[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:

------------------------------------------------------------------------
  Product Manager/Regulatory       Office location/                     
            Leader                 telephone number          Address    
------------------------------------------------------------------------
Marion Johnson (PM 10)........  Rm. 210, CM #2, 703-    1921 Jefferson  
                                 305-6788, e-            Davis Hwy,     
                                 mail:johnson.marion@e   Arlington, VA  
                                 pamail.epa.gov.                        
Indira Gairola (Reg. Leader)..  4th floor, CS #1, 703-  2800 Crystal    
                                 308-8371, e-mail:       Drive,         
                                 gairola.indira@epamai   Arlington, VA  
                                 l.epa.gov.                             
------------------------------------------------------------------------

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:
    [email protected]


    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