal toxicity, the
pups developed fully and were comparable to controls by study
termination.
C. Aggregate Exposure/Cumulative Effects
1. Dietary exposure. A chronic dietary assessment for fipronil use
in/on corn demonstrates that the most realistic scenario, i.e.
anticipated residues with estimated market share, results in exposures
of less than 3% of the RfD for all subgroups including the most
sensitive subgroup, children 1 to 6 years of age. Scenarios using
tolerances and estimated market share, as well as anticipated residues
and 100% crop treated, demonstrated exposures of less than 40% of the
RfD for the most sensitive subgroup (children 1 to 6 years of age) and
less than 15% of the RfD for the US population in general. Therefore,
chronic dietary exposure to fipronil residues from both primary and
secondary sources, as a result of its use on field corn, does not
represent a significant risk to any segment of the population.
An acute dietary analysis using tolerances, assuming fipronil in
milk fat only with a tolerance of 0.7 ppm, 1989-92 consumption data,
and a NOAEL of 5.0 mg/kg from the acute neurotoxicity study results in
Margins of Exposure (MOEs) for all segments of the population of over
2,000 for the 95th percentile and over 1,000 for both the 99th and
99.9th percentile. A more realistic assessment using anticipated
residues would result in considerably higher MOEs. However, even with
extremely conservative assumptions, sufficient MOEs exist for acute
dietary exposure to fipronil residues from both primary and secondary
sources. Therefore, fipronil use on field corn does not represent a
significant acute dietary risk to any segment of the population.
2. Drinking water exposure. The combined factors of low mobility,
moderate persistence, low application rates, and in-furrow application
result in fipronil and its metabolites having little potential to reach
groundwater as a result of movement through the soil profile or of
surface run-off. Thus, the potential for ground water and/or surface
water contamination by fipronil and its degradates is expected to be
very low.
3. Non-occupational exposure. Fipronil is currently registered for
use on golf and commercial turfgrass under the brand name CHIPCO
CHOICETM and for treatment of cats and dogs for fleas and ticks under
the brand name FRONTLINE . These uses are not expected to contribute
significantly to overall exposure. Fipronil has an extremely low vapor
pressure and low dermal penetration. These properties minimize the
amount of actual exposure that might occur. The application of fipronil
on golf and commercial turf using a slit applicator which places the
granule well into or below the thatch reduces the likelihood of post
application exposure. Further, as these areas have only limited human
activity involving minimal dermal contact with treated turf, potential
exposure is expected to be negligible. Exposure due to the application
of FRONTLINE is also expected to be low. The particle
sizecharacteristics of the spray product result in negligible
inhalation exposure while the use of gloves, as required on the label
in conjunction with the low dermal penetration rate of fipronil, result
in minimal exposure via the dermal route. The affinity of fipronil for
the sebum and hair of animals and its one to three month efficacy
indicate that the material remains on the pet and is not bioavailable
to those coming in contact with the pet. Pending uses which include use
of fipronil as a termiticide and use in ant/roach baits are also
anticipated to present negligible exposure.
4. Cumulative risk. Fipronil belongs to a novel chemical class of
insecticides known as phenylpyrazoles. It is the only compound from
this class of chemistry registered for use as an insecticide. Fipronil
exhibits a mode of action different from traditional organophosphate,
carbamate, or pyrethroid insecticides. Fipronil acts by binding within
the chloride channel of the GABA receptor. There is no indication that
effects from fipronil would be cumulative with any other pesticide.
D. Safety Determinations
5. U.S. general population. Both aggregate and dietary exposure
assessments demonstrate that all current and pending uses of fipronil
do not pose any significant risk to the general population. Therefore,
based on a very complete database, there is reasonable certainty that
no harm will result from aggregate exposure to the chemical residue
including all anticipated dietary exposures and all other exposures for
which there is reliable information.
6. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of fipronil, the
available developmental and reproductive toxicity studies were
considered. Developmental toxicity studies in two species indicate that
fipronil has no teratogenic potential at any dose level. Further, no
adverse effects on fetal development were observed in rats or rabbits
even in the presence of maternal toxicity. In a two-generation rat
reproduction study, effects on pups were seen only at the highest dose
tested in the presence of parental toxicity. In a developmental
neurotoxicity study, development of pups was delayed only at a dose
producing maternal toxicity which resulted in smaller, less developed
pups. However, even in the presence of maternal toxicity, the pups
developed fully and were comparable to controls by study termination.
Thus, maternal and developmental NOELs and LELs were comparable in all
studies indicating no increase susceptibility of developing organisms.
Further, the NOEL of 0.02 mg/kg/day from the 2-year rat study, which
was used to calculate the RfD for fipronil, is already lower
[[Page 33646]]
than the NOELs from developmental studies by a factor of 45 to 1,000
times. As a hundredfold uncertainty factor is already used to calculate
the RfD which is based on a NOEL significantly lower than NOELs from
all developmental and reproductive studies, an additional uncertainty
factor is not warranted and the RfD of 0.0002 mg/kg/day is appropriate
for assessing risk to infants and children.
E. International Tolerances
There are no Codex maximum residue levels established for fipronil.
(Marion Johnson)
3. Zeneca Ag Products
PP-6E4675
EPA has received a pesticide petition (PP 6E4675) from Zeneca Ag
Products, 1800 Concord Pike, P.O. Box 15458, Wilmington, Delaware
19850-5458, proposing pursuant to 408(e) of the Federal Food, Drug, and
Cosmetic Act, 21 U.S.C. 346a(e), to amend 40 CFR 180.1001(d) by
establishing an exemption from the requirement for a tolerance for
residues of the inert ingredient titantium dioxide when used in
pesticide formulations used on growing crops.
Pursuant to section 408 (d)(2)(A)(i) of the FFDCA, as amended,
Zeneca Ag Products has submitted the following summary of information,
data and arguments in support of their pesticide petition. This summary
was prepared by Zeneca and EPA has not fully evaluated the merits of
the petition. EPA edited the summary to clarify that the conclusions
and arguments were the petitioner's and not necessarily EPA's.
A. Residue Chemistry
Titanium(Ti) is the eighth most abundant element in the earth's
crust and consequently spontaneously enters the food chain to some
degree. Humans are estimated to consume approximately 300 g
Ti/day in food. Since the various forms of titanium, including titanium
dioxide, are so abundant as a background element, estimations of
residues resulting from use as an inert ingredient in a pesticide
formulation would not be of value in determining the overall impact of
this particular use.
Analytical method. There are two approved AIHA methods for analysis
of titanium residues: (1) Hydrogen peroxide colormetric method with a
sensitivity of 2 g Ti; and (2) Atomic absorption with a
sensitivity of 1.9 g/ml.
B. Toxicological Profile
Titanium dioxide (TiO2) is the most commercially
important of all the titanium compounds. TiO2 is an opaque
powder that is approved for use as a colorant in cosmetics (21 CFR
73.2575 and 21 CFR 73.3126), pharmaceuticals (21 CFR 73.575) and foods,
as well as in an extensive range of industrial uses (e.g. paper,
paints, enamels and plastics) throughout the world. Titanium dioxide is
exempt from the requirement for a tolerance when used as a colorant in
pesticide formulations (40 CFR 180.1001). In the Federal Register of
June 20, 1988, EPA announced that it was deleting titanium dioxide from
the list of toxic chemicals under section 313 of Title III of the
Superfund Amendments. This rule concluded that titanium dioxide will
not cause significant adverse effects to humans or to the environment.
The wide range of relatively unrestricted uses of titanium dioxide
reflects the fact that the compound is held to be toxicologically
inert, belonging to that group of materials classified as
Generally Accepted as Safe (GRAS). The scientific
committee on food coloring materials determined that no ADI need be set
for the use of titanium dioxide, as its use does not present any health
concerns (1983). Indeed, titanium dioxide is frequently used as a
negative control material in vivo chronic dust exposure studies and in
vivo assessments of fibrogenic potential of dusts.
1. Acute toxicity. Titanium dioxide (TiO2) has very low
acute toxicity with no deaths in rats administered as much as 24 grams/
Kg. No overt signs of toxicity occurred in a person that ingested
approximately 1 pound of TiO2. Skin and eye contact to the
dry powder produced no irritation to the skin and very slight
irritation to the eyes. An acute 4-hour inhalation exposure at
concentrations of 6.82 mg/L produced no mortalities. Intratracheal
administration also indicated a low level of acute toxicity. In a 2-
week inhalation study, rats exposed to 1.92 mg/L showed a typical dust-
cell reaction. Additionally, only a typical dust-cell reaction was
noted in rats exposed to 1 mg/L from 4-weeks up to 1-year.
2. Genotoxicity. Titanium dioxide has no genotoxic potential as
judged from unequivocal negatives in a range of studies in vitro and in
vivo.
3. Reproductive and developmental toxicity. No relevant data are
available for this material. However, the OECD Screening Information
Data Set (SIDS) Manual for 1996, which contains chemical data and
regulatory decisions agreed by scientists within the European
Community, stated that due to a lack of toxicity resulting from
subchronic and chronic exposure to titanium dioxide, specific testing
for reproductive and developmental toxicity were not required for
TiO2.
4. Subchronic toxicity. Repeated doses ranging from 800 to 1,500
mg/kg of Titanium dioxide for 2-13 months did not produce adverse
effects in all species tested. Some of these studies were limited in
terms of the number of animals used ( group sizes were 1 to 4).
In a comprehensive study reported as part of the NCI program,
groups of 50 male and 50 female F344 rats or B6C3F1 mice were fed diets
containing 25,000 or 50,000 ppm titanium dioxide for 103 weeks. Even
though these doses (equivalent to 1.25 g/kg or 2.5 g/kg in rats and
3.75 g/kg or 7.5 g/kg in mice) were very high (well in excess of the
modern guideline limit dose of 20,000 ppm in rat or 7,000 ppm in
mouse), there was no significant evidence of chronic toxicity.
5. Chronic toxicity --a. Carcinogenicity. In an NCI study groups of
50 male and 50 female F344 rats or B6C3F1 mice were fed diets
containing 25,000 ppm or 50,000 ppm titanium dioxide for 103 weeks.
There were no compound-related increases in tumors. There was a non-
statistically significant increase in C-cell adenoma and of thyroid
carcinoma in female rats which, it was concluded, was unrelated to
titanium dioxide.
In a study in which F344 rats were fed diets containing up to 5%
mica coated with titanium dioxide there was no increase in tumors. In
addition, there were no tumors in rats or mice injected
intraperitoneally (single or multiple doses) or subcutaneously and
observed for periods of 18 months or longer.
There are no epidemiological studies following purely oral exposure
to titanium dioxide. However, in studies of factory workers exposed to
titanium dioxide dust (primarily via inhalation) there was no evidence
of increased cancers.
b. Pulmonary effects of eitanium dioxide. TiO2 is
considered generally to be inert and this is confirmed by the very low
acute inhalation toxicity (LC50 6.82 mg/L). Single
administration of TiO2 by intratracheal instillation may
produce changes in the alveolar cell population, lung lining fluid
components and lung tissues. Such changes, the majority of which
reversed rapidly even with very high lung loading, were consistent with
administration of a relatively high dose of an inert, insoluble dust
into the lung. The acceptance that TiO2 is relatively inert
in the lung has led to the use of this as a negative control in many
studies investigating the pulmonary
[[Page 33647]]
effects of particles. Results in the majority of these studies are
again consistent with the inert nature of this material.
A number of repeat exposure inhalation studies have been conducted
to investigate either the inherent toxicity of TiO2 or again
to investigate the response of the lung to exposure to inert particles.
The majority of studies demonstrate that sub-chronic and chronic
exposure to realistic concentrations of TiO2 result in
minimal changes consistent with a steady accumulation of inert
particles in the lung.
In a 2-year inhalation study, groups of 200 rats were exposed 6-
hours a day, 5-days a week to 10, 50 or 250 mg/m of TiO2.
Survival of the exposed animals was comparable to that of the control
group, and there were no compound-related clinical signs of toxicity at
any dose level.
In rats, white foci of accumulated material were apparent on the
visceral surface and throughout the lung parenchyma at gross necropsy.
At 10mg/m this was minimal but marked increases were noted at 50 mg/m
and particularly at 250 mg/m. Microscopically, these foci represented
not only aggregates of dust or dust containing cells but in most
instances the additional biological response of the lung (e.g.
pleurisy, collagenized fibrosis associated with cholesterol granulomas,
alveoli bronchiolarization, pneumonia, and alveolar cell hyperplasia)
to the persistent presence of inert particles. At 250 mg/m in this
study, and at 10 mg/m in a subsequent study using a different type
(ultrafine) of TiO2, resulted in an increased incidence of
lung tumors at termination. These tumors were either broncho-alveolar
or epidermoid/squamous. Such tumors are now known to be a common
response of the lung to excessive lung burdens of insoluble dusts, are
seen only in the rat and are of questionable relevance to man.
A case-control epidemiology study of male employees exposed to
titanium dioxide did not demonstrate an increased risk for lung cancer.
In addition, there was no dose-response relationship between titanium
dioxide exposure and chronic respiratory disease, pleural thickening,
pleural plaques, or pleural nodules.
6. Animal metabolism. Data on the absorption of titanium compounds
is limited. When male and female rats were fed diet containing 100 g
titanium dioxide per kg of diet, for about 32 days, no retention of
titanium occurred in the liver, spleen, kidney, bone, plasma or
erythrocytes. However, there were measurable amounts (0.06 and 0.11 mg/
kg wet weight) in the muscles. Following intravenous injection of 250mg
titanium dioxide/kg to rats, there was an exponential disappearance
rate from the blood with only about 30% remaining after 10 minutes.
Seventy percent of the injected dose was detected in the liver after 5
minutes, rising to almost 80% by 15 minutes. The organ with the next
highest concentration was the spleen, after 6 hours. By 24 hours, the
highest concentration was in the celiac lymph nodes that drain the
lymph from the liver. 1-year after the single injection, the highest
tissue concentrations (178.9 mg/gm) were still in these lymph nodes.
7. Human data. In a study involving five adult males, each of whom
consumed 5g on three consecutive days, there was no significant
increase in urinary content of titanium indicating there had been no
significant absorption/excretion of the compound. However, titanium
dioxide has been found in the lymphatic systems of three workers
employed in processing titanium dioxide pigments, indicating the
compound can access the tissues, following inhalation exposure.
Titanium dioxide is also known to have a long residence time ( in the
order of a year) in the lung.
C. Aggregate Exposure
Titanium dioxide is currently approved for use in a significant
number of pharmaceutical, cosmetic, industrial and food products.
Therefore, the potential for aggregate exposure from dietary and non-
dietary routes does exist for titanium dioxide. However, the use of
titanium dioxide as an inert in a pesticide formulation would not be
expected to significantly raise the background levels found naturally
in the food chain or general environment. Also, since the acute,
subchronic and chronic toxicity testing has shown titanium dioxide to
be physiologically inert, there is no concern for adverse health
effects resulting from potential aggregate exposures.
D. Cumulative effects
Because of the low toxicity of titanium dioxide and because its
presence in the environment is primarily naturally-occurring, Zeneca
does not believe that there is any reason to be concerned about the
potential for cumulative effects of titanium dioxide and other
substances that may have a common mechanism of toxicity.
E. Safety Determination
Titanium dioxide has been shown to be physiologically inert by most
routes of exposure, and is classified as Generally Accepted
as Safe (GRAS). Based on this information, Zeneca believes
that is a reasonable certainty that no harm will result to infants,
children, or the general population from aggregate exposure to titanium
dioxide residues.
F. Existing Tolerances or Tolerance Exemptions
Titanium dioxide is currently approved by FDA for use in foods,
cosmetics and pharmaceuticals. Titanium dioxide also is exempt from the
requirement for a tolerance by EPA for use as a colorant in pesticide
formulations (40 CFR 180.1001). (Indira Gairola)
[FR Doc. 97-16213 Filed 6-19-97; 8:45 am]
BILLING CODE 6560-50-F
