EPA/PPTS-5/1998
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
PRO
*0
OFFICE OF
PREVENTION, PESTICIDES AND
TOXIC SUBSTANCES
MEMORANDUM
DATE:
22-MAY-1998
oo
P.
W
SUBJECT: PP#7F04832. ID#000264-00554. ID#065331-00003. ID#000264-LTT.
Fipronil for use on Rice (Regent®, Icon®) and Pets (Frontline®). HED Risk
Assessment. Chemical 129121. Barcodes D242090, D245656, D245627, &
D241676. Cases 288765, 031271, 060305, & 061662. Submissions S535772,
S541670, S541551,S534929.
FROM: George F. Kramer, Ph.D.
Marion Copley, D.V.M.
Jeffrey Evans, Biologist
Registration Action Branch I
Health Effects Division (7509C)
THROUGH: Melba Morrow, D.V.M., Branch Senior Scientist
Registration Action Branch I ~
Health Effects Division (75 09C)
TO: Susan Lewis, Manager, PM Team 03
Ann Sibold, Reviewer, PM Team 03
Registration Division (7505C)
Rhone-Poulenc AG Company has submitted a petition for the establishment of permanent
tolerances for residues of the insecticide fipronil in/on rice commodities. The proposed
tolerances, expressed as fipronil [5-amino-l-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4-[(lR,S)-
(trifluoromethyl)sulfmyl]-lH-pyrazole-3-carbonitrile] and its metabolites MB 45950 [5-amino-l-
(2,6-dichloro-4-(trifluoromethyl)phenyl)-4-[(trifluoromethyl)thio]-lH-pyrazole-3-carbonitrile];
MB 46136 [5-amino-1 -(2,6-dichloro-4-(trifluoromethyl)phenyl)-4-[(trifluoromethyl)sulfonyl]-
lH-pyrazole-3-carbonitrile]; and MB 46513 [5-amino-l-(2,6-dichloro*4-
(trifluoromethyl)phenyl]-4-[( 1 R,S)-(trifluoromethyl)]-1 H-pyrazole-3-carbonitrile] are:
Rice, grain 0.04 ppm
Rice, straw 0.10 ppm
Internet Address (URL) • http://www.Bpa.gov
R«cycl»d/R*cyclabl« • Printed with Vegetable OK Based Inks on Recyded Pap«r (Minimum 20% Postconsumer)
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The present petition proposes to use an 80% water-dispersible granular (WDG) formulation
(Product name = ICON™ 80"WG Insecticide), a 56"°/o tlbwable solid (FS) formulation (Product
name = ICON™ 6.2 FS Insecticide), and a 56% soluble concentrate (SC) formulation (Product
name = ICON™ 6.2 SC Insecticide), Tolerances for residues of fipronil in/on and animal
commodities have recently been established corn (40 CFR § 180.517(a)). The following are the
tolerances for animal RACs (expressed as parent and metabolites MB 45950 and MB 46136):
i .
Liver" 0.10 ppm j Milk, fat .; 1.50 ppm
! (reflecting 0.05 ppm in whole milk)
Fat* .... 0.40 ppm | Eggs 0.03 ppm
Meat* 0.04 ppm | Poultry Fat 0.05 ppm
Meat Byproducts 0.04 ppm j Poultry Meat 0.02 ppm
(except liver)' j
Hog Fat 0.04 ppm j Poultry Meat Byproducts .. 0.02 ppm
Hog Meat Byproducts .... 0.01 ppm j Hog Liver 0.02 ppm
(except liver)* . ,- j
i
{ Hog Meat . 0.01 ppm
*of cattle, goat, horse and sheep
Three fipronil products are conditionally registered by Rhone-Merial for flea and tick control,
Frontline® Spray Treatment (65331-1), Top Spot™ for Cats (65331-2) and Dogs (65331-3).
These registrations expire on May 31,1998. Merial has submitted several non-dietary exposure
studies to support the permanent registration for use of fipronil on dogs and cats. Two studies
address the application of fipronil: 1) Dermal and Inhalation Exposure of Commercial Pet
Groomers During Application of Frontline Spray Treatment, and 2) Dermal Exposure of
Commercial Pet Groomers During the Application of Frontline Top Spot. Four studies address
the dislodgeable residues of fipronil from dogs and cats following the application of both the
spray treatment and the top spot treatment (MRID# 444333).
Fipronil is also currently registered for use on commercial turf in the U.S. In addition, a petition
for establishment of temporary tolerances in/on cottonseed and cottonseed processing fractions
(PP#5G04583) is currently in reject status pending receipt of revised Sections B and F and
proposed tolerances for milk and eggs (CBTS No. 16288, DP Barcode D219819, G. Kramer,
11/12/96).
A summary of the findings and an assessment of human risk resulting from the proposed use of
fipronil are provided in this document The hazard assessment was provided by Marion Copley,
D.V.M. of RAB1; the product and residue chemistry data review by George Kramer, Ph.D. and
Susie Chun of RAB1; the incident data review by Virginia A. Dobozy, V.M.D., M.P.H. of HED;
the dietary risk assessment by Andrew Rathman of RABland Brian Steinwand of CEB1; the
drinking water exposure assessment by Gail Maske and Jim Hetrick of EFED; the occupational
exposure assessment by Jeffrey Evans of RAB1.
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1
TABLE OF CONTENTS
I. EXECUTIVE SUMMARY 6
II. BACKGROUND 8
III. SCIENCE ASSESSMENT 9
A. Physical and Chemical Properties Assessment 9
1. Identification of Active Ingredients 9
2. Structural Formulae (Fipronil and Metabolites) .9
3. Physical and Chemical Properties 10
B. Human Risk Assessment 11
1. Hazard Assessment 11
a. Acute Toxicity 12
b. Subchronic Toxicity 13
c. Chronic Toxicity .......... 16
d. Developmental Toxicity 17
e. Reproductive Toxicity , 19
f. Neurotoxicity 20
g. Mutagenicity ., 23
h. Metabolism 24
i. Dermal Absorption 26
j. Special Studies 27
k. Other Toxicological Considerations 29
2. Dose Response Assessment 30
FIPRONIL 31
a. Special Sensitivity to Infants and Children •.....'..,*.., 31
b. Reference Dose (RfD) _..' 33
c. Carcinogenic Classification and Risk Quantification 34
d. Dermal Absorption .* 34
e. Other Toxicological Endpoints 34
i. Acute Dietary 34
ii. Short- and Intermediate-Term Occupation and Residential 35
iii. Chronic Occupation and Residential (Non-Cancer) 35
iv. Inhalation Exposure (Any time period) .'35
MB46513 '.- 37
a. Special Sensitivity to Infants and Children 37
b. Reference Dose (RfD) 39
c. Carcinogenic Classification and Risk Quantification 41
d. Dermal Absorption 41
e. Other Toxicological Endpoints 41
i. Acute Dietary 41
ii. Short- and Intermediate Term Dermal Exposure 42
iii. Chronic Dermal Exposure 43
iv. Inhalation Exposure 43
v. Recommendation for Aggregate Exposure Risk Assessments 43
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3. Dietary Exposure and Risk Assessment/Characterization 45
a. Dietary Exposure (Food Source) 45
i. Directions for Use 45
ii. Nature of the Residue - Plants :...:.,. ...-. 45
iii. Nature of the Residue - Animals 48
iv. Residue Analytical Methods 50
v. Multiresidue Methods 52
vi. Storage Stability Data 52
vii. Crop Field Trials 52
viii. Processed Food/Feed 54
ix. Meat, Milk, Poultry, Eggs 55
x. Water, Fish, and Irrigated Crops 56
xi. Food Handling 56
xii. Confined Accumulation in Rotational Crops ., 56
xiii. Field Accumulation in Rotational Crops 56
xiv. Tolerance Reassessment Table 56
xv. Anticipated Residues 57
b. Dietary Exposure (Drinking Water Source) 63
i. Ground Water (tiered assessment) . 63
ii. Surface Water (tiered assessment) 64
c. Dietary Risk Assessment and Characterization 65
i. Chronic Risk (TMRC, ARC) 65
ii. Carcinogenic Risk 66
iii. Acute Dietary Risk 66
iv. Drinking Water Risk (Acute and Chronic) 67
d. Statement of the adequacy of the dietary exposure database to assess
infants' and children's exposure .69.
4. Occupational and Residential Exposure and Risk Assessment 70
a. Occupational and Residential Exposure ..-. 70
i. Summary of Use Patterns and Formulations 70
ii. Handler Exposures and Assumptions 72
iii. Post-Application Exposures and Assumptions 73
iv. Mixer/Loader/Application Exposure Assessment 74
v. Post-Application Exposure Assessment 78
b. Occupation and Residential Risk Assessment/Characterization 81
. i. Risk from Dermal and Inhalation Exposures 81
ii. Risk from Post-Application Exposures 81
iii. Restricted Entry Interval (REI) 82
iv. Incident Reports : 82
c. Statement of the adequacy of the residential exposure data base to assess
infants' and children's exposures 86
5. Aggregate Exposure and Risk Assessment/Characterization 86
a. Acute Aggregate Exposure and Risk 86
b. Short- and Intermediate-Term Aggregate Exposure and Risk 87
c. Chronic Aggregate Exposure and Risk 87
6. Other Food Quality Protection Act (FQPA) Considerations ., 88
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a. Cumulative Risk 88
b. Endocrine Disruption 88
c. Determination of Safety 89
7. Data Requirements 89
a. Toxicology 89
b. Chemistry • 90
c. Occupational and Residential Exposure 90
t
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I. EXECUTIVE SUMMARY
HED has reviewed toxicology and residue data submitted by Rhone-Poulenc AG Company in
accordance with the Federal, Fungicide, and Rodenticide Act (FIFRAJ and 40 CFR §158, to
support pending registration containing the active ingredient (ai) fipronil for use as an insecticide
on rice and pets.
There are no data gaps for the standard Subdivision F Guideline requirements for a food-use
chemical by 40 CFR Part 158 for Fipronil and the hazard endpoints have been identified. There
is high confidence in the quality of the studies and the reliability of the toxicity endpoints
identified for use in risk assessment The data base for the photodegradate of concern MB 46513
is not complete by itself. However, the HED Hazard ID Assessment Review Committee
(HIARC) determined that there is confidence in using fipronil studies with an additional factor of
10 to adjust the NOELs for the increased toxicity over fiproniK There are no additional studies
required at this time for either chemical.
Fipronil is a broad-spectrum insecticide belonging to the phenylpyrazole class of insecticides.
The toxicology data base provides evidence of neurotoxic activity as evidenced by neurologic
signs in several studies. Fipronil is also associated with alterations in the thyroid-pituitary
hormonal status, resulting in alterations in thyroid hormonal levels and thyroid follicular cell
tumors. MB 46513, a photodegradate of fipronil, appears to be more toxic than the parent (see
HIARC document dated 18-DEC-1997 for details).
In acute toxicity studies, fipronil exhibits low to moderate toxicity, depending on the route of
exposure and the species used. Fipronil has moderate acute toxicity (toxicity category II) by the
oral and inhalation routes in rats. By the dermal route, it is of moderate toxicity in rabbits, and
low toxicity in rats (III). Fipronil technical is relatively non-irritating to the skin (TV) and eye
(III) and is not a sensitizer. Dermal absorption in rats is less than 1 %.
Fipronil is neurotoxic in both rats and dogs as evidenced by signs in the acute and subchronic
screening batteries in the rat; developmental neurotoxicity and chronic carcinogenicity studies in
the rat; and in two chronic dog studies.
Although there is no evidence of enhanced pre or post natal susceptibility in infants and children
in the developmental and reproduction studies, the developmental neurotoxicity study
identified a developmental NOEL which is less than the maternal NOEL indicating an apparent
susceptibility, issue. However, HIARC concluded that the apparent increased susceptibility
in the developmental neurotoxicity study was not supported by the overall weight-of-the-
evidence.
Fipronil has been classified by the HED Cancer Peer Review Committee (document dated 18-
Jul-1997) as a Group C - Possible Human Carcinogen, based on increases in thyroid follicular
cell rumors in both sexes of the rat, which were statistically significant by both pair-wise and
trend analyses. The RfD methodology should be used to estimate human risk because the thyroid
tumors appear to be related to a disruption in the thyroid-pituitary status. There was no apparent
concern for mutagenicity (no mutagenic activity). Dietary risk concerns due to long-term
6
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f
consumption of fipronil residues are adequately addressed by the ORES chronic exposure
analysis using the RfD.
Based on the existing lexicological database, HED's level of concern for acute risk is 100% of
the RfD. Aggregate acute risk estimates do not exceed HED's level of concern. Using refined
exposure assumptions (anticipated residues for blended commodities), for the population
subgroup of children (1-6 years old) the calculated risk for dietary (food only) exposure is 12% of
the RfD. Potential residues in drinking water are not greater than HED's level of concern. The
acute drinking water level of concern (DWLOC) for fipronil (+ metabolites including MB 46513)
in children (1-6 years old) is 220 ppb. The peak (day-0) Tier I (GENEEC) estimated
environmental concentrations for fipronil (+ MB 46136, MB 45950, and MB 46513) in drinking
water was 2.3 ppb. HED concludes that there is a reasonable certainty that no harm will result
from acute aggregate exposure to fipronil (+ MB 46136, MB 45950, and MB 46513) residues for
children.
Short- and intermediate- term Margins of Exposure (MOEs) do not exceed HED's level of
concern. An aggregate systemic (oral) and dermal exposure risk assessment is not appropriate
due to differences in the toxicity endpoints observed between the oral (neurotoxicity and
alterations in clinical chemistry and thyroid parameters) and dermal (decreases in body weight
gain and food consumption) routes. An aggregate oral and inhalation risk is not required due to
the lack of exposure potential via the inhalation route based on the current use pattern.
Chronic aggregate risk estimates do not exceed HED's level of concern. Based on the available
data and assumptions used for dietary/water/residential exposure and risk estimates, the
population group estimated to be the most highly exposed to fipronil is non-nursing infants (< 1
year old) with a risk estimate from combined sources equaling 16.7% of the RfD. Chronic
dietary exposure estimates for fipronil and MB 46513 utilized anticipated residues-Ancle
projected market share and are thus highly refined. For chronic exposure to fipronil (+ MB
46136 and MB 45950), the adult D WLOC is 6.67 ppb and for children (1 -6 years old), the
DWLOC is 1.77 ppb. Tier I (GENEEC) chronic EECs (56-day*value) for fipronil (+ MB 46136
and MB 45950) were less than 0.9 ppb. For chronic exposure to MB 46513, the adult DWLOC
is 0.69 ppb and for children (< 1 year old), the DWLOC is 0.19 ppb, Tier I (GENEEC) chronic
EECs (56-day value) for MB 46513 were less than 0.01 ppb. HED thus concludes that there is a
reasonable certainty that no harm will result from chronic aggregate exposure to fipronil (+ MB
46136 and MB 45950) and MB 46513 residues.
Occupational exposure risk estimates do not exceed HED's level of concern. The MOE for
mixer/loaders of the 80% WG formulation is > 1000; for mixer/loaders of the 1.5 G formulation,
> 6000. There are no available data to assess the application of these products as soil.
incorporated insecticides. However, exposure during application is expected to be an order of
magnitude lower than that of the mixer/loader. Therefore, the exposure while applying fipronil
will not significantly impact the MOE. Additional data are required to assess exposures during
seed treatment.
The residue chemistry, exposure, and toxicological data bases are adequate to support
time-limited tolerances and a conditional registration for the use of fipronil on rice in terms
,!»'
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of human health risk. HED recommends that the petitioner be required to submit: 1) the results
of one additional rice field trial; 2) a storage stability study for MB 46513; 3) Subdivision U
Guideline requirements for Dermal Exposure at Indoor Sites (233) and Inhalation Exposure at
Indoor Sites (234) during seed treatments; and; 3) a developmental neurotoxicity (or other) study
on the photodegradate (MB 46513) if conducted. To provide for the periodic evaluation of the
anticipated residues, the Agency will require under Section 408(bX2)(E) residue data be
submitted every five years as long as the proposed tolerances remain in force. The registrant
must also submit, upon EPA's request and according to a schedule determined by the Agency,
such information as the Agency directs to be submitted in order to evaluate issues related to
whether fipronil share(s) a common mechanism of toxicity with any other substance and, if so,
whether any tolerances for fipronil need to be modified or revoked.
The exposure and lexicological data bases are adequate to support an unconditional
registration for the use of fipronil on pets in terms of human health risk. HED recommends
that the petitioner be required to submit: 1) rates of suspected adverse events for all three pet-care
products at the end of 1998; 2) add the following label statement: " If signs persist, or become
more severe within a few days of application, consult a veterinarian immediately;" 3) individual
incident reports on the Bichon Frise breed rather than include them with the summary reporting
which will be required as of June 16, 1998 under the final 6(aX2) Rule and; 4) monitoring of
misuse of the products on rabbits or instillation of the products into the ears for treatment of ear
mites and if such misuse continues, then the label should be revised to warn against these
practices.
II. BACKGROUND
Fipronil is a broad-spectrum insecticide belonging to the phenylpyrazole class of insecticides.
Fhenylpyrazoies affect the central nervous system of insects, apparently by blocking the
Y-aminobutyric- (GABA-) regulated chloride channel. The proposed use on rice is intended to
control the rice water weevil, an insect which feeds on the roots of rice plants in the larval stage
and on the upper leaf surfaces in the adult stage. Larval damage in heavily infested fields results
in reduced yields. Fipronil is currently used on rice in other countries (Thailand, China, and the
Philippines). Additionally, three fipronil products are conditionally registered for flea and tick
control, Frontline® Spray Treatment (65331-1), Top Spot™ for Cats (65331-2) and Dogs
(65331-3):
Fipronil, also called MB 46030, is an insecticide. The toxicology data base for fipronil has
previously been evaluated and was considered adequate to support registration for use on com.
A photodegradate, MB 46513, has been identified that appears to have greater toxicity than the
parent, fipronil. This photodegradate is not an animal metabolite and, while not present on
com, is potentially present on rice due to the foliar application.
Tolerances for residues of fipronil in/on com and animal commodities have recently been
established (40 CFR § 180.517). Fipronil is currently registered for use on commercial turf and
pets (conditionally) in the U.S. Exposures from these uses will be considered in addition to rice
^
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1
when assessing aggregate exposure. In addition, a petition for establishment of temporary
tolerances in/on cottonseed and cottonseed processing fractions (PP#5G04583) is currently in
reject status pending receipt of revised Sections B and F and proposed tolerances for milk and
eggs (CBTS No. 16288, DP Barcode D219819, G. Kramer, 11/12/96).
III. SCIENCE ASSESSMENT
A. Physical and Chemical Properties Assessment
1. Identification of Active Ingredients
Chemical Name: [5-amino-l-{2,6-dichloro-4-{trifluoromethyl)phenyl)-4-
[(1 R,S)-(trifluoromethyl)sulfiny 1]-1 H-pyrazole-3-
. . carbonitrile]
Common Name: Fipronil
PC Code Number: 129121
CAS Registry No.: 120068-37-3
Empirical Formula: C,2H4C12F6N4.
Molecular Weight: 437.15
2. Structural Formulae (Fmronfl »ad Metabolites)
Fipronil * MB 46513
O
CF3
CF3
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MB 46136
O
MB 45950
-S CN
H2N N
,N
CF,
3. Physical and Chemical Properties
CF3
Physical and Chemical Properties for Fipronil
Color
Physical State
Odor
Melting Point
Boiling Point
Density, Bulk Density, or Specific Gravity
Solubility
Vapor Pressure
Dissociation Constant
Octanol/Water Partition Coefficient
pH
white
powder
moldy odor at 23°C
195.5°-203°C
N/A; JGAI is a solid
1.6262g/mLat20°C
Solvent "- Solubility '
deionized water 1.9mg/L
water, pH 5 0.0024 g/L
water, pH 9 0.0022 g/L
acetone 545.9 g/L
2-propanol 363. g/L
dichloromethane 223 g/L
ethyl acetate 264.9 g/L
hexane 0.028 g/L
methanol 137.5 g/L
toluene 3.0 g/L
octanol 12.2 g/L
2.8 x 10-'mmHgat20°C
N/A
Pro = 10,154 ± 1326 (log ?„. = 4.01)
5.90 - 6. 10; 1% aqueous suspension with 2%
acetonitrile at 23°C
10
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1
Physical and Chemical Properties for Fipronil
Stability
Flammability
Viscosity
Miscibility
slight decomposition (96.53%-93.79%) at 23°C
sunlight; stable at room temperature for 1 year,
for 92 days, 52°C for 30 days, and 54°C for 14
Unstable in the presence of Fe ion .
in
35°C
days;
N/A; TGAI is a solid
N/A; TGAI is a solid
N/A; TGAI is a solid
B. Human Risk Assessment
1. Hazard Assessment
See Table 1 for the requirements (CFR 158.135) for Food/Feed Use for Fipronil Technical.
Table 1
Test
81-1 Acute Oral Toxicity
81-2 Acute Dermal Toxicity
81-3 Acute Inhalation Toxicity
81-4 Primary Eye Irritation
81-5 Primary Dermal Irritation
81-6 Dermal Sensitization
§1-7 Acute Delayed Neufotox. (Hen)
81-8-ss Acute Neurotox. Screening Battery
(Rat)
82-1 Oral Subchronic (Rodent)
82-1 Oral Subchronic (Non-Rodent)
82-2 21-Day Dermal
82-3 90-Day Dermal
82-4 90-Day Inhalation
82-5 90-Day Neurotoxicity (Hen)
82-5 90-Day Neurotoxicity (Mammal)
82-7 90 Day Neurotoxicity Screening Battery
(Rat)
83-1 Chronic Toxicity (Rodent)
83-1 Chronic Toxicity (Non-rodent)
83-2 Oncogenicity (Rat)
83-2 Oncogenicity (Mouse)
83-3 Developmental Toxicity (Rodent)
83-3 Developmental Toxicity( Non-rodent)
83-4 Reproduction
83-5 Chronic/Oncogen icity
83-6 Develop. Neurotoxicity Rat)
Technical
Required
Y
Y
Y
Y
Y
Y
N
Y
Y
Y
Y
N1
N'
N
N
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Satisfied
Y
Y
Y
Y
Y
Y
"
V
Y
Y
Y
-
-
-
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Photodegradate
Acceptable studies
Y
V
-
-
-
-
-
Y
Y
Y
-
•
-
,
:
.
.
-
-
Y
-
-
-
-
11
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Table 1
Test
-: - • ' --••' ',-••- '• -.•..;•::...
84-2 Mutagenicity — Gene Mutation, Bact.
84-2 Mutagenicity — Gene Mutation, Mam.
84-2 Mutagenicity — Struct. Chrom. Aber.
84-4 Mutagenicity — Other Genotoxic Effects
85-1 General Metabolism
85-2 Dermal Penetration
86-1 Domestic Animal Safety
Technical
Required
Y
Y
Y
N
Y
Y
N
Satisfied
Y
Y
Y
N
Y
Y
-
Photodegradate
Acceptable studies
Y
Y
Y
-
.
Y
-
Y yes, N no
1 Not required based on low dermal toxicity observed in the 21-day dermal study, and based on expected exposure.
1 Not required since significant exposure via inhalation not expected.
a. Acute Toxicity
Adequacy of data base for acute toxicitv (Series 81-1 to 81-6"): The data base for acute toxicity for technical fipronil
is considered complete. No additional studies are required at this time.
FIPRONIL PARENT - toxicity categories
§81-1 acute oral - MRID 42918628 , [II] - cf 92/9 103 mg/kg; rf+9 97 mg/kg
§81-2 acute dermal - MRID 42918629, fill} - > 2000 mg/kg [rat]
§81-2 acute dermal - MRID 42918630, [II] - 354 mg/kg [rabbit]
§81-3 acute inhalation - MRID 43544401, [II] - 2000 mg/kg [rat]
x§81 -3 acute inhalation - no study
x§81-4 primary eye irritation - no study
§81 -5 primary dermal irritation - no study
§81-6 dermal sensitization - no study
FIPRONIL METABOLITE (MB45897) - toxicity categories
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1
§81-! acute oral - MRJD 44262819, [III] - 2,000 mg/kg/?>2,000 mg/kg
§81-2 acute dermal - MRJD 44262820, [III] - > 2000 mg/kg [rat]
b. Subchronic Toxicity
Adequacy of data base for subchronic toxicity (Series 82): The data base for subchronic toxicity is considered
complete. No additional studies are required at this time.
i. Fipronil
82 la Subchronic Oral Toxicity Feeding - Rat
Fipronil (95.4% a.i.) was administered in the diet to groups often male and ten female CD rats per group at dosages
of 0, 1, 5, 30 or 300 ppm daily for thirteen weeks (MRID # 42918643). Overall mean body weight gain was
decreased by 9% in the 300 ppm group females as compared to the controls. The 300 ppm group males and females
had higher total protein concentrations than the controls in association with higher values for alpha-1, alpha-2 and
beta globulins and lower albumin/globulin (A/G) ratios. The 5 and 30 ppm group males and females had similar
alterations in protein values but the A/G ratios were not affected. At necropsy, the 300 ppm group males and
females had higher absolute and relative thyroid weights. Absolute thyroid weights were increased in the 30 ppm
group females. Absolute liver weights were increased in the 300 pm group males and in females which received 5
ppm or greater. Relative liver weights were increased in the 30 and 300 ppm group males and females. On
histopathology, there was a significant increase in the incidence of hypertrophy of the follicular epithelium of the
thyroid in the 300 ppm group males and females. Liver sections stained with OH-Red-O showed a higher incidence
and distribution of fat in the liver of the 300 ppm group males. LOEL - 30 ppm for males (1.93 mg/kg/day) and
females (2.28 mg/kg/day) based on alterations in serum protein values and increased weight of the liver and
thyroid. NOEL = 5 ppm for males (0.33 mg/kg/day) and females (0.37 mg/kg/day).
Classification: Minimum
82-la Subchronic Oral Toxicity Feeding-Mouse
In a subchronic toxicity study (MRID 44262804), MB46030 (fipronil; 95.4-96.5% a.i.) was administered to CD-I
albino mice (12/sex/dose) in the diet at nominal dose levels of 0, 1,3, 10,.of 25 ppm (13-week measured mean 0,
0.13,0.38, 1.27, and 3.20 mg/kg/day, respectively, formates, and 0,0.17,0,57, 1.72, and4.53 mg/kg/day,
respectively, for females) for 13 weeks. Ophthalmoscopic examinations and blood and urine analyses were not
conducted. Liver was the only tissue routinely examined histologically. • ' ~
There were no deaths, clinical signs of toxicity or effects on food consumption. Male and female mice in the 25 ppm
treatment group had mean body weight gains 2.3-3.2 g lower (22 and 34%, respectively) than the controls. Liver
abnormalities were observed in all male treatment groups. Minimal to moderate liver cell periacinal hypertrophy
with cytoplasmic vacuolation was present in 0/12,2/12, 3/12,6/12 and 10/12 rats from controls to high dose group.
There was one 10 ppm male with a grossly enlarged liver. Absolute and relative liver weights were increased 23 and
33 % above controls, respectively at 25 ppm. Females did not exhibit a similar response to treatment. One female in
the 25 ppm group and two in the 10 ppm group exhibited slight midzonal hepatocytic fatty vacuolation, and mean
relative liver weights for both groups were 8-13% higher than the controls. The above treatment induced changes
are considered adaptive rather than toxic. No neoplastic tissue was observed. The LOEL was 25 ppm (3.2 and
4.53 mg/kg/day, for males and females, respectively) based on a possible decreased body weight gain. The
NOAEL was 10 ppm (1.27 and 1.72 mg/kg/day, for males and females, respectively). The NOEL a less than
or equal to 1 ppm (0.13 and 0.17 mg/kg/day for males and females, respectively) based on hepatic
hypertrophy at all doses.
This 90-day subchronic toxicity study (dietary) is classified acceptable (non-guideline) due to its abbreviated
protocol and its design as a range finding study and does not satisfy the Subdivision F guideline requirement for a
subchronic toxicity study in rodents (§82-laX
*>
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82-1 b Subchronic Oral Toxicity (capsule) - Dog
Fipronil (95.4% a.i.) was administered in capsules to groups of four male and four female beagle dogs per group at
dosages of 0, 0.5, 2.0 or 10.0 mg/kg/day for 13 weeks (MR1D# 42918642). One male and three females in the 10
mg/kg/day group were euthanized during the second week of treatment'due to poor condition.
Extensive clinical signs of toxicity, including those involving the nervous system, were also seen in the surviving
animals in this group. The only clinical sign of toxicity in the 2.0 mg/kg/day group was inappetence in two of four
females. Abnormal findings in the routine physical and neurological examinations during the course of the study
were confined to the 10.0 mg/kg/day group. Mean body weight gain over the course of the study was decreased in
females in the 2.0 and 10.0 mg/kg/day groups by 17% and 12%, respectively, in comparison to the controls. (Mean
values for females in the 10.0 mg/kg/day group were based on only one animal after Day 14.) No other treatment-
related findings were reported. LOEL - 10.0 mg/kg/day for males (based on clinical signs of toxicity) and 2.0
mg/kg/day for females (based on clinical signs of toxicity and decreased body weight gain). NOEL = 2.0
mg/kg/day for males and 0.5 mg/kg/day for females.
Classification: Guideline
82-2 Repeated Dose Dermal - Rat
M&B 460430 (96.7% a.i.) was applied in a 0.5% solution of carboxymethylcellulose to the intact skin of 6 New
Zealand White rabbits/sex/group at doses of 0,0.5,1.0, 5.0 or 10.0 mg/kg/day for six hours per day for 15 doses
over a 21-day period (MRID # 42918644). Males and females in the 10 mg/kg/day group had decreased mean body
weight gain and food consumption in comparison to the control group. One male and one female in the 10
mg/kg/day group exhibited signs of extreme hyperactiviry that may have been treatment-related. Systemic LOEL -
10 mg/kg/day based on decreased body weight gain and food consumption; Dermal irritation LOEL> 10.0
mg/kg/day. Systemic NOEL - 5.0 mg/kg/day; Dermal irritation NOEL i 10.0 mg/kg/day.
Classification: Guideline
ii. MB 46513
82 la Subchronic Oral Toxicity Feeding - Rat %
*
In this Subchronic rat study (MR1D # 43559501), MB 46513 was administered in the diet to groups often male and
ten female CD rats at dosages of 0,0.5,3, 10 or 30 ppm (males: 0,0.029,0.177,0.594 and 1.772 mg/kg/day;
females: 0, 0.035,0.210,0.709, and 2.101 mg/kg/day, respectively) daily for 90 days.
There were four deaths in both sexes of the 30 ppm group during the treatment period. There was an increased
incidence of clinical signs of neurotoxicity (aggressivity, irritability to touch, increased motor activity and curling up
on handling) in the 10 and 30 ppm group males and females. One-male in the 3 ppm group was also observed to
display most of these signs. Mean body weights were statistically decreased in the 30 ppm group males and females
and the 10 ppm group males at multiple weekly measurements during the study. Overall mean body weight gains for
the 10 and 30 ppm group males was decreased 15.4% and 12.9%, respectively. Mean weekly food consumption and
food conversion efficiency for the 30 ppm group males and females were lower than the controls during the first two
weeks of the study only. There were no treatment-related changes in hematology or urinalysis parameters.
Alterations in clinical chemistry parameters were of no lexicological significance. Treatment-related decreases were
seen in T4 at weeks 2 and 10 in the 30 ppm group males and in the 30 ppm group females at week 10. There was
also a decrease in T3 in the 30 ppm group males at week 10. However, there were no changes in TSH, or the thyroid
gland on macroscopic or microscopic examination. Therefore, the lexicological significance of the hormone
alterations is questionable. There were no treatment-related macroscopic or microscopic necropsy changes. The
study demonstrates that the photodegradate is more toxic than the parent chemical (MB 46*030) when
administered to rats for 90 days. The Lowest Observed Effect Level (LOEL) was 3 ppm (0.177 and 0.210
mg/kg/day for males and females, respectively) based on the occurrence of agressivity, irritability to touch
14
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t
and increased motor activity in one male (these signs are also observed in the mouse). The No Observed
Effect Level (NOEL) was 0.5 ppm (0.029 and 0.035 mg/kg/day for males and females, respectively).
This study is classified as Acceptable and satisfies ihe data requirements for a subchronic rat study (82-1).
82-la Subchronic Oral Toxicity Feeding - Mouse
In a subchronic toxicity study (MRID 44262811), MB46513 (a photodegradate of fipronil; 96% a.i.) was
administered to OF1 mice (10/sex/dose) in die diet at nominal dose levels of 0,0.5,2, or 10 ppm (13-week measured
mean 0, 0.08,0.32 or 1.74 mg/kg/day for males; 0,0.11, 0.43, or 2.15 mg/kg/day for females) for 13 weeks.
In die 10 ppm treatment group, 9/10 males died prematurely (between days 20 and 62) and 1/10 was sacrificed
moribund (day 84); 1/10 females died on day 5. On one occasion each, two of the males exhibited excessive jumps,
and on several occasions one male exhibited aggressiveness and/or irritability. Diffuse centrilobular hypertrophy of
the liver was noted in 6/10 males. The severity of the condition was described as mild in the five males that died
prematurely and moderate in the one male that was sacrificed. The liver of the sacrificed animal also had moderate
multifocal mitotic figures and mild multifocal extramedullary hematopoiesis. In addition, three males had enlarged
livers and four had atrophied thymus glands. The organs of males in the 10 ppm treatment group were not weighed.
The organs of females in the 10 ppm treatment group appeared normal. In the 2 ppm treatment group, two males on
two occasions each exhibited aggressive and irritable behavior with increased motor activity in one of them.
Although 1 male and 1 female in the 0.5 ppm treatment group exhibited aggressive behavior (total of four occasions)
this could not be definitively attributed to treatment because; 1) low frequency, 2) only one sign; 3) no effect in
females at any higher dose. No differences in organ weights or gross or microscopic pathology were observed
between mice in the 2 or 0.5 ppm treatment groups and the controls. Body weights, food consumption, and clinical
blood chemistry were not affected in any treatment group. No neoplastic tissue was observed in mice in die
treatment and control groups. Hematology, ophthalmoscopic and urine analyses were not conducted during die
study. The LOEL for this study is 2 ppm (0-32 mg/kg/day), based on the aggressive and irritable behavior
with increased motor activity in males. The NOEL is 0.5 ppm (0.08 mg/kg/day).
This 90-day subchronic toxicity study (dietary) is classified acceptable and satisfies the Subdivision F guideline
requirement for a subchronic toxicity study in rodents (§82-la).
82-la Subchronic Oral Toxicity Feeding-Dog
In a subchronic toxicity study (MRID 44262812 - main; 44262810 - range-finding), MB46513 (96.0% a.i.), a
photodegradate of fipronil, was administered to 5 beagle dogs/sex/dose by feeding at dose levels of 0,3.5,9.S, or
35 ppm (mean achieved dosages of 0,0.10,027, or 0.95 mg/kg/day for males and 0,0.10,0.29r or 1.05 mg/kg/day
for females) for 90 days. In a range finding study, 2 dogs/sex/dose (0,27, 80, or 270 ppm) were treated with MB
46513 for 28 days. "
In the 28 day range finding study V4 males at 27 ppm (1 mg/kg/day) had convulsions at 28 days and animals at 80
ppm had clinical signs as early as day 4 (mis group had to be sacrificed early due to extreme toxicity). In the main
study, 35 ppm group, 1/5 females was sacrificed prematurely after exhibiting increase salivation, prostration,
writhing, tremors, absence of rotular reflex, noisy breathing, and dyspnea. Histopathological examination of this
female after 28 days revealed multifocal myocardial necrosis associated with intramural coronary arteritis.
Behavioral changes were observed in a second female in the 35 ppm treatment group consisting of excessive barking
and aggressivity on one occasion and irritability, tremors, and increased salivation on another occasion. No other
treatment-related behavioral effects were observed in the 35 ppm treatment group. No treatment-related behavior
effects were observed in any dogs in the 9.5 or 3.5 ppm treatment groups. No treatment-related differences in
ophthalmology, hematology, clinical blood chemistry or urinalysis parameters or gross pathology were observed
between dogs in any treatment group and the controls. No neoplastic tissue was observed in any of the treatment
groups. The LOEL is 35 ppm (1.05 mg/kg/day), based on behavioral changes in 2/5 females. The NOEL is 9.5
ppm (0.29 mg/kg/day).
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This subchronic toxicity study is classified acceptable and satisfies the guideline requirements for a subchronic oral
study (§82-Ib) in non-rodents.
c. Chronic Toxicity
Adequacy of data base for chronic toxicity ffteries 83-1. 83-S): The data base for chronic toxicity is considered
complete. No additional studies are required at this time.
83-la Chronic Feeding - Rat
Fifteen (15) CD rats/sex/group were administered fipronil (95.4%) in the diet for 52 weeks to assess the chronic
toxicity of the chemical (MRID # 42918648). An additional 15 rats/sex/group were fed the chemical for 52 weeks
and then were untreated for an additional 13 weeks to test the reversibility of treatment-related changes. Fifty
rats/sex/group were supposed to be treated for 104 weeks to assess the carcinogenic potential of the chemical. The
doses administered in all the phases were 0,0.5, 1.5,30 and 300 ppm. The carcinogenic phase of the study was
terminated after 89 and 91 weeks in males and females, respectively, due to excessive mortality and to ensure that a
sufficient number of animals were available for the terminal sacrifices. No treatment related differences in mortality
between the groups were observed.
Evidence of treatment-related toxicity included: 1) neurotoxicity (including seizures which resulted in death) in the
1.5, 30 and 300 ppm group males and females; 2) decreased body weight gain in the 300 ppm group males and
females and the 30 ppm group females; 3) decreased food consumption and food conversion efficiency in the 300
ppm group males and females at the beginning of the study; 4) decreased hematology parameters in the 300 ppm
group males and females in comparison to the control groups (values were comparable to pretreatment measures); 5)
alterations in clinical chemistry (increased cholesterol and calcium values; protein alterations with increased total
protein, decreased albumin and increased globulins) mostly in the 30 and 300 ppm group males and females; protein
alterations were seen in the 1.5 ppm group males after 76 and 81 weeks of treatment; 6) alterations in thyroid
hormones (increased TSH and decreased T« levels) in all treated groups at some time points with the 30 and 300 ppm
group males and females consistently affected; 7) alterations in urinalysis parameters (lower pH, higher protein,
elevated urine volume with decreased specific gravity) in the 30 and 300 ppm groups (predominately males); 8)
changes on gross necropsy (large and/or pale kidneys and large livers, adrenal glands and thyroids) in the 30 and 300
ppm group males and females; 9) increased absolute and relative weights of the liver and thyroids in the 30 and 30O
ppm group males and females; 10) increased incidence and severity of progressive senile nephropathy in the 30 and
300 ppm group males and females. LOEL -1.5 ppm for males (0.059 mg/kg/day) and females (0.078
mg/kg/day) based on an increased incidence of clinical signs and alterations in clinical chemistry and thyroid
parameters. NOEL = 0.5 ppm for males (0.019 mg/kg/day) and females (0.025 mg/kg/day).
Benign (follicular ceil adenoma) and malignant (follicular ceil carcinoma) neoplastic changes were observed in the
thyroid gland in increased incidences in ail the treated animals as compared to the control group. However, only the
300 ppm group males and females exceeded the historical incidence of these tumors, either alone or in combination,
for this strain of rat in this laboratory. The study demonstrated that fipronil b carcinogenic to rats at doses of
300 ppm in males (12.68 mg/kg/day) and females (16.75 mg/kg/day).
Classification: Minimum
83-1 b Chronic Oral Toxicity (capsule) - Dog
N
Male and female beagle dogs were administered fipronil (96.8% a.i.) in capsules at dosages of 0,0.2,2.0 or 5.0
mg/kg/day for 52 weeks (MRID # 42918645).
•One male in the 2.0 mg/kg/day group and two males in the 5.0 mg/kg/day group were sacrificed during the study due
to poor condition. Clinical signs of neurotoxicity (including convulsions, vocalization, overactivity, body
twitches/tremors, salivation, stiffened limbs, ataxia and incoordination) were seen in the 2.0 and 5.0 mg/kg/day
gi ps beginning in Week 2. Abnormal neurological examinations (including tenseness, nervous and excitable
'> ,6
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behavior, abnormal stiffness or positioning of the hindlimbs, twitching of the facial muscles and hyperesthesia) were
observed in males and females in the 5.0 mg/kg/day group and in females in the 2.0 mg/kg/day group. Body weight
gain was decreased in the 5.0 mg/kg/day group females, however the mean decrease was due to reduced gain in one
female. LOEL = 2.0 mg/kg day based on clinical signs of neurotoxicity and abnormal neurological
examinations. NOEL - 0.2 mg/kg/day.
Classification: Guideline
8 3-2a Carcinogenicity Study - rat
This study (MRID 42918648) is presented in the Chronic Toxicity Section, see 83-5 above.
83-2a Carcinogenicity Study - rat
This study (MRID 42918648) is presented in the Chronic Toxicity Section, see 83-5 above.
83-2b Carcinogenicity [feeding] - Mouse
Six groups of 20 male and 20 female CD-I mice/group were administered fipronil (95.4% a.i.) in the diet at dosages
of either 0, 0.1, 0.5, 10,30 or 60 ppm for 52 weeks to test the chronic toxicity of the chemical (MRID # 42918649).
An additional six groups of 52 male and 52 female mice were treated at the same dosages of 78 weeks to test the
carcinogenic potential of the chemical. Due to excessive mortality, animals in the 60 ppm group were sacrificed
during Week 10 of the study.
Signs of toxicity in the remaining groups included: 1) decreased body weight gain in the 30 ppm group males and
females at most of the evaluation periods; values for me 10 ppm group were also decreased, although not as
consistently; 2) decreased food consumption in the 30 ppm group females; 3) decreased food conversion efficiency
in the 10 and 30 ppm group males; 4) altered white blood cell differential counts in the 30 ppm group females; 5)
increased incidence of liver pathology on gross examination in the 30 ppm group males in die Carcinogenicity phase;
6) increased absolute and/or relative liver weights in the 10 and 30 ppm group males and females in both the toxicity
and Carcinogenicity phases; 7) increased incidence of periacinar and microvesicular vacuolation in the liver of the 10
and 33 ppm group males at the toxicity aad earcifiugeniciiy phase necropsies; §} btreased iaddeiice of
hepatocellular hyperplasia and chronic degenerative changes in the liver o£ihe 30 ppm group males which died or
were sacrificed during the treatment period of the Carcinogenicity phase. There was an increased incidence of
malignant hepatocellular tumors in males in the30 ppm group as compared to the controls at the Carcinogenicity
phase necropsy. However, the incidence in the control group was lower than the historical incidence with this
species and this laboratory. In addition, the difference in incidence was not statistically significant, and when benign
and malignant tumors were considered together, the incidences were similar. LOEL -10 ppm (1.181 mg/Vg/day
for males and 1:230 mg/kg/day for females) based on decreased body weight gain, decreased food conversion
efficiency (males), increased liver weights and increased incidence of hepatic histopathological changes.
NOEL - 0.5 ppm (0.055 mg/kg/day for males and 0.063 mg/kg/day for females).
The study demonstrated that fipronil is not carcinogenic to CD-I mice when administered at doses of 30 ppm.
Classification: Minimum
d. Developmental Toxicity
Adequacy of data base for Developmental Toxicitv (Series 83-3): The data base for developmental toxicity is
considered complete. No additional studies are required at this time.
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i. Fipronil
83-3a Prenatal Developmental Study - Rat
Specific Pathogen Free female rats of the Crl:CD* (SD) BR VAF/PIus strain from Charles River, St. Aubin les
Elbeuf, France, received either 0, 1,4, or 20 mg/kg/day fipronil (93% a.i.) by oral gavage from gestation days 6
through 15, inclusive (MRJD # 429779-03).
Maternal toxicity was noted at 20 mg/kg/day in the form of reduced body weight gain during the dosing period
(82.6% of control, gestation days 6-16) and to a lesser extent for the period including the dosing plus post dosing
period (90.1% of control, gestation days 6 though 20) and for the entire gestation period (91.8% of control, gestation
days 2 through 20). There was an increase in water consumption in the high dose group throughout the study
ranging from a 3 to 28% increase as compared to control; there was an 18% increase over control in the high dose
group for gestation days 6-15. Food consumption was slightly decreased in the high dose group at the beginning of
the dosing period (days 6-11) with an overall reduction of 90% of control for gestation days 6-15, after which no
treatment-related effect was noted. There was a slight reduction in the high dose group food efficiency during the
dosing period, 27.8, 28.5, 27.0 and 25.3% for the control, low, mid and high dose groups, respectively. No effects
were noted in developmental toxicity parameters.
Maternal toxicity LOEL » 20 mg/kg/day based on reduced body weight gain, increased water consumption,
reduced food consumption and reduced food efficiency. Maternal toxicity NOEL - 4 mg/kg/day.
Developmental toxicity LOEL - greater than 20 mg/kg/day. Developmental toxicity NOEL - 20 mg/kg/day or
higher.
Classification: Minimum
83-3b Prenatal Developmental Study - Rabbit
/
Sexually mature virgin female New Zealand White rabbits from Ranch Rabbits, Crawley Down, Sussex, England,
received either 0,0.1, 0.2, 0.5 or 1.0 mg/kg/day fipronil (95.4% a.i.) by oral gavage from gestation days 6 through
19, inclusive (MRID # 42918646).
Maternal toxicity was noted at all dose levels tested in the form of reduced body weight gain at ail gestation day.
periods evaluated. Body weight gains for the treatment period (gestation days 6-20) were 73,73, 50 and 30% of
control for the 0.1,0.2, 0.5 and 1.0 mg/kg/day groups, respectively. For gestation days 20-28, weight gains of the
treated animals exceeded the controls. For gestation days 0-28, gains were 88, 86, 81 and 67% of control for the 0.1,
0.2,0.5 and 1.0 mg/kg/day groups. All treated groups consumed less food than that of the control group during the
dosing period; the differences were statistically significant for the two highest dose groups. Food efficiency was
decreased in all treated groups. No effects were noted in developmental toxicity parameters.
Maternal toxicity LOEL a 0.1 mg/kg/day based on reduced body weight gain, reduced food consumption and
efficiency. Maternal toxicity NOEL is < 0.1 mg/kg/day.
Developmental toxicity LOEL> 1.0 mg/kg/day. Developmental toxicity NOEL * 1.0 mg/kg/day.
Classification: Minimum
ii. MB 46513
83-3a Prenatal Developmental Study - Rat
In a developmental toxicity (teratology) study (MRID# 44275001), adult virgin female rats (CD strain, Sprague
Dawley Crl: CD (SD) BR from Charles River Laboratories, St Aubin ies Elbeuf, France) received either 0, 0.5, 1.0,
or 2.5 mg/kg/day of MB 046513 (Purity: 992 g/kg, Batch 805 DAP/DA999) suspended (w/v) in an aqueous solution
^
18
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of methylcellulose 400 (Fluka, Mulhouse, France) at 0.5% by oral gavage from gestation days 6 to 15 inclusive of
presumed gestation. Maternal parameters included clinical signs of toxicity, body weights (on gestation day 0, daily
from gestation day 6-16 and on gestation day 20) and food consumption (interval gestation day 0-6, daily from
gestation days 6-15 and the interval of gestation day 16- 20). All surviving animals were sacrificed on gestation day
20 and each female was subjected to macroscopic examination of the visceral organs, the reproductive tract was
weighed (gravid uterine weight), dissected out and the number of corpora lutea in each ovary, the number of
implantation sites, number and localization of resorption sites (classified as early and late), the number and
distribution of live and dead foetuses in each uterine horn were determined along with the sex of viable fetuses and
the individual weights of viable fetuses and placenta were measured. The viable fetuses were sacrificed, subjected to
an external examination and the approximately half of the viable fetuses from each litter were prepared for soft tissue
examination and the remaining for skeletal examination.
Maternal toxicity was noted as clinical signs in the high dose animals as hair loss on either the paws, limbs, flanks,
abdomen and/or thorax. The high dose group had lower body weight gains on study days 6-16 (58.1% of control),
study days 0-20 (90.0% of control), study days 6-20 (83.9% of control) and days 0-20 corrected for gravid uterine
weights (78.3% of control). The high dose group also consumed less food during the dosing period and there was
lower food efficiency relative to the control group except for the post dosing period where an increase was noted
which is indicative of a rebound relative to toxicity. The Maternal Toxicity LOEL was i£ mg/kg/day and the
NOEL was 1.0 mg/kg/day based an increase in clinical signs of toxicity on reduced body weight gain, food *
consumption and food efficiency.
Developmental toxicity was noted as a very slight increase in the fetal and Inter incidence of incomplete or reduced
ossification in several bones in the high dose group, including the hyoid body, 5th/6m sternebrae, 1st thoracic body?
pubic bone and 1 or 2 metatarsi. There was also a slight reduction in fetal body weight (males 97.5% of control,
females 97.7% of control) in the high dose group, although statistically significant, the changes are too small to be
biologically relevant. The Developmental Toxicity LOEL was 2.5 mg/kg/day and the NOEL was 1.0 mg/kg/day
based on the slight increase in fetal and litter incidence of reduced ossification of several bones.
This study is classified as Acceptable-Guideline and satisfies the guideline requirements (§ 83-3a) for a
teratology study in rats.
e. Reproductive Toxicity
Adequacy of data base for Reproductive Toxicity (Series 83-4V The data base for reproductive toxicity is
considered complete. No additional studies are required at this time. 4 ' '
83-4 Two-Generation Reproduction Study - Rat . ~
Thirty CD rats/sex/group received fipronil (95.4% a.i.) continuously in the diet at concentrations of 0,3,30 and 300
ppm (equivalent to 0, 0.25,2.54 and 26.03 and 027,2.74 and 28.40 mg/kg/day for mates and females, respectively)
(MRID # 42918647). Parental (systemic) toxicity was noted in the form of the following: 1) increased mortality in
the 300 ppm group males and females in the F, and F, generations; 2) decreased body weight gain pre-mating in the
300 ppm group males and females in the F, and F, generations and in die 300 ppm group females'during gestation
and lactation in the F0 generation; 3) food consumption in the 300 ppm group males and females during pre-mating
in the F0 generation; 4) increase in the absolute and relative weights of the thyroid glands and liver in the 30 and 300
ppm group males and females of the F0 and F, generations; decrease in the absolute and relative weights of the
ovaries in the 300 ppm group females in the F0 generation; decrease in die absolute weight of the pituitary gland in
the 30 and 300 ppm group females and decrease in the relative weight in all the treated female groups in the F,
parental animals; decrease in the absolute and relative weights of the testes in the 300 ppm group males in the F,
parental animals; 5) increased incidence of centriacinar fatty vacuolation in the livers of the 300 ppm group females
in both the F0 and F, generations; and 6) increased incidence of follicular epithelial hypertrophy of the thyroid glands
in the 300 ppm group males and females in the F0 generation and in the 30 and 300 ppm group females in the F,
generation.
Reproductive toxicity was noted in the form of the following findings in the 300 ppm group: 1) clinical signs of
i>
19
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1
toxicity in the F, and F, offspring; 2) decreased litter size in the F, and F2 litters; 3) decreased body weights in the F,
and F: litters; 4) decrease in the percentage of F, parental animals mating; 5) reduction in fertility index in F,
parental animals; 6) reduced post-implantation survival and offspring postnatal survivability in the F2 litters;.and 7)
delay in physical development in the 300 ppm group of the F| and F2 litters.
The Lowest Observed Effect Level (LOEL) for parental (systemic) toxicity was 30 ppm (2.54 mg/kg/day for
males and 2.74 mg/kg/day for females) based on increased weight of the thyroid glands and liver in males and
females; decreased weight of the pituitary gland in females; and an increased incidence of follicuiar epithelial
hypertrophy in the females. The No Observed Effect Level (NOEL) for parental (systemic) toxicity was 3
ppm (0.25 mg/kg/day for males and 0.27 mg/kg/day for females).
The LOEL for reproductive toxicity was 300 ppm (26.03 mg/kg/day for males and 28.40 mg/kg/day for
females) based on clinical signs of toxicity in the F, and F, offspring; decreased litter size in the F, and F,
litters; decreased body weights in the F, and F, litters; decrease in the percentage of F, parental animals
mating; reduction in fertility index in F, parental animals; reduced post-implantation survival and offspring
postnatal survivability in the F2 litters; and delay in physical development in the F, and F, offspring. The
NOEL for reproductive toxicity was 30 ppm (2.54 mg/kg/day for males and 2.74 mg/kg/day for females).
Classification: Minimum
f. Neurotoxicity
Adequacy of data base for Neurotoxicity fSeries 81-8. 82-7. 83-6V. The data base for neurotoxicity is considered
complete. No additional studies are required at this time.
i. Fipronil
81-8 Acute Neurotoxicity - Rat
1) A single dose of fipronil (96.7% a.i.) in com oil was administered by gavage to four groups of 15 CD
rats/sex/group at dosages of either 0,0.5,5.0 or 50.0 mg/kg. .
Five ma!es_and.one female in tHe 50 mg/kg grmip died during ths study (MRID # 42915635). Treatment-related
clinical signs of toxicity, including neurotoxicity, were seen with the 50 mg/kg group animals, especially the males.
Males in the SO mg/kg group had decreased body weights in comparison to the controls. During the open field .
evaluations of the functional observational battery (at 7 hours, 7 days and 14 days post-treatment), effects of both
stimulation and depression of the nervous system were seen. Those parameters for which there were statistically
significant changes in males included gait, fine tremors (females also), coarse tremors, urination, mean number of
rears (females also), approach response, pupil size, muscle tone (females also), air righting and mean hind leg splay
(females also). Mean rectal body temperature was also decreased in the males and females of this group. The only
treatment-related effects in the 5.0 mg/kg group at this time point were decreased mean body temperature in males
and decreased mean hind leg splay in males and females. On Days 7 and 14, the effects were minor in comparison,
but females in the SO mg/kg group had a statistically significant increase in hind leg splay at both evaluations. Mean
motor activity was decreased by 90 and 93% in the SO mg/kg group males and females, respectively, at the 8-hour
evaluation. At Day 7, significant increases in mean activity for the 0.5 and 5.0 mg/kg group males were observed.
However, supplemental statistical analysis demonstrated that the test substance did not alter motor activity when
compared with pretreatment activity. There were no significant differences between the treated and control groups at
Day 14. There were no treatment-related gross or microscopic changes on post-mortem examination of the central
and peripheral nervous systems. The No Observed Effect Level (NOEL) = 0.5 mg/kg for males and females.
The Low Observed Effect Level (LOEL) - 5.0 mg/kg for males and females based on decreased hind leg splay
at the 7 hour post-treatment evaluation in males and females.
Classification: Minimum
2) In an acute neurotoxicity study (MRID 44431801) a single dose of fipronil (97.9%) was administered by gavage
20
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1
to 10 Crl: CD BR rats/sex/group at levels of 0 (corn oil control, 10 ml/kg), 2.5, 7.5 or 25 mg/kg. Study assessment
(functional observational battery and motor activity) time points were pre-treatment and at time of peak effect (7
hours after dosing) and at 7 and 14 days after dosing. Animals were sacrificed on day 14.
On the day of treatment, there were no clinical signs of toxicity. In the 7.5 mg/kg males there was decreased
hindlimb splay (8.7, 7.8, 6.7, 6.3 cm, controls to high dose) at 7 hours post dosing. No other parameters were
affected in males at this dose. For females at 7.5 mg/kg, during the first week there was a decrease in bodyweight
gain (16, 15, 7,4 g, controls to high dose), food consumption (165, 152, 138, 125 g, controls to high dose), and food
efficiency. There was also a decrease in grooming in all females at this dose during the 14 day FOB.
In the 25 mg/kg group, at 7 hours, there was unusual behavior observed during the FOB. One male and female were
stationary with their chin on the floor. Changes in males and females at 7 hours included decreased hind limb splay
(for males, see above; females 7.1,7.1,6.1, 5.6, controls to high dose), increased grip strength (males 0.91,0.98,
0.97, 1.11 kg; females 0.90, 0.90,0.94,0.97 kg, controls to high dose), and decreased body temperature. Only
females were affected with decreased activity counts (16,17, 16, 8, controls to high dose) and rearing counts (6, 7, 6,
3, controls to high dose). Motor activity changes included decreased large movements during the first 10 minutes
only for both males and females. On day 2 post treatment, there were signs of toxicity in males and females
including stained fur and soiled anogenital region, lasting only a few days. Treatment related effects at 7 days were
limited to decreased body weight, food consumption and food efficiency in males and females and decreased
grooming in females. By 14 days all of the previous effects were resolved except for decreased grooming in all
females. The LOEL is 7.5 mg/kg, based on decreased body weight gains, food consumption and feed efficiency
in females, decreased hindlimb splay in males (at 7 hours post test) and decreased grooming in females (14
days post test). The NOEL is 2.5 mg/kg.
This acute neurotoxicity study is classified acceptable(guideline) and satisfies the guideline requirement for an acute
neurotoxicity study (81 -8ss) in the rat.
82-7 Subchronic neurotoxicity Screening Battery - rat
In this subchronic neurotoxicity study, male and female Sprague-Dawley rats (15/sex/dose) were fed test diets
containing M&B 46030 at 0 (basal diet), 0.5, 5.0, or 150 pom (equivalent to 0,0.0297^0.301, or 8.89 me/kg/day, _
•dales; 0,0.0354, S.3 51 or 10.8 mg/kg/day, females) (MRlDNoJ 43291703). Neurobehavioral screening, consisting
of Functional Observational Battery and motor activity evaluations, was performed at pretreatment, and during
Weeks 4,9 and 13. At terminal sacrifice, six animals/sex/dose were anesthetized and perfusion fixed in situ for
neuropathological evaluation. With the exception of one low-dose female which was found dead on Day 16, all
remaining animals survived to terminal sacrifice without the appearance of any treatment-related clinical signs. *
Decreases in mean body weight, observed in high-dose males and females at Week 1 of treatment, were judged to be
slight (6.5%, males; 6.9%, females). The decrease in body weight was accompanied by a concomitant decrease in
food consumption, which would suggest a palatability problem, rather than a treatment-related effect FOB findings
revealed minimal effects in high-dose animals at the Weeks 4,9 and 13 evaluations. High-dose males had a
decreased incidence of no urination and an increased incidence of exaggerated tail pinch response. High-dose males
and females had an increased incidence startle responses in the manipulative observations. High-dose females had
increased forelimb grip strength at Week 13. The mean body weights of treated males were significantly greater than
the concurrent control values. Necropsy findings did not reveal any treatment-related gross pathological or
histopathoiogical findings. Although histopathological lesions were observed, incidences were low and attributed by
the study pathologist to animal variation and artifactual changes. Based on the results (FOB findings) of this
study, the LOEL was established at 150 ppm (8.89 mg/kg/day, males; 10.8 mg/kg/day, females); the NOEL
was established at 5.0 ppm (0301 mg/kg/day, males; 0351 mg/kg/day, females).
This study is classified as Acceptable and satisfies guideline requirements (§82-7) for a subchronic neurotoxicity
screening battery in the rat
21
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83-6 Developmental Neurotoxicity - Rat
In a developmental neurotoxicity study (MRJD 44039002), fipronil (96.1% a.i.) was administered to 30 female
Sprague-Dawley rats/group in the diet at dose levels of 0, 0.5, 10 or 200 ppm (0.05, 0.90 or 15 mg/kg/day,
respectively) from Gestation Day 6 to Lactation Day 10.
There was no evidence of a treatment-related effect on maternal survival or clinical signs of toxicity. Two females in
the 200 ppm group died during lactation, but there was no evidence that the deaths were treatmentrrelated. Mean
maternal body weight values for the 200 ppm group were reduced 15.5%, 10.0% and 8.6% in comparison to the
controls on Gestation Days 10, 15 and 20, respectively. Mean body weight gain was statistically decreased for
Gestation Day interval 6-10, but increased for interval 10-15. Statistically significant reductions in mean body
weight were seen in the 200 ppm group on Lactation Days 0 and 4. Mean body weight gain was statistically
increased on Lactation Days 4-11. A statistically significant reduction in group mean food consumption was noted in
the 200 ppm group for Gestation Days 6 to 10 but was comparable to the controls for other intervals. Pregnancy rate
and gestation length for treated animals were comparable to the control group. There was no evidence of a
treatment-related effect on gross necropsy findings. The maternal LOEL is 200 ppm (15 mg/kg/day), based on
decreased body weight, body weight gain and food consumption. The maternal NOEL was 10 ppm (0.90
rag/kg/day).
At 200 ppm, liner size was not affected by treatment, but the live birth index was decreased (not statistically
significant). The pup viability index (survival from Postnatal Days 0-4) for the 200 ppm group was significantly
decreased (98.9% for control vs. 75.5% for 200 ppm group). The weaning index (survival from Postnatal Days 4-
21) was decreased for this group, but the difference was not statistically significant Pup sex distribution was not
affected. There was a statistically significant decrease in group mean body weights of both males and female
offspring at all recorded intervals during lactation (9.2-34.1% and 8.1-33.8% decrease in males and females,
respectively) and for various periods post-weaning. Statistically significant increases in the mean day of achieving
pinna detachment, upper and lower incisor eruption, vaginal patency and preputial separation were noted. At 10 ppm
there was a statistical decrease in pup weight gain and delayed preputial separation. At 0.5 ppm there were no
treatment related effects. The developmental toxicity LOEL is 10 ppm (0.90 mg/kg/day), based on a marginal
but statistically significant decrease in group mean pup weights during lactation, and significant increase in
time of preputial separation in males. The NOEL for developmental toxicity is 0.5 ppm (0.05 mg/kg/day).
At 200 ppm auditory startle testing on Postnatal Day 22 demonstrated a statistically significant decrease in the
maximum response for males and females. There was no significant difference in the time to maximum response or
average response. There were no changes in this parameter on Postnatal Day 60. Swimming direction scores on Day
6 were reduced for the males and females, although only the males were statistically significant On Day 14, the
scores were comparable. Water "Y" maze time trials for learning and memory showed a statistically significant
increase in time required to complete the maze for females in Trials 5 and 6 on Day 24. There were no statistically
significant differences for either sex on Days 25, 30,60,61 or 65. Statistically significant decreases in absolute
brain weights for both sexes, compared to control values, were found on. Postnatal Days 11 (20% and 11% decrease
in males and females, respectively) and 60 (= 7% decrease in males and females). Terminal body weights were also
decreased foe this group on these days. On Day 11, the relative brain weights for both sexes were significantly
increased in comparison to the controls^ On Day 60, the values for the control and 200 ppm groups were
comparable. There was no evidence of a treatment-related effect on the gross macroscopic or microscopic
examinations (including the central and peripheral nervous systems) of the pups sacrificed on Postnatal Days 11 and
60. The developmental neurotoxicity LOEL is 200 ppm (15 mg/kg/day) based on: decreased auditory startle
response; reduced swimming direction scores, group mean angle measurements and water "Y" maze times
trails; and decreased absolute brain weights. The NOEL for developmental neurotoxicity is 10 ppm (0.90
mg/kg/day).
It is noted that developmental toxicity occurred at a dose lower than the maternal toxicity NOEL in this
study. However, the HED Hazard ID Assessment Review Committee (meeting dated 22-APR-19981 did not
consider this to indicate increased susceptibility to infants and children (see discussion section below and the
HI ARC document for details)
The developmental neurotoxicity study in the rat is classified acceptable/guideline and does satisfy the guideline
^
22
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requirement for a developmental neurotoxicity study (OPPTS 870.6300) in the rat.
ii. MB 46513
81-8 Acute Neurotoxicity - Rat
In an acute neurotoxicity study (MRJD 44262808), MB46513, a photometabolite of fipronil (99.5% a.i.), was
administered in com oil by oral intubation to Crl:CD BR rats (12/sex/dose) at dose levels of 0,0.5, 2, or 12 mg/kg.
The rats were evaluated for reactions in functional observations and motor activity measurements at 6 hours, 7 days,
and 14 days post dosing. Clinical signs, body weights, and food consumption were monitored. At study termination,
brains were weighed and measured, and neural tissues were processed for microscopic evaluation.
No animals died and there were no treatment-related clinical signs of toxicity. At 12 mg/kg, significant decreases in
body weight gains and food consumption were noted for the high-dose males and females during the week following
treatment. By the second week, both had returned to the control levels. Body weight gains and food consumption
for the low- and mid-dose groups and mean body weights for all treated groups were not significantly different from
the controls throughout the study. Food efficiency was not affected by treatment Behavioral responses were also
affected by treatment with MB46513 at 12 mg/kg. At the estimated peak response time, 6 hours post dosing,
significant decreases in locomotor activity during the first 30 minutes of observation were noted among high-dose
males and females. There were no significant differences in any dose group on days 7 and 14. Treatment-related
decreases in hindlimb splay and rectal temperature at 6 hours post dose were observed in high-dose males and
females. In addition, decreases in the proportion of high-dose males with an immediate righting reflex on days 7 and
14 were possibly treatment related. Decreased forelimb grip strength in high-dose males on day 7 and increased
forelimb grip strength in high-dose females at 6 hours post dosing was possibly related to the treatment, because. _J.
there were also slight increases in forelimb grip strength in high-dose males at 6 hours and slight decreases in
forelimb grip strength in high dose females at 7 days and in high-dose males and females at 14 days. There were no
significant differences among groups in neuropathology. Based on these findings, the neurobehavioral LOEL for
rats is 12 mg/kg. The NOEL is 2 mg/kg.
This study is classified acceptable (guideline) and does satisfy the guideline requirement for an acute neurotoxicity
study in rodents (§81-8). ',._. . -'
•- s~ '• . -
g. Mutagenicity - ui fe^*^
Adequacy of data base for Mutagenicity (Series 84V The available studies indicate that fipronil and me fipronil '
photodegndate, MB46513 are not mutagenic in bacteria and are not clastogenic in vitro or in vivo up to doses that
showed clear test material interaction with the target cells. Based on these considerations, the Committee concluded
that there is no concern for mutagenicity.
•The submitted test battery for both compounds satisfy the new mutagenicity initial testing battery guidelines. No
further studies are required at this time. The data base for Mutagenicity is considered adequate. Based on the
available mutagenicity studies, there are no concerns for mutagenicity at this time.
23
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STUDY TYPE
REFERENCE
CONCLUSIONS -. .
FIPRONIL
Gene Mutation/bacteria
Salmonella typhimurium
(MRID# 429 18652)
Gene Mutation///! vitro assay in
mammalian cells
Chinese hamster V79 cells
(MRID* 429 18651)
Cytogenetics/Human lymphocytes
(MRID #429 18653)
Cytogenetics In vivo mouse
micronucleus assay
(MRID #4368080 1)
Fipronil (90.6% a.i.) was not mutagenic
Classification: Acceptable
Fipronil (972% a.i.) was negative for inducing forward gene mutations at
the HGPRT locus in cultured Chinese hamster V79 cells.
Classification: Acceptable
There was no evidence of a clastogenic effect when human lymphocytes
were exposed in vitro to fipronil (90.6% a.i.)
Classification: Acceptable
There was no evidence of a clastogenic or aneugenic effect at any MB
460030 (96.2%) dose or at any harvest time.
Classification: Acceptable
MB 465 1 3 (photodegradate)
Gene Mutation/bacteria
Salmonella typhimurium
(MRID #4329 1721)
Gene Mutation//i> vitro assay in
mammalian cells
HPRT locus in Chinese Hamster
Ovary (CHO) cells
(MRID 442628 14)
Cytogenetics/ in vivo mouse bone
marrow micronucleus assay
MRID 442638 13)
There was no evidence of a mutagenic response at any dose.
Classification: Acceptable
MB46513, (99.5% a.i.) did not induce forward mutations at the HPRT
locus in CHO cells at any dose level tested.
Classification: Acceptable
There was no significant increasfe in the frequency of MPCEs in bone
marrow after any MB46513 (99.5%, a.L) treatment time; therefore, the
test ankle is considered negative in this micronucleus assay.
Classification: Acceptable •
h. Metabolism
Adequacy of data base for metabolism (Series 85-1. 85-2): The data base for metabolism (both 85-1 and 85-2) is
considered to be complete. No additional studies are required at this time.
85-1 Metabolism -Rat
1. Studies Conducted with Fipronil
NC-Fipronil (M-C fipronil, >97.0% radiochemical purity; unlabeled fipronil, >99% a.i.) was administered orally in
aqueous methylcellulose to groups (5 sex/dose) of male and female Sprague-Dawley rats at doses of 4 and 150
mg/kg (single dose) and 4 mg/kg x 14 days (repeated dose) (MRID # 42918655). The rate and extent of absorption
appeared similar among ail dose groups, but may have been decreased at the high dose. Distribution data showed
24
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significant amounts of residual radioactivity in carcass, G.I. tract, liver, adrenals, and abdominal fat at 168 hours
post-dose for all rats in all dose groups. Repeated low oral dosing or a single high oral dose resulted in an overall
decrease in the amount of residual radioactivity found, but an increase in the amount in abdominal fat, carcass, and
adrenals. Feces appeared to be the major route of excretion forTipronil derived radioactivity, where 45-75% of an
administered dose was excreted. Excretion in urine was between 5-25%. Increases in the percentages excreted in
urine and feces were observed with repeated low oral dosing or a single high dose, while the percentage found in all
tissues combined decreased. There were no significant sex-related differences in excretion. Major metabolites in
urine included two ring-opened products of the metabolite M&B 45,897, two oxidation products (M&B 46,136 and
RPA200766), and parent chemical (M&B 46,030). In feces, parent M&B 46,030 was detected as a significant
fraction of the sample radioactivity as well as the oxidation products M&B 46,136 and M&B 45,950. Whole blood
half-life ranged from 149.4-200.2 hours in male and female rats at 4 mg/kg, with 0-168 hours AUCs approximately
equal between sexes. At 150 mg/kg, whole blood half-life was noticeably decreased to 54.4 hours in male rats and
51.2 hours in female rats. Blood AUCs at this dose were approximately proportional to the increase in dose.
Classification: Minimum
2. Studies Conducted with Pbotodegradate MB 46513
In a rat metabolism study (MRID 44262817), [U-"C-phenyl] MB465I3 (>99% a.i.) was administered to five
Sprague-Dawley CD strain rats/sex/dose by gavage as a single dose at 1 or 10 mg/kg or as a single dose at 1 mg/kg
following a 14-day pretreatment with uniabeied MB46513 at t mg/kg.
Within 168 hours of dosing, 93-101% of the administered dose was recovered from both sexes of each dose group*
of which 46.4-69.5% was in the feces, 19.9-41.1% was in the tissues and carcass, and 4.4-10.8% was in the urine. In
all test groups, fecal excretion was higher for males (60.1-69.5%) than for females (46.4-56.0%), and less
radioactivity was retained in the carcasses and tissues of males (19.9-26.6%) than females (30.0-41.1%). Levels of
urinary excretion were comparable between sexes. Excretion of the radioactivity was increased slightly by
pretreatment and at the high dose level. Within 168 hours of dosing, the single low-dose (SOLD) animals excreted
51.6-67.1% of the dose in feces and urine (including cage washX whereas the repeated low-dose (ROLD) animals
excreted 66.4-73.7%, and the single high-dose (SOHD) animals excreted 69.9-80.6%. Radioactivity was excreted
gradually by all dose groups, but the rate of excretion differed between dose groups. Fecal excretion peaked on Day-
1 for the SOLO group, on Day-6 for the ROLD group, and on Day-5 for me SQHD^roup. Urinary excretion
showed a similar pattern within dose groups. Maximum concentrations of radioactivity in blood were attained within
46 to 73 hours of dosing and were similar between sexes within dose group jflow dose^O.lS ppm; high dose, 2.03-
2.31 ppm). For both dose groups, elimination half-lives were 156-170 hours for males and 210-221 hours for
females. The ratio of the areas under the concentration curves (AUQ for high to low-dose animals was 152 for
males and ld.9 for females, reflecting die difference in dose levels.' The general distribution of radioactivity among
tissues was the same between dose groups and sexes, ahhough'the actual levels differed between dose groups and
sexes. Concentrations of radioactivity were highest in fat [fat/plasma ratios: 6J-12.8 in mates and 16.4-25.2 in.
females], followed usually by the adrenals and liver. Females also had high concentrations associated with the
ovaries. The lowest concentrations of radioactivity were generally associated with the brain, spleen, muscle, whole
blood, and stomach. With the exception of whole blood and plasma, concentrations of radioactivity in all tissues
were generally higher for females than for males, e.g. radioactivity in fat was 1.6-2.8 times higher in females than in
males. Among the dose groups, "C-residues were lowest in tissues from the SOLD group with the exceptions of
residual carcass and skin plus fur. Pretreatment with MB46513 increased the residue levels in tissues, and residue
• levels in tissues from the SOHD group were 10-30 times higher than in tissues from the SOLD group. The major
radioactive component identified in excreta was unchanged MB46513 (males, 28.6-44.2%; females, 35.4-39.6%),
nearly all of which was found in the feces. Unchanged MB46513 in urine accounted for <0.1% of the dose. The
only other components in excreta accounting for >5% of the dose were MB46400 (males, 5.7-10.6%; females, 3.1-
7.1%) and the 4-cyano-5-{N)cysteine conjugate of MB46513 (males, 7.2-14.2%; females, 3.3-9.2%). Other minor
-components identified in excreta included: RPA 105048; the sulfate conjugate of MB46513 (s2.4%); a 4-cyano-5-
(N) cysteine glycine conjugate of MB46516 (0.7-3.8%); and a 5-(N) cysteine conjugate of MB46513 (1.9-3.5%).
Within each dose group, the metabolite profile was the same among sexes, although metabolite levels were generally
higher in males than females. The metabolic profile was also similar between dose groups, although there were
differences in the relative levels of metabolites. Pretreatment resulted in lower levels of MB46513 and higher levels
of metabolites than in SOLD animals. LeveJsW MB46513 were similar in excreta of SOHD and SOLD groups, but
25
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levels of metabolites were generally higher for the SOHD group. These data indicate that fecal excretion of
unchangedMB46513 is the principal pathway for elimination of MB465 13 from rats. The metabolism of MB465 13
in rats involves substitution of the trifluoromethyl or cyano groups on the pyrazole ring and/or sulfate, glucuronide
or glutathione conjugation at the amide on the pyrazole ring. The high levels of radioactivity in fat compared to
blood and the prolonged elimination half-life indicate that there is a potential for bioaccumulation of MB46513 in
fatty tissues.
\
This metabolism study in the rat is classified Acceptable (Nonguideline) as it is not a required guideline study. It is
acceptable for the purposes for which it was intended (metabolism information on MB46513, a photolytic metabolite
of fipronil) as a special study.
i. Dermal Absorption
85-2 Dermal Absorption - Rat
I. Studies Conducted with Fipronil
In this dermal absorption study (MRID: 43737308; Guideline No.: §85-2), male rats were dosed at 0.071, 0.688 and
3.88 mg/cm2 for exposures of 0.5, 1,2, 4, 10 and 24 hours with fipronil. Quantity of fipronil in washed skin was
1 .14-2.45%, 0.60-3.29% and 0.35-0.80% at the respective doses. Quantity of fipronil absorbed was <1% at all
doses. The system was saturated at 3.88 mg/cm2. The dermal absorption rate was calculated to be <1% at 24 hours.
2. Studies Conducted with Photodegradate MB 46513
In a dermal absorption study (MRID 44262816), 24 male CrlrCD BR rats/dose group were dosed dermally with
[14C]MB4613 (99% a.i.) as a 1% carboxymethylcellulose aqueous suspension at dose levels of 0.081, 0.881, or 7.17
mg/rat (0.006, 0.071, or 0.574 mg/cm2). Four rats/dose were sacrificed for assessment of dermal absorption after
0.5, 1, 2, 4, 10, and 24 hours of exposure.
Dosed radioactivity was quantitatively recovered from each dose group (92.5-103%). After 24 hours of exposure,
dermal absorption of MB465 13 was minimal. For all dose groups, the majority of the dose was not absorbed (90.2-
1 02.3%), and only trace amounts (i 0. 1 %) of radioactivity were excreted in the urine and feccs. For the low- and
niid-dose groups, radioactivity remaining in/on ihe skin after washing increased with* the duration of exposure,
reaching maximums of 3.97% and 1.05% of the dose, respectively, by 24 hours. However, duration of exposure had
no effect on accumulation of radioactivity in/on the skin for the high-dose gVoup. For the low-dose group, absorption
(measured as amount excreted plus amount retained in the body) increased over time from <0.005% of the dose at
0.5 hours to 2.64% of the dose at 24 hours. Potential absorption (amount absorbed plus amount retained in/on skin)
also increased over time from 0.74% of the dose at 0.5 hours to 6.61% of the dose at 24 hours. For the mid-dose
group, absorption increased over time from <0.01% of the dose at 0.5 hours to 0.35% of the dose at 24 hours.
Potential absorption increased from 0.28% of the dose at 0.5 hours to 1.40% of the dose at 24 hours. For the high-
dose group, the maximum amount of absorption was 0. 14% of the dose at 0.5 hours, and the maximum potential
absorption was 0.66% of the dose at 4 hours.
SELECT DERMAL ABSORPTION VALUES
(Total % adhered to the skin and absorbed)
ave. dose
0.006 mg/cm2
0.071 mg/cm2
0.574 mg/cm2
1 hour
-------
There was 2.35% adhered to the skin and absorbed at the 10 hour time point with the lowest dose applied
(0.006 mg/cra1).
This study is classified as Acceptable (Guideline) and satisfies the requirement for a dermal absorption study (§85-
2) in the rat.
j. Special Studies
1. Studies Conducted with Fipronil
1) Thyroid Function/Rat: Four groups of 27 male Crl:CD (SD) BR rats per group were administered either
methylcellulose (vehicle control), 10 mg/kg/day fipronil (95.4% a.i.) 1,200 mg/kg/day propylthiouracil (PTU) or 50
mg/kg/day Noxyflex for 14 days. On Day 15, each animal received Na'MI at a dose level of 1 uCi IMI (MRID #
42977904). Six hours later, 9 males per group received either 10 or 25 rag/kg potassium perchiorate or 0.9% saline
solution. The treatment with fipronil or Noxyflex appeared to result in stimulation of the thyroid glands as
evidenced by increased accumulation of I25I in the thyroid glands and by increases in the ratios of radioactive
distribution between the blood and thyroid. These changes were accompanied by increases in thyroid weight
Treatment with PTU produced decreases in the amount of I23I incorporated in the thyroid and in the blood:thyroid
ratios along with elevated levels of I23I in the blood. However, the weights of the thyroids from these animals were
increased by over 2.5 fold compared to the controls and therefore, the ratio of ml in the blood to thyroid weight was
reduced. The administration of perchiorate produced further reductions in the IUI content in the thyroids and in the
bloodrthyroid I2SI radioactivity ratio. There was no evidence of an inhibition of iodide incorporation by either
fipronil or Noxyflex.
Classification: Supplementary
2) Thyroxine Clearance: Six groups of six male Crl:CD (SD) rats per group were administered either fipronil
(95.4%) (10 mg/kg/day by gavage), phenobarbital (80 mg/kg/day intraperitoneally) or 0.5% methylcellulose (vehicle
control at 5 ml/kg by gavage) for a duration of either one day or fourteen days (MRID # 42918654. Four hours after
the final dose of either test substance, each rat received ['"!] thyroxine at a dosage of 10 uCi/kg. fipronil had no
effect on mortality or other ante mortem parameters. Phenobarbttal-treated animals were observed to have collapsed
pasture, lethargy s&d shallow biCiUhLig os the fir* day of iicouufcui. Tiusc WBS BO effect of upronii on clearance
after one day of treatment, however after 14 days, there was a decrease in terminal half life (52% of control level) •
and increases in clearance and volume of distribution (261% and 137% of control level, respectively). The effects
seen with phenobarbital treatment were similar,' although quantitatively not as severe and were evident on Day 1 of
treatment . .
Classification: Supplementary
3) 28-Dav Study with Fipronitr Conclusions: Five Crl:CD (SD)BR rats/sex/group were treated with fipronil (93%
a.i.) 1 in the diet for four weeks at doses of either 0,25, 50,100,200 or 400 ppm (3.4,6.9, 12.6,24.5 and 45.3
mg/kg/day, respectively for males; 3 J, 6.7,12.9,24.9 and 54.9 mg/kg/day, respectively, for females (MRID
Number 4402801)). One female in the 400 ppm group died during the treatment period; the cause of death could
not be determined. Group mean body weight was decreased in both sexes of the 200 and 400 ppm groups the first
five days of the study, most likely due to decreased palatability. Overall (weeks 0-4) group mean body weight gain
(BWG) was decreased by 18 and 23% in the 200 and 400 ppm group males, respectively. Overall BWG was
decreased by 21,24 and 26% in the 100,200 and 400 ppm group females, respectively. Group mean food
consumption was decreased for both sexes of the 100,200 and 400 ppm groups at Day 5, but was comparable to the
controls after one week for females and three weeks for males. There were no treatment-related changes in
. hematology parameters. Total protein and globulin were statistically increased in all the orated male and female
groups; cholesterol was increased in the 400 ppm group males and all treated females. On gross pathological
examination, the liver was enlarged in 5/5 male rats and 3/5 female rats in the 400 ppm group, 2/5 females in the 200
ppm group, 1/5 males in the 100 ppm group and 1/5 females in the 50 ppm group. Increased group mean liver
weights were seen in all treated males and females, however the differences in males treated at 100 ppm and below
were not statistically significant Group meaii(thyroid weights were increased in all the treated females; however, the
v
27
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differences were not statistically significant or dose-related. There was an increased incidence of follicular
hypertrophy of the thyroids in all treated male and female rats. The change was graded as moderate'in the male rats
at 200 and 400 ppm and minimal in all other treated groups. A dose-related increase in generalized hepatocyte
enlargement was seen in males and females in the 200 and 400 ppm groups and in males in the 100 ppm group.
The LOEL is s, 25 ppm (3.4 mg/kg/day in males; 3.5 mg/kg/day in females) based on clinical laboratory
changes, increased absolute liver weights in females and histopathological alterations in the thyroid glands.
The NOEL is < 25 ppm.
Classification: Acceptable (Nonguideline)
2. Studies Conducted with Photodegradate MB 46513
In a 28-day range-finding study (MRID 44262809), MB 46513 (a photodegradate of fipronil; 97.5% a.i.) was
administered to Sprague-Dawley rats (10/sex/dose) in the diet at nominal dose levels of 0,0.5,3, 30 or 100 ppm
(equivalent to 0, 0.04, 0.23,2.20 or 3.74 mg/kg body weight/day, respectively, for males; 0, 0.04, 0.24, 2.32 or 3.8
mg/kg body weight/day, respectively, for females). In addition to evaluation of standard study parameters, thyroid
hormone levels were measured on days 7 and 23.
No treatment-related effects were observed in the 3 and 0.5 ppm treatment groups. One male in the 30 ppm group
was found dead on day 6 and all 100 ppm group animals died within the first 2 weeks of study. Clinical signs at 30
and 100 ppm included piloerection (M 9/10 and 4/10 at 30 and 100 ppm; F 5/10 and 6/10 at 30 and 100 ppm),
curling up at handling (M 6/10 and 4/10 at 30 and 100 ppm; F 8/10 and 5/10 at 30 and 100 ppm); thin (M 5/10 and.
4/10 at 30 and 100 ppm; F 6/10 and 6/10 at 30 and 100 ppm); increased motor activity (F 1/10 and 2/10 at 30 andb
100 ppm) and irritability with convulsions at 100 ppm in 1 female. There was a decrease in body weight (9-18% and
26-36% for 30 and 100 ppm) and food consumption (8-34% and 69-73% for 30 and 100 ppm). Clinical chemistry
parameters affected at 30 ppm included bilirubin (decrease - 28-33%) and aspartate aminotransferase (increased F -
22%). At 30 ppm on day 7 or 23, males had decreased T3 and T4 levels (33-49%) and females had decreased T4
levels (61%) compared to the controls. While at 100 ppm T3 levels were decreased 46% (females only), and T4
levels were decreased-50-63%. No treatment-related differences in hematology or urine parameters, organ weights
or gross postmortem or microscopic appearance were observed.. No neoplastic tissue was observed.
Ophthalmoscopk examinations were not conducted. The LOEL for this study is 30 ppm (2JM) and 2 J2 . :
mg/kg/day for M and F, respectively), based on clinical signs including piloerection, curling .up and thin
appearance; and decreased body weightsTn "both sexes. The NOEL is 3 ppm (0.23 and 0.24 mg/kg/day for M
and F, respectively). *-
This 28-day dietary feeding study js classified acceptable (non-guideline) as it is not a required guideline study. It
is acceptable for the purposes for which it was intended It is recommended that a maximum treatment rate between
3 and 30 ppm be used in longer term studies.
3. Studies Conducted with Metabolite MB 45897
In a subchronic toxicity study (MRID 44262821), MB 45897 (intermediate of fipronil; 99.7 a.i.) was administered to
CD rats (5/sex/dose) by gavage at nominal dose levels of 0, 50, 200 or 1000 mg/kg/day for 4 weeks.
In the 1000 mg/kg/day treatment groups, the livers of males and females had increased absolute (32-58%) and
relative (53-70%) weights, and the livers of 3/5 males exhibited periacinal hypertrophy with cytoplasmic
vacuolation. Total plasma protein levels were increased (10-19%) in both sexes, and alanine aminotransferase
activity (48%) was increased in females. All rats salivated excessively (days 2-28), and exhibited hunched posture
(days 8, 9, 11, and 12), underactivity (days 8-13), and staggered gaits (day 8). Males (4-5) and females (2-3) had
hair loss (days 3-28). Both sexes had reduced body weight gains (16%), and females were slightly anemic. In the
•200 mg/kg/day treatment groups, all rats salivated excessively (days 3-28) and exhibited hunched posture (days 8
and/or 11 and 12). Males had increased (9%) total plasma protein levels. In the 50 mg/kg/day treatment groups, all
rats salivated excessively (days 8-15, males; days 8-28, females) This may have been due to local irritation of the test
material. No rats died as a result of treatment. Ophthalmoscopic exams and urinalysis were not conducted. No
treatment-related differences in food consumption were observed in any treatment group. No neoplastic tissue was
' */
28
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1
observed in treated or control rats. The LOEL for this study is 200 mg/kg/day, based on hunched posture in ail
rats treated at this dose level. The NOEL is 50 mg/kg/day.
This 4-week oral toxicity study is classified acceptable (non-guideline) as it is not a required guideline study. It is
acceptable for the purposes for which it was intended, that being to assess the systemic toxic effects following 4
weeks of repeated daily administration (gavage) of the test substance.
4. Studies Conducted with Metabolite RPA 200766
28-Dav Study with RPA 200766: Conclusions: Ten Sprague-Dawley rats/sex/group were administered RPA 200766
(962% a.i.), a fipronii metabolite, in the diet at dose of either 0, 50, 500, 5000 or 15000 ppm for 28 days (mg/kg/day
doses respectively: males - 3.80, 38.16, 385.07 and 1087.05; females - 4.44,43.97,386.75 and 1062.84XMRID
Number 44017701). One female in the 15000 ppm group died during the study; the cause of death was attributed to
difficulty in blood collection. Body weight was significantly decreased from Day 8 to Day 28 for males and females
in the 5000 and 15000 ppm groups. Mean body weight gain over the course of the study was decreased by 27% and
61 % in the 5000 and 15000 ppm group males, respectively; it was decreased by 46% and 77% for the 5000 and
15000 ppm group female's, respectively. Mean food consumption over the course of the study was decreased by
11% and 25% in the 5000 and 15000 ppm group males, respectively; it was decreased by 22% and 33% in the 5000
and 15000 ppm group females, respectively. Mean hemoglobin values were decreased at 500 ppm and above for
males and females; all were statistically significant, except for the 15000 ppm group females. Mean hematocrit
values were decreased at 5000 ppm and above; all were statistically significant, except for the 15000 ppm group
females. Mean corpuscular hemoglobin values were decreased in the 15000 group males and females and in the
5000 ppm group males. Mean cholesterol values were significantly increased in males and females at 500 ppm and
above. Mean triglyceride values were increased in the 5000 and 15000 ppm group males and females. Urea nitrogen
was increased in the 5000 and 15000 ppm group females, whereas creatinine values were increased in males at 500
ppm and above. There were no histopathological changes in the kidneys, therefore, these changes are of doubtful
toxicoiogical significance. Dose-related increases in absolute and relative liver weights were seen in males and
females at 500 ppm and higher. Liver-to-brain weights were also increased in these groups. Significantly increased
adrenal weights were seen in all the treated males. Thyroid weights were increased in males at 50 ppm and above,
however the increases were not consistently found in all males in the group. In addition, there were no microscopic
changes in the thyroid. Therefore, these findings are of questionable toxicoiogical significance, although the parent
compound, fipronii, is known to be a thyroid toxicant Microscopic examination of the tissues from males and
females is ths 15000 ppm were not conducted -Starts mod^^ in the
adrenals of males and females at 5000 ppm. Slight to moderate extra-meduHary hematbpoiesis was observed in
males and females at 5000 ppm. A fine/coarse vacuolation of the zona fasciculata was observed in males at 50 ppm
and higher and in females in the 5000 ppm group. The NOEL was 50 ppai (3.80 mg/kg/day for males and 4.44
mg/kg/day for females). The LOEL was 500 ppm (38.16 mg/kg/day for males and 43.97 mg/kg/day for -
females) based on decreased hemoglobin values, increased cholesterol values and increased liver weights in
both sexes. -
Classification: Acceptable (Nonguideline)
k. Other Toxicoiogical Considerations
i. Toxicity of the photodegradate MB46513 as compared to the parent fipronii
The photodegradate MB46513 is not an animal metabolite. However in several
toxicity studies it has been determined that it is more toxic that the parent fipronii.
Since this photodegradate is present in rice it has been included in the dose response
assessment below.
ii. Data gap for acute inhalation with the ICON™ 6.2FS formulation
This study (MRJD 44260904) was classified by RD as unacceptable for the
following reason;, I) data too variable in both sexes, 2) it couldn't be determined
whether the toxicity category was a I or II, 3) in addition the chamber concentration
29
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varied greater than 20 % in several doses, 4) and the particle size was only
determined once per exposure in only 3 groups. This study needs to be repeated
Until this is done, the HED recommends that the formulation be considered a
category I for inhalation exposure as it relates to labeling and protective clothing.
2. Dose Response Assessment
t
The HI ARC met on 10-JUL-1997 to select appropriate endpoints for acute
dietary and short-, intermediate-, and long-term occupational exposure (dermal
and inhalation) for fipronil and on 9-DEC-1997 (document dated 18-DEC-1997)
to select appropriate endpoints for acute dietary and short-, intermediate-, and
long-term occupational exposure (dermal and inhalation) for the fipronil
photodegradate. On 22-JAN-1998 (document dated 29-JAN-1998) the
Committee reassessed the potential sensitivity of infants and children and to
discuss the uncertainty factors (UF) and/or Margins of Exposure (MOE) for both
the parent, fipronil and the photodegradate. On 22-Apr-1998, the HI ARC met
again to reevaluate the endpoints for fipronil and its photodegradate based on
new and reevaluated data (document dated 7-MAY-1998). The FQPA Safety
Factor Committee met on 27-APR-1998. The above documents contained the
endpoints for acute dietary, chronic dietary (RfD) as well as occupational and
residential exposure risk assessments (short-, intermediate-, and long-term
occupational exposure (dermal and inhalation)), carcinogenic potential and
sensitivity of infants and children from exposure to fipronil and the
photodegradate as required by the Food Quality Protection Act (FQPA) of 1996.
EPA generally defines the level of appreciable risk as exposure that is greater
than 1/100 of the no observed effect level in the animal study appropriate to the
particular risk assessment "This 100-fold uncertainty factor/margin ofexpojsure
(safety) is designed to account for inter-species, extrapolation and intra-species
variability. Under the Food Quality Protection Act (FQPA), P.L. 104-170, which
was promulgated in 1996 as an amendment to the Federal Food, Drug and
Cosmetic Act (FFDCA), the Agency was directed to "ensure that there is a
reasonable certainty that no harm will result to infants and children" from
aggregate exposure to a pesticide chemical residue. The law further states that in
the case of threshold effects, for purposes of providing this reasonable certainty
of no harm, "an additional tenfold margin of safety for the pesticide chemical
residue and other sources of exposure shall be applied for infants and children to
take into account potential pre- and post-natal toxicity and completeness of the
data with respect to exposure and toxicity to infants and children.
Notwithstanding such requirement for an additional margin of safety, the
Administrator may use a different margin of safety for the pesticide residue only
if, on the basis of reliable data, such margin will be safe for infants and children."
30
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FIPRONIL
a. Special Sensitivity to Infants and Children
The following discussion represents the information that was considered and the
following conclusions were drawn by the Hazard Identification Assessment
Review Committee taking into account results of the 2-JUL-1997,29-JAN-1998
and 22-APR-1998 meetings and the FQPA Safety Factor Committee meeting of
27-APR-1998.
1. Neurotoxicity: Fipronil has demonstrated neurotoxicity in the acute
and subchronic rat neurotoxicity studies as well as in the rat
chronic/oncogenicity and chronic dog studies.
2. Developmental Toxicity: There are acceptable rat and rabbit
developmental toxicity studies. There is no evidence of developmental
toxicity in either study.
3. Reproductive Toxicity: There is an acceptable two generation
reproduction study in the rat. Toxicity to the offspring (clinical signs of
toxicity, decreased litter size, decreased body weights, decreased pre- and
postnatal survival, and delays in physical development) occurred only at
levels where there was maternal toxicity (including maternal mortality).
4. Developmental Neurotoxicity: In an acceptable developmental
neurotoxicity study, the maternal LOEL is 200 ppm (15 mg/kg/day), based
on decreased body weight, body weight gaia'aad food coosumpiioa. The
"maternalNOEL was 10ppm(0.90mg/kg/d^)?Tnedevelopmental toxicity
LOEL is 10 ppm (0.90 mg/kg/day), based on a marginal but statistically
significant decrease in group mean pup weights during lactation, and
significant increase in time of preputial separation in males. The NOEL for
developmental, toxicity is 0.5 ppm (0^*05 mg/kg/day). The developmental
neurotoxicity LOEL is 200 ppm (15" mg/kg/day) based on: decreased
auditory startle response; reduced swimming direction scores, group mean
angle measurements and water "Y" maze times trails; and decreased
absolute brain weights. The NOEL for developmental neurotoxicity is 10
ppm (0.90 mg/kg/day).
5. Adequacy of data: An acceptable two-generation reproduction study in
rats (MRID# 42918647) and acceptable prenatal developmental toxicity
studies in rats (MRIDM2977903) and rabbits (MRID# 42918646) have
been submitted to the Agency, meeting basic data requirements, as defined
for a food-use chemical by 40 CFR Part 158. In addition, an acceptable
developmental neurotoxicity study was conducted with fipronil and
reviewed by the Agency. There are no data gaps for the assessment of the
effects of fipronilion developing animals following in utero and/or early
*»
31
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postnatal exposure.
6. Recommendation for a Development^ Neurotoxicitv Study A
developmental neurotoxicity study is available and has been considered
together with the rest of the toxicity data base for fipronil; therefore an
additional study with fipronil is not needed.
7. Determination of Susceptibility: Although there is no evidence of
enhanced pre or post natal susceptibility in infants and children in the
developmental and reproduction studies, the developmental
neurotoxicity study identified a developmental NOEL (0.05 mg/kg/day)
which is less than the maternal NOEL of 0.9 mg/kg/day indicating an
apparent susceptibility issue. However, the HIARC determined that the
evidence was not convincing (regarding susceptibility) due to the equivocal
nature of the findings. Valid arguments both for and against the biological
relevance of the statistically significant decrease in offspring body weight
gain and delayed sexual maturation data (delayed time to preputial
separation) at 0.9 mg/kg/day were considered. The more conservative
conclusion regarding the offspring developmental NOEL and LOEL for the
study was agreed upon by the HIARC, although it was recognized that:
a) the effects observed in the offspring at the LOEL of 0.9 mg/kg/day,
although statistically significant, were marginal and appeared to define
a threshold response level for this study;
b) the body weight findings of this study are not supported by results of
the two-generation reproduction study in rats at similar treatment
•- levels; aftd ""•"•-' ; " ;'"_ " """ "' ' ' '" "'"" ~" '
*
c) increased susceptibility to the offspring is not demonstrated following
pre- and/or postnatal dosing in the prenatal developmental toxicity
study nor the two-generation reproduction study in rats.
The HIARC concluded that the apparent increased susceptibility in the
developmental neurotoxicity study was not supported by the overall
weight-of-the-evidence (including no evidence for increased
susceptibility in the developmental and reproduction studies) from the
fipronil data base.
8. Determination of the FOP A Safety Factor
The FQPA Safety Factor Committee recommended (document dated 13-
MAY-1998) that the 10X factor for enhanced sensitivity to infants and
children (as required by FQPA) should be removed for fipronil and its
photodegradate, MB 46513.
32
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Rationale for Selection of the FOP A Factor
* The HIARC determined that the data provided no indication of
increased susceptibility of rats or rabbits to in utero and/or postnatal
exposure to fipronil. In the prenatal developmental toxicity studies in
rats and rabbits and the two-generation reproduction study in rats,
effects in the offspring were observed only at or above treatment levels
which resulted in evidence of parental toxicity.
»• No increased susceptibility was seen in the prenatal developmental
toxicity study in rats following in utero exposure to the
photodegradate, MB 46513.
*• The HIARC concluded that the apparent increased susceptibility in the
developmental neurotoxicity study was not supported by the overall
weight-of-the-evidence.
* Exposure assessments do not indicate a concern for potential risk to
infants and children based on: 1) the dietary exposure estimates using
field study data and anticipated market share information result in an
overestimate of dietary exposure; 2) modeling data is used for ground
and surface source drinking water exposure assessments resulting in
estimates considered to be reasonable upper-bound concentrations; 3)
there is the potential for residential exposure associated with the pet
uses, however, the use of chemical and site specific data in the
exposure assessment provide a realistic estimate of the potential
exposure to infants and children.
b. Reference Dose (RfD)
The Hazard ID Assessment Review Committee (document dated 7-MAY-1998)
assigned an RfD for fipronil of 0.0002 mg/kg/day using a NOEL of 0.019
mg/kg/day (0.5 ppm) established from a combined chronic toxicity/
carcinogenicity study in rats and an uncertainty factor of 100. The LOEL = 1.5
ppm (M: 0.059 mg/kg/day; F: 0.078 mg/kg/day), based on an increased incidence
of clinical signs (seizures and death) and alterations in clinical chemistry
(protein) and thyroid parameters (increased TSH, decreased T4) (MRID#
42918648).
O.Q19 mg/kg/dav (NOELt = 0.0002 mg/kg/day
100 (UF)
33
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1
c. Carcinogenic Classification and Risk Quantification
Cancer Classification and Basis: According to the proposed new guidelines, this
chemical has been classified by the HED Cancer Peer Review Committee
(document dated July 18, 1997) as a Group C - Possible Human Carcinogen,
based on increases in thyroid follicular cell tumors in both sexes of the rat, which
were statistically significant by both pair-wise and trend analyses. The RfD
methodology should be used to estimate human risk because the thyroid tumors
appear to be related to a disruption in the thyroid-pituitary status. There was no
apparent concern for mutagenicity (no mutagenic activity).
d. Dermal Absorption
% Absorbed: < 1% at 24 hours based on a dermal absorption study
(MRID#42918635).
e. Other Toxicological Endpoints
i. Acute Dietary (one day)
Dose and endpoint for use in risk assessment: In an acute
neurotoxicity study in rats the NOEL— 2.5 mg/kg/day based on
decreased body weight gains, food consumption and feed efficiency in
females, and decreased hindlimb splay in males at 7 hours post dosing
at 7.5 mg/kg/day (LOEL) (MRID# 44431801).
Comments about study and/or endpoint: Although a developmental
neurotoxicity study with the parent compound fipromi was available
(MRID No. 4403902), the Committee did not use this study for acute
dietary risk assessment In that study, the developmental NOEL was
0.05 mg/kg/day and the LOEL was 0.9 mg/kg/day and was based on
significant decreases in group mean pup weight during lactation and
significant increase in time of preputial separation in males. The
developmental neurotoxicity NOEL was 0.9 mg/kg/day and the LOEL
was 15 mg/kg/day based on decreased auditory startle response;
reduced swimming direction scores, group mean angle measurements
and water "Y" maze times trails; and decreased absolute brain weights.
The Committee determined that these effects are not attributable to a
single exposure (dose) and therefore are not appropriate for acute
dietary risk assessments.
This risk assessment is required.
34
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ii. Short- and Intermediate-Term Occupation and Residential
(dermal)
Dose and endooint for use in risk apresftmcnr in a 21-day dermal study
the NOEL = 5 mg/kg/day based on decreased body weight gain and
food consumption in male and female rabbits observed at the LOEL of
10 mg/kg/day (MRID# 42918644).
Comments about Study/Endpoint; The dermal NOEL is supported by
the oral NOEL of 0.05 mg/kg/day established in a developmental
neurotoxicity study when used in conjunction with a dermal absorption
factor of 1 %. This yields an equivalent dermal dose of 5 mg/kg/day
(i.e., 0.05 mg/kg/day •*• 0.01 dermal absorption factor - 5 mg/kg/day).
This risk assessment is required. .
-y
iii. Chronic Occupation and Residential (Non-Cancer)
Dose and endpoint for use in risk flfi.^ ^srnent: In a combined chronic
toxicity/carcinogenicity study [rat], the NOEL is 0.5 ppm (M: 0.019
mg/kg/day; F: 0.025 mg/kg/day), based on an increased incidence of
clinical signs (seizures and death) and alterations in clinical chemistry
(protein) and thyroid parameters (increased TSH, decreased T4) at 1.5
ppm (M: 0.059 mg/kg/day; F: 0.078 mg/kg/day) (MRED# 42918648).
Comments about study and/or endpoint: Since the; NOEL identified is
from an oral study, a dexiual absorption factor of •*• iyo should be used _
in risk calculations. NOTE: This stu4y/dose was ajlftj used to establish
the chronic RfD. ',. ^ "' '^^A 7A;
"••*•
This risk assessment is-required. " , ^^
iv. Inhalation Exposure (Any lime period)
There are three critical acute inhalation studies, one with the technical
and two with formulations.
Study 1: Acute inhalation study (technical) - Guideline §81-3, MRID
No. 43544401
Executive Summary: Sprague-Dawley rats (5/sex) were exposed
nose-only to fipronil at doses of 0.33, 0.52 and 0.72 mg/L for four
hours. At 0.72 and 0.52 mg/L, 100% mortality was observed. At the
0.33 mg/1 exposure, 2 male rats died, one on day 1 post-exposure and 1
on day 6 post-exposure. At the 0.72 mg/1 dose, the following were
noted in all rats on the day of exposure: urogenital, body and
i<>
35
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periocular wetness; unkempt fur; fine whole body tremors. In one
male at this dose, incoordination was observed on post-exposure days
4 through 7, hyperactivity on post-exposure day 4 and hypoactivity and
swollen penis on post-exposure day 7. This rat died on day 8. In one
female rat at this dose, perioral, perinasal and periocular red
encrustation was observed on post-exposure days 1 through 11,
hyperactivity on post-exposure days 2 through 4, hypoactivity on post-
exposure days 7 through 10 and incoordination on post-exposure days
6 through 11. This rat died on day 12. At the 0.52 mg/L dosq, the
same signs as mentioned for all rats at the 0.72 mg/L exposure
concentration were observed without any additional signs. At the 0.33
mg/L dose, similar signs were recorded, with the following additions
in males: perioral, perinasal, and periocular red encrustation up to day
5 post-exposure; incoordination in 4 of 5 male rats up to post-exposure
day 3; hypoactivity in 4 of 5 male rats up to post-exposure day 2. In
female rats at this exposure concentration, similar signs were observed
as for males. The incoordination did not appear until post-exposure
day 3 in 4 of 5 female rats and did not last beyond this point. The LC^
in rats was 0.36 mg/L, 0.42 mg/L and 0.39 mg/L in males, females and
the combined sexes, respectively (Toxicity Category II).
Study 2: Acute inhalation study (1.6% formulation) - Guideline §81-3,
MRID No. 4291 8638
LCy> > 5. 1 1 mg/L (Toxicity Category IV)
Study 3: Acute inhalation study (0.242% formulation) - Guideline
jo > 5.06 mg/L (Toxicity Category IV)
Dose and Endpoint For Use in Risk Assessment: None
Comments and Rationale: In the acute inhalation study on the
technical, death occurred at the lowest dose tested. At the next higher
dose, there were deaths and clinical signs of toxicity. The lack of a
NOEL in an inhalation study with the technical chemical would
usually require an additional Uncertainty Factor. However, using the
lowest dose in the acute inhalation study (0.33 mg/L) and available
exposure data demonstrated an adequate margin of exposure
(>68,000).
Therefore a separate risk assessment is not required.
36
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MB46513
a. Special Sensitivity to Infants and Children
See discussion in the flpronil section.
i. Adequacy of data: There are no data gaps for the assessment of the
effects of flpronil and/or the photodegradate on developing animals
following in utero and/or early postnatal exposure.
ii. Susceptibility Issuey In determining susceptibility, the toxicity of the
photodegradate MB46513 and the parent compound will be
considered simultaneously. The oral perinatal and prenatal data with
the parent compound fipronU demonstrated no indication of increased
sensitivity of rats or rabbits to in utero exposures. No additional
sensitivity was identified in the prenatal developmental toxicity study
in rats following in utero exposure to flpronil photodegradate
MB46513.
1. Developmental Toxicity
In a prenatal developmental toxicity study, pregnant Sprague-
Dawley rats (25/group) received oral administration of flpronil
photodegradate MB 46513 (99.2%) in aqueous methylcellulose
(10 ml/kg) at dose levels of 0,0.5,1.0, or 2.5 mg/kg/day during
gestation days 6 through 15. The dams were sacrificed on
. —geststsos day 20* Fcr agieraal tcxislty, the NOEL was 1.0 ~~
mg/kg/day and the LOEL was 2.5 mg/kg/day based on an increase
in clinical signs of toxicity (hair loss) and on reduced body
' weight gain, food consumption^ and food efficiency. For
developmental toxicity, the NOEL was 1.0 mg/kg/day and the
v'- '' ' LOEL was 2.5 mg/kg/day based on a slight increase in fetal and
litter incidence-of reduced ossification of several bones (hyoid,
5th/6th stemebrae, 1st thoracic vertebral body, pubic bone, and 1
or 2 metatarsi).. [Note that most of the reduced ossification is
weak evidence of a developmental effect. Although the minor
decrement in fetal weight at 2.5 mg/kg/day has questionable
biological relevance, the decrement is supported by the delayed
ossificatioa] (MRID No. 44275001).
In both the prenatal developmental toxicity studies in rats and
rabbits with flpronil, there was no evidence of developmental
toxicity at the highest doses tested (20 mg/kg/day in rats and 1.0
mg/kg/day in rabbits). Maternal toxicity (decreased body weight
gain, food consumption and/or water consumption) was observed
at these same doses, with a maternal NOEL of 4 mg/kg/day for
&
37
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rats and <0.1 mg/kg/day for rabbits (MRID Nos. 42977903 and
42918646). :
2. Reproduction Toxicity
In the two-generation reproduction study in rats with fipronil,
offspring toxicity was observed only in the presence of parental
toxicity. In the parental animals, reproductive toxicity
(reductions in mating and fertility) was also observed at the 30
ppm dietary level. For parental systemic toxicity, the NOEL was
3 ppm (0.25-0.27 mg/kg/day) and the LOEL was 30 ppm (2.54-
2.74 mg/kg/day) based on increased weight of the thyroid gland
and liver in both sexes, decreased weight of the pituitary gland in
the females, and increased incidence of follicular epithelial
hypertrophy in the females. For offspring toxicity, the NOEL was
30 ppm (2.54-2.74 mg/kg/day) and the LOEL was 300 ppm
(26.0-28.4 mg/kg/day) based upon clinical signs of toxicity,
decreased litter size, decreased body weights, decreased pre- and
postnatal survival, and delays in physical development. (MRID
No.42918647).
3. Developmental Neurotoxicity
In a developmental neurotoxicity study in rats with fipronil, there
was evidence of increased sensitivity of offspring to alterations in
functional development following pre- and/or postnatal exposure!
Specifically, the developmental and developmental-neuroioxicity,
- the NOEL.of.QL5 ppm (Q.QS mf/kg/day) was lower-fean the—-
maternal toxicity NOEL of 10 ppm (0.9 mg/kg/day). In the
offspring, decreased pup weigHts, increased time of preputial
separation in males, and increased motor activity count in female
pups was observed at the developmental LOEL of 10 ppm (0.9
mg/kg/day), while maternal toxicity (decreased body weight,
body weight gain, and food consumption) were observed at the
developmental LOEL of 200 ppm (15 mg/kg/day) (MRID No.
44039002).
iii. Determination of the FOP A Safety Factor: The FQPA Safety
Factor Committee recommended that the 10X factor for
enhanced sensitivity to infants and children (as required by
FQPA) should be removed for fipronil and its photodegradate,
MB 46513. See the discussion for fipronil for details.
(a) Developmental toxicity studies in rats with fipronil as well
as the photodegradate MB46513 showed no increased
sensitivity in fetuses as compared to maternal animals
^ ,.
-------
following in utero exposures. ------
(b) Developmental toxicity study in rabbits with fipronU
showed no increased sensitivity in fetuses as compared to
maternal animals following in utero exposures.
3. A two generation reproduction toxicity study in rats with
fipronil showed no increased sensitivity in pups when
compared to adults.
(d) Sensitivity was defined in the developmental neurotoxiciry
study in rats with fipronil. The NOEL is well defined for
the offspring for the photodegradate MB46513 as well as
fipronil, the parent compound.
(e) The toxicology profiles of the parent and the
photodegradate indicates that there is a 10 fold difference
in toxicity potency for the photodegradate when compared
to the parent compound. Therefore, a 10 fold potency
factor was used in the dose used to derive the RfD.
iv. Recomrnendatifl" ^or a Developmental Neurotoxicity Study: A
developmental neurotoxiciry study was not recommended for
MB46513 (a fipronil photodegradate). A developmental
neurotoxicity study was however conducted for the parent,
fipronil. If the Registrant conducts a developmental
- - nrursi\mdtysuidy with MB4631 3 (or any of 'the studies with "
this compound) it should be submitted to the Agency. ;
./•';••' <•." -' '--&; '•:.-• .... -... ''•"'
b. Reference Dose (RfD) *
'. .- .-- '.•••• •' ' ' -" '"• ~--'l"
The Hazard ID Assessment Review Committee (document dated December 18, -
1997) assigned an RfD of 0.00002 mg/kg/day (Study MR1D 42918648), based on
an adjusted NOEL of 0.0 1 9 mg/kg/day for the photodegradate (see discussion
below relating to the adjusted NOEL) and an Uncertainty Factor of 100. Effects
seen at the LOEL, 0.059 mg/kg/day were an increased incidence of clinical signs
indicative of neurotoxicity as well as alterations in clinical chemistry and thyroid
parameters. The 22- JAN- 1998, decision of the HIARC to use a UF of 1000 has
been superseded by the 7-MAY-1998 document recommending only a 100 UF
resulting in an RfD of 0.00002 mg/kg/day.
Dose and Endpoint for establishing the RfD: Adjusted NOEL = 0.0019 mg/kg/day for the
photodegradate MB46513. This adjusted dose was derived by the application of a Potency
Adjustment Factor (PAF) of 10 to the chronic NOEL of 0.019 mg/kg/day for the parent
compound (i.e., NOEL of 0.019 mg/kg/day +10 PAF = 0.0019 mg/kg/day).
39
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Comments about Study. Dose ?nrt FndirMnf The toxicity profile of the fipronil
photodegradate MB46513 indicate this material to be approximately 10 times more potent
than the parent compound when the NOELs/LOELs are compared A comparison of the
NOELs/LOELs established for the photodegradate and fipronil are presented in the table
below:
STUDY
Acute Oral
28-Day Oral - Rat
90-Day Oral - Mouse
90-Day Oral - Rat
Developmental -Rat
Photodegradate
LDJO= 16mg/kg
NOE17LOEL = 0.23 / 2.2 mg/kg/day
NOEL/LOEL = 0.08 / 0.32.mg/kg/day
NOEL/LOEL = 0.029 / 0. 1 8 mg/kg/day
Maternal NOEL/LOEL =1/2.5 mg/kg/day
Develop. NOEL/LOEL =1/2.5 mg/kg/day
Fipronil
LD5o = 92mg/kg
NOEL/LOEL = 3.4 mg/kg/day (LDT)
NOEL/LOEL = 1 .7 / 3.2 mg/kg/day
NOEL =0.33 / 1 .9 mg/kg/day
Maternal NOEL/LOEL = 4/20 mg/kg/day
Develop. NOEL/LOEL= 20 mg/kg/day
(HDT)
RiD =
As shown above, results of acute oral as well as the 28 day and 90 day subchronic
oral studies and oral developmental studies consistently demonstrated an
approximately 10-fold greater potency of the photodegradate MB46513 as
compared to the parent compound, fipronil.
For fipronil, the RfD was derived from the NOEL of 0.019 mg/kg/day
established in a combined chronic toxicity/carcinogenicity study in rats and an
Uncertainty Factor (UF) of 100 for inter-and intra-species variation. The LOEL
of 0.059 mg/kg/day was based on thyroid hypertrophy and neurological signs.
Since no long-term (chronic or carcinogeniciryj studies are available for the
photodegradate, the Committee concluded that there is sufficient experimental
evidence to warrant the application of a 10 fold Potency Adjustment Factor
(PAF) to the chronic NOEL for the parent compound to calculate a chronic
NOEL for the degradate in the absence of test data on the chemical. Thus, the
application of the adjustment factor to the chronic rat NOEL of (X019 mg/kg/day
for the parent resulted in a adjusted chronic NOEL of 0.0019 mg/kg/day for the
degradate.
Uncertainty Factor (UF}: An UF of 100 was applied to account for inter (10 x)-
and intra-(10 x) species variation. The 10X was not retained to accpunt for
sensitivity to infants and children (see discussion for fipronil).
Adjusted NOEL= 0.0019 mg/kg/day') = (0.00002 mg/kg/day rounded off)
100 (UF) .
Chronic Dietary Risk Assessment: The FQPA Safety Factor Committee
determined that the 10 x factor to account for enhanced sensitivity of infants and
40
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children (as required by FQPA) should not be retained. For chronic dietary risk
assessment, a UF of 100 is adequate for the protection of the general U.S.
population including infants and children from exposure to the photodegradate
MB46513. The UF of 100 following a 10-fold adjustment of the NOEL for
flpronil to account for the increase in potency of the photodegradate is required
based on the following weight-of-the-evidence considerations as discussed for
flpronil, above.
c. Carcinogenic Classification and Risk Quantification
No carcinogenicity studies are available with the photodegradate
MB46S13. Fipronil, the parent compound, was classified as a Group C
Carcinogen (Possible Human Carcinogen) by the HED's Carcinogenicity
Peer Review Committee (CPRQ. The CPRC based this classification on
statistically significantly (pair-wise and trend analyses) increased incidences
of thyroid follicular cell tumors in both sexes of Charles River CD rats. The
CPRC recommended that the RfD methodology for the quantification of
human risk be used because the thyroid tumors appeared to be related to a
disruption in the thyroid-pituitary status and there was no apparent concern
for mutagenicity or available information from structurally related analogs
(Memorandum: V. Dobo2y, HED to R. Keigwin, RD^ dated July 18,1997).
d. Dermal Absorption ' .,
% Absorbed: Approximately 2% at 10 hours based on a dermal
absorption study with the photodegradate.(MRID# 44262816).
- •
e. Other Toxicological Endpoints
L Acute Dietary .
.'•"•-"' ' . v^r'
- "•'".••
Dose and Endpojnt for Risk Assessment: NOEL55! mg/kg in an acute
neurotoxicity study in rats (with the photodegradate) based on
significant decreases m locomqtor activity m both sexes during the
first 30 minutes as well as decreases in hindlimb splay and rectal
temperature in both sexes at 6 hours post dosing at 12 mg/kg/day
(LOEL). (44262808)
Comments about Study and Endpoint: Effects were seen on the day of
treatment after a single oral exposure (dose) and thus is appropriate for
this risk assessment.
This risk assessment is required.
Although a developmental neurotoxicity study with the parent
compound flpronil was available (MRID No. 4403902), the
&
41
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Committee did not use this study for acute dietary risk assessment. In
that study, the developmental and developmental neurotoxicity NOEL
was 0.05 mg/kg/day and the LOEL was 0.9 mg/kg/day. The
developmental LOEL was based on significant decreases in group
mean pup weight during lactation and significant increase in time of
preputial separation in males and the developmental neurotoxicity
LOEL was based on a significant increase in mean locomotor activity
counts in females on Postnatal Day 17. The Committee determined
that these effects are not attributable to a single exposure (dose) and
therefore are not appropriate for acute dietary risk assessments.
Acute Dietary Risk Assessment: The FQPA Safety Factor Committee
determined that the 10 x factor to account for enhanced sensitivity of
infants and children (as required by FQPA) should not be retained.
For acute dietary risk assessment, a Margin of Exposure (MOE) of
100 is adequate for the protection of the general U.S. population
including infants and children from acute exposure to fipronil
photodegradate MB 46513.
ii. Short- and Intermediate Term Dermal Exposure (1 to 7 days) (1
week to several months)
Dose and Endpoint for Risk Assessment: Adjusted Dose= 0.5
mg/kg/day. This dose was derived by dividing the actual study NOEL
of 5 mg/kg/day by the Potency Adjustment Factor (PAF) of 10 (5^-10 =
0.5 mg/kg/day). The LOEL was based on decreases in body weight
gain and food consumption. (42918644)
Comments about Study and Endpoint: The Committee selected the
dose and endpoint from the 21-day dermal study with the parent
compound for the following reasons: 1) a 21-dermal toxicity study
with the photodegradate is not available; 2) low potential for risk
from dermal exposure due to minimal dermal absorption as indicated
for both the parent (<1%) and the photodegradate (2%) materials; and
3) when the developmental/developmental neurotoxicity NOEL of
0.05 mg/kg/day for fipronil (established in the developmental
neurotoxicity study) is adjusted for 1% dermal absorption (DA), results
in a comparable dermal dose of 5 mg/kg/day (i.e., 0.05 mg/kg/day •*•
1% DA = 5 mg/kg/day) which essentially is the same as the NOEL for
fipronil in the 21-day dermal toxicity study. In addition, for
occupational exposures, the photodegradate is not expected to form
during the mixing/loading or application of fipronil. Reentry exposure
is unlikely as the product is to soil incorporated or the treated seed
covered within 48 hours. Residential exposure to the photodegradate
is not expected while spraying or handling a recently treated pet as
42
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1
these are brief periods usually occurring indoors. Postappfication
exposure to the degradate is also not expected due to the products
reportedly strong affinity to the sebum and epidermis of pets.
A MOE of 100 is adequate for short and intermediate occupational
and/or residential exposures to fipronil photodegradate MB 46513,
for the same reasons stated under Acute and Chronic dietary exposure
risk assessments..
This risk assessment is required.
iii. Chronic Dermal Exposure (Several Months to Lifetime)
Dose and Endpoint for Risk Assessment: Not Applicable
Comments about Study and Endpoint: Based on the current use
pattern for the photodegradate (i.e., 1 application/year at planting),
Long-Term exposure via the dermal route is not expected.
Commercial applicators are expected to be exposed during the planting
season only. Residential exposures are not chronic in nature as label
uses for pets indicate treatment every 1 to 3 months.
This risk assessment is NOT required.
iv. Inhalation Exposure (Any time period)
Dose-andEndpoint for Risk Assessment* Not Applicable.
Comments about Study and Endpoint: Potential inhalation exposure is
mitigated by the use of respirators antt the unlikelihood of the
photodegradate forming during the application activities.
This risk assessment is NOT required.
v. Recommendation for Aggregate Exposure Risk Assessments
An aggregate systemic (oral) and dermal exposure risk assessment is
not appropriate due to differences in the toxicity endpoints observed
between the oral (neurotoxicity and alterations in clinical chemistry
and thyroid parameters) and dermal (decreases in body weight gain and
food consumption) routes. An aggregate oral and inhalation risk is not
required due to the lack of exposure potential via the inhalation route
based on the current use pattern.
43
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TABLE 2 ENDPO1NTS FOR FIPRQNIL CParent)
EXPOSURE
SCENARIO
Acute (Dietary)
Chronic (Dietary)
Short- Term (Dermal)
Intermediate-Term
(Dermal)
Long-Term (Dermal)
(Inhalation)
Cancer (Dietary/
Dermal/Inhalation)
Dose (nig/kg/day}
NOEL =
2.5 mg/kg
UF=100
NOEL =
O.OI9mg/kg/day
UF = 100
NOEL =
5 mg/kg/day
NOEL =
5 mg/kg/day
NOEL =
0.0 19 mg/kg/day1
NA
ENDPOiNTANPTOXiCOLOGICAL
EFFECT >
Decreased hind leg splay in male and
female rats hi an acute neurotoxicity study
in rats.
Acute RfD = 0.025 mg/kg
Increased incidence of seizures and death,
alterations in clinical chemistry (protein)
and t TSH, I T4.
Chronic RID -0.0002 mg/kg/day
Increased body weight gain and food
consumption in
-------
1
TABLE 3. ENDPOINTS FOR PHOTODEGRADATE (MB46513)
EXPOSURE
SCENARIO
Acute (Dietary)
Chronic (Dietary)
Short-Term (Dermal)
Intermediate-Term
(Dermal)
Long-Term (Dermal)
All time periods
(Inhalation)
Cancer (Dietary/
Dermal/Inhalation)
Dose (mg/kg/day)
NOEL = 2.0 mg/kg
UF=100
•Adjusted NOEL =
0.00 19 mg/kg/day
UF=100
•Adjusted NOEL =
0.5 mg/kg/day
•Adjusted NOEL =
0.5 mg/kg/day
NA
ENDPOINT AND TOX1COLOGICAL
EFFECT - .
Decreased locomotor activity as well as
decreases in hindlimb splay and rectal
temperature
Acute RfD = 0.02 mg/kg
Increased incidence of seizures and death,
alterations in clinical chemistry (protein)
and t TSH, I T4.
Chronic RfD = 0.00002 mg/kg/day
Increased body weight gain and food
consumption in rfs and Ss in a 21-day
dermal study in rabbits. Supported by a
NOEL of 0.05 mg/kg/day in a
developmental neurotoxicity rat study
based in 1 pup weight during lactation, an
I in time to preputial separation in males,
and an t in mean motor activity counts for
2 on Postnatal Day 17.
Same as Short Term
Not required. Use pattern ( 1 appl/year)
does not indicate a potential for this
exposure; risk assessment not required.
Not required ^
it
Group C - Possible Human Carcinogen
(increases in thyroid follicular cell tumors
with fipronil (M&F)). Use RfD to
estimate human risk.
STUDY • I!
Acute
neurotoxicity
Chronic/onco rat
study (fipronil)
21 -day dermal
study (fipronil) ||
2 1 -day dermal [I
study(fipronil) H
* = Adjusted NOEL obtained by dividing the actual NOELs established in the studies conducted with
the parent compound fipronil and Potency Adjustment Factor of 10. A Potency Adjustment Factor of
10 was determined by the Committee based on the toxicity profiles of the photodegradate MB41513
and fipronil.
45
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3. Dietary Exposure and Risk Assessment/Characterization
a. Dietary Exposure (Food Source)
i. Directions for Use
The petitioner provided specimen labels for an 80% water-dispersible
granular (WDG) formulation (Product name = ICON™ 80 WG
Insecticide), a 56% flowable solid (FS) formulation (Product name =
ICON™ 6.2 FS Insecticide) and a 56% soluble concentrate (SC)
formulation (Product name = ICON™ 6.2 SC Insecticide) proposed for
use on rice for the control of rice water weevil. The proposed use
patterns for rice are described below.
These formulations are proposed for a single preplant broadcast
application to the soil of dry-seeded rice and water-seeded rice at
0.025-0.05 Ib ai/A. For dry-seeded rice, fipronil is to be applied as a
broadcast treatment to a dry soil surface prior to planting. For water-
seeded rice, fipronil is to be applied as a broadcast treatment to a dry
soil surface and incorporated prior to establishing a flood for water
seeding. The labels specify that to prevent loss of insecticidal activity,
fipronil must be incorporated within 48 hours of application. Fipronif
is to be mixed with water and incorporated into the top 2-3 inches of
soil. The labels state that application may be made using either aerial
or ground equipment. For application using ground equipment,
fipronil is to be sprayed in 10-40 gal/A; for aerial equipment, a
minimum of 5 gal/A.
The labels propose a plantback interval of 5 months for root crops and
leafy vegetables, and a rotational crop restriction of 12 months for
small grains or other rotational crops. A restricted entry interval of 12
hours is specified. The labels prohibit the fishing or commercial
growing offish, shellfish, or crustaceans on treated rice acreage. The
labels specify that applications are not to be made directly to water, to
areas where surface water is present, to intertidal areas below the mean
high water mark, or on blooming crops or weeds.
The 6.2 FS formulation is also proposed for use as a seed treatment at
a rate of 0.025-0.05 Ib ai/A. For water-seeded rice, fipronil is to be
applied after germination. Use of an EPA-registered dye is required.
ii. Nature of the Residue - Plants
Rhone-Poulenc has submitted data from a study (MRID 43827002)
investigating the metabolism of uniformly phenyl-ring labeled
['4C]fipronil in rice. The qualitative nature of the residue in rice is
-------
adequately understood based on this metabolism study in which rice
plants were separately treated with [phenyl-l4C]fipronil as a granular
application and a foliar application. The total radioactive residues
(TRR) were 0.755 ppm in/on immature rice plants (stem and leaves),
0.801 ppm in the solvent wash of immature plants, and 0.120 ppm
in/on immature roots harvested 1 day following the last of two foliar
spray applications of [MC]fipronil at a total rate 0.054 Ib.ai/A/season
(1.2x the maximum proposed seasonal rate). The TRR were 0.101
ppm in/on mature rice roots, 0.247 ppm in/on mature rice straw, 2.096
ppm in/on panicle, 0.495 ppm in/on husk, 0.155 ppm in/on bran, 0^024
ppm in/on brown rice, and 0.013 in/on polished rice harvested 42 days
following treatment.
Approximately 47->100% of TRR were characterized/identified in rice
commodities receiving foliar treatment. Fipronil was detected in all
rice commodities, at 35.9-80.0% of TRR (0.096-0.271 ppm) in
immature commodities and 22.7-51.6% of TRR (0.005-0.478 ppm) in
mature commodities. The photodegradate MB 46513 was also
detected in all commodities, at 7.1-13.2% of TRR (0.016-0.053 ppm)
in immature commodities and 1.5-26.9% of TRR (<0.001-0.565 ppm)
in mature commodities. The metabolites MB 45950, MB 46136, MB
45897, RPA 200766, and RPA 104615 were also identified.
The TRR were 0.053 ppm in/on immature rice plants (stem and
leaves), 0.001-0.005 ppm in immature plant solvent washings, and
0.070 ppm in/on immature rice root harvested 31 days following a
single granular broadcast application of.[l4C]fipronil at 0.045 Ib ai/A
(IX the maximum proposed seasonal rate). The total radioactive
residues were 0.066 ppm in/on mature rice roots, 0.099 ppm in/on
mature rice straw, 0.326 ppm in/on panicle, 0.073 ppm in/on husk,
0.022 ppm in/on bran, 0.005 ppm in/on brown rice, and 0.004 in/on
polished rice harvested 72 days following treatment
Approximately 48->100% of TRR were identified in rice commodities
receiving granular treatment Fipronil was detected in all rice
commodities, at 14.8-15.3% of TRR (0.008-0.010 ppm) in immature
commodities and 6.3-25.4% of TRR (0.001-0.027 ppm) in mature
commodities. The photodegradate MB 46513 was also detected in all
commodities, at 11.7-17.9% of TRR (0.008-0.010 ppm) in immature
commodities and
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substance labeled in the pyrazole ring (CBTS No. 15943, D217612
8/29/95, G. Kramer). HED will extend this decision to rice, and
concludes that a rice metabolism study using pyrazole-labeled fipronil
is not required.
The HED Metabolism Committee, in a meeting held on 5/28/97, has
determined that the fipronil residues of concern for the tolerance
expression and dietary risk assessment in plants animals are the parent
and its metabolites MB 46136 and MB 45950. The Committee also
concluded that residue data for photodegradate MB 46513 will be
required for crops for which metabolism data indicate that this
photodegradate comprises a significant portion of the total radioactive
residue (i.e., rice, potatoes, and rotational crops).
Photodegradate MB 46513 was identified as a significant component
in/on rice commodities. The Agency, therefore, concurs with the
petitioner that the residues of concern for the proposed tolerances are
fipronil and its metabolites MB 45950, MB 46136, and MB 46513.
iii. Nature of the Residue-Animals
Ruminants
In the ruminant metabolism study (MRIDtf 434011-05), [phenyl(U>
l4C]-fipronil was administered orally to lactating goats. The goats
were dosed at a rate of 0.02 ppm, 2 ppm or 10 ppm. Doses were
administered twice daily for 7 consecutive days. Of the administered
. radioactivity, 1-8-64% _was.recovered-in f 48
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1
each of three lactating goats twice daily for 7 consecutive days at
respective does rates of 10 ppm, 2 ppm, and 0.05 ppm. An additional
goat served as a control. The submitted ruminant metabolism study for
MB 46513 is acceptable. Following oral administration of [I4C]MB
465 1 3 to lactating goats at 1 0 ppm in the diet for 7 days, the TRR were
0.0502-0.3580 ppm in milk, 2.815 ppm in liver, 0.468 ppm in kidney,
0.180 ppm in muscle, and 2.681 and 2.215 ppm in omental and renal
fat, respectively. MB 46513 was the major component identified at
93.8% of TRR (0.164 ppm) in 32-h milk, 94.1% of TRR (0.337 ppm)
in 152-h milk, 58.1% of TRR (1.637 ppm) in liver, 49.2% of TRR
(0.230 ppm) in kidney, 69.6% of TRR (0.125 ppm) in muscle, 81.6%
of TRR (2. 1 88 ppm) in omental fat, and 85.6% of TRR ( 1 .896 ppm) in
renal fat. Three additional metabolites were tentatively identified in
liver: 5-deaminated ring-opened RPA 105048 (3.42% of TRR, 0.096
ppm), RPA 108058 (2.06% of TRR, 0.058 ppm), and 5-deaminated
ring-opened RPA 1 06889 (2.96% of TRR, 0.083 ppm).
Poultry
In the poultry metabolism study (MRID# 43401 1-06), [phenyl(U)-'4C]-
fipronil was administered orally to laying hens. The hens were dosed
at a rate of 0.02 ppm, 2 ppm or 10 ppm. There were five birds in each
dosing group. Doses were administered daily for 28 consecutive days.
Of the administered radioactivity, 28-42% was recovered fn excreta,
15-18% in the eggs and 1-5% was recovered in the tissues. The total
recovery was 52-58%. The greatest tissue residues were observed in
fat (56 ppm al : JO. ppm dose)., JResidues in eggs,wj?malso extremely.. _ _
high (30 ppm in yolks at 10 ppm dose) and had not plateaued by the
end of the study (28 days). MB46136 was the predominant component
of the residue in tissues and eggs, accounting for 95-99% of the TRR.
Fipronil was also identified in egg yolk, skin, fat and liver, accounting
for 1-3% of the TRR. A total of 95-100% of the TRR was identified.
Rhone-Poulenc has submitted data from a study (MRID 44262836)
investigating the metabolism of MB 465 1 3 in laying hens. MB465 1 3
is a photodegradate of fipronil which was identified in rice and cotton
metabolism studies and in the confined rotational crop study but was
not identified in ruminant or poultry metabolism studies. The test
substance, phenyl-labeled [14CJMB46513 was administered orally to
each of three groups of five laying hens once daily for 14 consecutive
days at respective dose rates of 10 ppm, 2 ppm, and 0.05 ppm. Three
hens served as controls. The submitted poultry metabolism study for
MB 46513 is acceptable. Following oral administration of [I4C]MB
46513 to laying hens at 10 ppm in the diet for 14 days, the TRR were
0.843 ppm in egg whites, 7. 1 82 ppm in egg yolks, 4.089 ppm in liver,
0.508 ppm in muscle (breast and thigh), 9.683 ppm in omental fat, and
49
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T
5.891 ppm in skin with fat.
MB 46513 was the major component identified at 83.3% and 85.1% of
TRR (0.350 ppm and 0.717 ppm) in Day 5 and Day 14 egg whites,
56.37% and 59.33% of TRR (0.827 ppm and 4.261 ppm) in Day 5 and
Day 14 egg yolks, 13.83% of TRR (0.565 ppm) in liver, 69.68% of
TRR (0.354 ppm) in muscle, 90.9% of TRR (1802 ppm) in omental
fat, and 86.9% of TRR (5.119 ppm) in skin with fat. In addition, RPA
108058 was tentatively identified in Day 5 egg yolks (2.53% of TRR,
0.037 ppm), and Day 14 egg yolks (1.23% of TRR, 0.088 ppm), and
liver (5.62% of TRR, 0.230 ppm); and MB 46400 was also tentatively
identified in Day 5 egg yolks (0.99% of TRR, 0.015 ppm), Day 14 egg
yolks (5.21% of TRR, 0.375 ppm), and liver (3.26% of TRR, 0.133
ppm). The glucuronide conjugate of MB 46513 was tentatively
identified in Day 5 and Day 14 egg yolks (1.42% of TRR, 0.021 ppm,
and 6.01% of TRR» 0.432 ppm, respectively), and the sulfate conjugate
of MB 46513 was tentatively identified in liver (2.07% of TRR, 0.084
ppm). Three additional metabolites were tentatively identified in liver:
ring-opened RPA 105048 (1.76% of TRR, 0.072 ppm), ring-opened
RPA 106889 (3.69% of TRR, 0.151 ppm), and the monodechloro,
monohydroxy MB 46513 (2.27% of TRR, 0.093 ppm).
In the residue trials, the levels of MB 46513 were
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1
fipronil and its metabolites MB 45950, MB 46136, MB 46513, and
RPA 200766 in/on plant commodities. Fipronil and its metabolites are
analyzed in a single chromatographic separation. The LOQ for each
analyte is 0.003-0.01 ppm depending on the matrix. This method has
undergone a successful PMV (DP Barcode D234562, G. Kramer,
4/29/97), and will be suitable for enforcement purposes for fipronil and
its metabolites once the revisions recommended by ACL have been
incorporated. Note that all directions pertaining to RPA 200766
should also be removed as this metabolite has been determined to not
be of regulatory concern. Briefly, samples of rice grain and straw were
extracted with ACN:water and vacuum filtered. The filtrates were
combined and mixed with ACN:aqueous NaCl, then partitioned with
hexane. The aqueous layers following phase separation were
combined, and ACN was removed by rotary evaporation. The
remaining aqueous phase was extracted with dichloromethane.
Following phase separation, the combined dichloromethane extracts
were concentrated by rotary evaporation and cleaned up with column
packed with Florisil, acidic alumina, silica gel, activated charcoal, and
anhydrous sodium sulfate. Residues were eluted with ACN:methanol
and the eluate was concentrated by rotary evaporation and dissolve in
ACN prior to GC analysis. GC analyses were conducted using a DB-
1701 column and mass selective or electron capture detection (MSD or
ECD).
Rice grain samples from the processing study were analyzed using the
same method with minor modifications. The final eluate was analyzed
by GC/ECP. GC analyses were conducted using a DB-5 column,
The GC methods used for the analyses of samples collected from the
rice crop field trials and processing study are adequate for collection of
residue data. Adequate method validation and concurrent method
recovery have been submitted for these methods. These methods are
similar to the GC method proposed for cottonseed which has
undergone a successful PMV.
Animals:
A method for the determination of residues of fipronil and its
metabolites MB 45950 and MB 46136 in animal commodities was
previously reviewed in conjunction with a petition for corn and animal
RACs (PP#5F04426; CBTS No. 15436, DP Barcode D214376, G.
Kramer, 7/25/95 and CBTS Nos. 16773 and 16774, DP Barcodes
D222541 and D222350, G. Kramer, 4/1/96), and has undergone a
successful PMV (CBTS No. 16339, DP Barcode D220222, G. Kramer,
10/26/95).
51
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v. Multiresidue Methods
A report on Multiresidue testing of fipronil and its metabolites MB
^ s 45950.and.ME46.136 (MRID# 434011-07) has been received and
forwarded to FDA (Memo, G, Kramer 5/9/95). Acceptable recoveries
of fipronil and its metabolites were obtained in com grain using
Protocol E. Recoveries in forage were 38-65% using Protocol E. A
report on Multiresidue testing of MB 46513 (MRID# 443748-01) has
been received and forwarded to FDA (Memo, S. Chun 12/2/97).
Acceptable recoveries of MB 46513 were obtained in com forage
using Protocol E and cottonseed using Protocol F. Recoveries were
98.6 ± 9.4% using Protocol E and 89 ± 6.2% using Protocol F.
vi. Storage Stability Data
Samples from the submitted field trials and the processing study were
stored frozen for a maximum of 11 months prior to analysis. Storage
stability data were previously submitted and reviewed in conjunction
with a petition for com and animal RACs (PP#5F04426; CBTS Nos.
16773 and 16774, DP Barcodes D222541 and D222350, G. Kramer,
4/1/96 and CBTS No. 15436, DP Barcode D214376, G. Kramer,
7/25/95). The data demonstrated that residues of fipronil and its
metabolites MB 45950, MB 46136, RPA105048, and RPA200766 are
stable under frozen conditions for up to 2 years in/on corn grain, and
for 12 months in/on com forage, fodder, silage, crude oil, refined oil,
grain dust, meal, and starch. The available frozen storage stability data
support the storage intervals of the submitted field trials; however, data
depicting the storage stability^ of the photpdegradate MB[46513 in/on
rice grain and straw stored frozen foe up to 11 months are required.
We note that the petitioner had reported that a 1-year freezer stability
study for residues of fipronil and its metabolites (which include MB
46513) in cotton commodities was in progress (CBTS No. 16288,
D219819, G. Kramer 11/12/96). If the results of this study are
acceptable, these data may be adequate to support the rice field trials
and processing study.
vit. Crop Field Trials
Rhone-Poulenc has submitted data from 17 crop field trial studies
(MRID 44261910 & 44355401) depicting residues of fipronil in/on
rice.
Seventeen field trials were conducted in AR(5), CA(3), LA(5), MS(2),
and TX(2). A field trial was conducted in MO, but no samples were
obtained. At each site rice grain and straw were harvested at normal
maturity, 107-143 days following a preplant incorporated (PPI)
^ 52
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broadcast application of the 80% WDG formulation at -0.05 Ib ai/A
(IX the maximum proposed application rate) or seed treatment with a
10% liquid fprmulation_equivale.nt to -OJ)5 Ib ai/A at the stated
seeding rate. Trials conducted in MRJD44355401 utilized a 56%
liquid formulation for both the PPI broadcast application and the seed
treatment equivalent to -0.05 Ib. ai/A (IX the maximum proposed
application rate).
Preplan! incorporated applications were made in 8-21 gal of water/A
using ground equipment (CO2 backpack or tractor-mounted sprayers);
seed treatment was made either to dry seed using a laboratory-sized
seed treatment apparatus after which seed was air dried for 12 hours, or
to seed which had been soaked with water for 24 hours by mixing the
seed in a plastic bag with the fipronil formulation and a polymer
additive. Rice seed was planted using normal cultural practices: dry
seeding or water seeding (flooding). For the seed treatments, dry seed
was used for dry seeding and pre-soaked seed was used for water
seeding; the petitioner noted that the use of pre-soaked seed for water
seeding is not yet a commercial practice. The total application rates
for PPI treatments were 0.047-0.053 Ib ai/A and for seed treatments
were 0.044-0.052 Ib ai/A.
The LOQ is 0.01 ppm. The method was validated over a range of
0.01-5.0 ppm for rice RACs. The average percent recovery for rice
grain was fipronil (94%), MB 45950 (90%), MB 46136 (102%), MB
46513 (98%), and RPA 200766(110%). The average percent recovery
for rice straw was fiprpnil (89%), MB 45950 <88%)s MB 46J 36 (96.%V
MB 46513 (93%), and RPA 200766 (104%). In the eight field trials
submitted separately (MRID #44355301), no percent recoveries were
obtained for RPA 200766. *
Residues of fipronil and its four metabolites were each less than the
LOQ (<0.010 ppm) in/on 10 samples each of untreated rice grain and
straw.
A total of 17 field trials for each formulation and application type were
conducted with rice in Regions 4(12 trials), 6 (2 trial), and 10 (3
trials). The number and location of field trials is not adequate to
support the proposed use of the fipronil on rice. One additional trial is
required in Region 5.
The submitted data indicate that the combined residues of fipronil, MB
45950, MB 46136, and MB 46513 will not exceed the proposed
tolerances for rice straw (0.10 ppm) and rice grain (0.04 ppm) in/on
samples harvested at maturity following either a preplant incorporated
(PPI) broadcast application of the 80% WDG formulation or seed
&
53
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treatment with a 10% liquid formulation at -0.05 Ib ai/A (IX the
proposed maximum rate). The combined residues in/on rice following
the above treatments were less than the combined LOQ (<0.04 ppm)
in/on rice grain (34 samples each from PPI and seed treatments), and
<0.04-<0.053 ppm in/on rice straw from PPI treatments and
<0.04-<0.054 ppm in/on rice straw from seed treatments (34 samples
each).
Based on the highest residue value obtained from samples harvested
following the proposed PPI or seed treatments at the proposed
maximum use rate, the proposed tolerance levels of 0.10 ppm for rice
straw and of 0.04 ppm for rice grain are appropriate.
viii. Processed Food/Feed
Rhone-Poulenc submitted the data (MRID 44261911) depicting the
potential for concentration of fipronil residues in the processed
commodities of rice.
Two trials were conducted in LA(1) and TX(1). At each site, rice
grain was harvested at normal maturity, 110-119 days following a PP!
broadcast application of the 80% WDG formulation at -0.25 Ib ai/A
(5x the maximum proposed application rate) or seed treatment with a
10% liquid formulation equivalent to -0.30 Ib ai/A at the stated
seeding rate (6x the maximum proposed application rate). Preplant
incorporated applications were made in 17 and 18 gal/A of water using
ground equipment; seed treatment was made to dry seed using seed
treatment apparatus.. Total application rates for PP! treatments were
0.251 and 0.254 Ib ai/A (5x the maximum application rate) and for
seed treatments were 0.304 and 0.293 Ib ai/A (6x the maximum
application rate).
The control and bulk treated samples were collected either
mechanically or manually from the designated test plots. Composite
samples from the LA and TX sites were shipped to South Texas Ag
Research (Brookshire, TX) for processing. Samples were processed
according to simulated commercial procedures into hulls, bran, and
polished rice.
Apparent residues of fipronil and its metabolites MB 45950, MB
46136, MB 46513, and RPA200766 were each less than the LOQ
(<0.01 ppm) in/on two samples each of untreated rice grain and on
reanalysis of hydrated samples. Residues were less than the LOQ
(<0.01 ppm) in/on two samples each of treated rice grain from the PPI
and seed treatments and on reanalysis of hydrated samples. Because
quantifiable residues were not obtained from rice grain treated at 5x
54
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the maximum proposed application rate, no analyses were performed
on the processed samples of hulls, bran, or polished rice.
The submitted rice processing data are adequate. The data indicate
that total residues of fipronil and its metabolites MB 45950, MB
46136, MB 46513, and RPA200766 are less than the LOQ (<0.01
ppm) in/on rice grain harvested at maturity following preplant
incorporated broadcast application of the 80% WDG formulation at
-0.25 Ib ai/A (5x the maximum proposed seasonal rate) or seed
treatment with a 10% liquid formulation equivalent to -0.30 Ib ai/A at
the stated seeding rate (6x the maximum application rate). Because
treatment at 5-6x did not result in quantifiable levels of fipronil
residues of concern in rice grain, all further requirements for the
processing study are waived, and no tolerances are required for the
processed commodities of rice.
ix. Meat, Milk, Poultry, Eggs
Rice grain, straw, hulls, and bran are animal feed items. The available
animal metabolism studies suggest that tolerances for animal
commodities are required. According to Section F of the current
petition, tolerances for meat, milk, eggs, liver, kidney, meat
byproducts, and fat were established in conjunction with the tolerance
petition PP#5F04426 for fipronil use in/on com. The petitioner stated
that these tolerances are adequate to cover the additional uses of
fipronil on rice.
Fipronil: The maximum theoretical dietary burden of fipronil to beef
and dairy cattle, based only on the proposed tolerances of 0.04 ppm for
rice grain and 0.10 ppm for rice straw, is 0.04 ppm. The maximum
theoretical dietary burden of fipronil to poultry, based only on the
proposed tolerances of 0.04 ppm for rice grain, is 0.04 ppm
Acceptable cow and poultry feeding studies were submitted and
reviewed in conjunction with PP#5F04426 (CBTS No. 15436, DP
Barcode D214376, G. Kramer, 7/25/95). Based on these studies, the
Agency has recommended appropriate tolerance levels for fipronil
residues in/on animal commodities (DP Barcode D235683, G. Kramer,
8/11/97). The tolerances for animal commodities established in
conjunction with PP#5F04426 are adequate to support the proposed
use on rice.
Based on the expected dietary contribution of fipronil residues in/on
eggs, milk, and tissues as the result of the current rice petition and
established/proposed tolerances for corn, cotton, and potatoes, the
Agency may have to reassess the results of the animal feeding studies
,\ 55
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to determine the appropriate tolerance levels for animal commodities.
MB 46513: The maximum theoretical dietary burden of MB 46513 to
beef and dairy cattle is 0.007 ppm, based on the method LOQ of 0.01
ppm. The maximum theoretical dietary burden of fipronil to poultry,
based on the method LOQ of 0.01 ppm, is ,0.01 ppm.
In the ruminant metabolism study conducted at 10 ppm (1400X),
maximum residues of MB 46513 were seen in fat at levels up to 2.1
ppm, which corresponds to 1.6 ppb when normalized to IX. In the
poultry metabolism study conducted at 10 ppm (1000X), maximum
residues of MB 46513 were seen in fat at levels up to 9.7 ppm which
correspond to 9.7 ppb when normalized to IX. Based on low potential
for residues in meat, milk and eggs, HED will not require animal
feeding studies to be conducted with MB 46513.
x. Water, Fish, and Irrigated Crops - Not Applicable
xi. Food Handling - Not Applicable
xiL Confined Accumulation in Rotational Crops
An acceptable confined rotational crop study with radishes, lettuce,
grain sorghum, and wheat was submitted and reviewed Jn conjunction
with PP#5F04426 (CBTS Nos. 16773 and 16774, DP Barcodes
D222541 and D222350, G. Kramer, 4/1/96; CBTS No. 17402,
D228385, G. Kramer, 8/26/96; DP Barcode D235683, G. Kramer,
e/« f /t\*j\ Tn=« -^—i*^ ..^"//. i lib iCoviiv* \ji Uiw Uiuujr mvUv-tiu, uiai iipioiiu 10 iiiCUmviii^Xvi
in rotational crops by: (i) hydrolysis to the amide, RPA 200766, with
further hydrolysis to the carboxylic acid, RPA 200761; (ii) oxidation to
the sulfone, MB 46136; (iii) desulfurization to MB 46513; or (iv)
reduction to MB 45950. Data from the confined rotational crop study
support plantback intervals of 1 month for leafy vegetables, 5 months
for root crops, and 12 months for small grains and all other crops. The
petitioner has reported that limited rotational crop field trials are in
progress. .
xiii. Field Accumulation in Rotational Crops - Not Applicable
xrv. Tolerance Reassessment Table - Not Applicable
56
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xv. Anticipated Residues
Table 4. Summary of Fipronil + 1MB 46136 + MB 45950 Anticipated Residues for Dietary Risk Assessment
(Chronic Endpoints) hased-oa field-trial data. The anticipated market share was suoolied bv BEAD.
Commodity
Com Grain1
Includes processed commodities
Com Forage
Com Stover
Rice Grain4
Includes processed commodities
Excludes wild rice
Meat
Liver
Meat by-products (except liver)
Fat
Milk Fat2
Hog Meat
Hog Liver
Hog Meat by-products (except liver)
Hog Fat
Poultry meat
Poultry meat by-products
Poultry fat
Eggs
Recommended
Tolerance
(ppm)
0.02
0.15
0.30
0.03
0.04
0.10
0.04
0.40
1.50
0.01
0.02
0.01
0.04
0.02
0.02
O.OS
0.03
Anticipated
Residue in RAC
(ppm)
0.015
0.035
0.061
0.015
0.0005
0.0016
0.0004
0.005
0.011
0.00014
0.00042
0.00011
0.0013
0.00018
0.00074
0.0018
0.0011
Anticipated
Market Share
(%)
7
7
7
11
Anticipated Residue
for ORES Run
(ppm)
0.00 10
0.0024
0.0043
0.0016
0.00051
0.0016'
0.00041
0.0051
0.011
0.00014
0.00042
0.00011
0.0013
0.00018
- 0.00074
0.0018
0.0011
Since residues do not concentrate in processed commodities of com, the anticipated residue of 0.001 ppm
should be-used fur such cunimorimes in the Dkr.S run (i.e. cofn dif, meat, etc:) except corn sugar for which
processing data are not available.
All residues in milk are assumed to concentrate in fat, a value of 0 ppm should be used for other milk fractions
These anticipated residues should also be used for meat, fat and meat by-products of horses, goats and sheep
in the ORES run.
Since residues do not concentrate in processed commodities of rice, the anticipated residue of 0.0016 ppm
should be used for such commodities in the ORES run (i.e. flour, etc.).
For acute dietary risk assessment, anticipated residues in blended
commodities (such as com and rice processed commodities) may be
used, without the adjustment for percent crop treated; however,
tolerance level residues should be used for fat, meat by-products and
meat of cattle, goats, hogs, horses, sheep and poultry; and eggs [milk is
a blended commodity, and therefore an anticipated residue value may
be used].
57
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Commodity
Com Grain'
Includes processed commodities
Rice Grain*
Includes processed commodities
Excludes wild rice
Meat
Liver
Meat by-products (except liver)
Fat
Milk Fat2
Hog Meat
Hog Liver
Hog Meat by-products (except liver)
Hog Fat
Poultry meat
Poultry meat by-products
Poultry fat
Eggs
Recommended
Tolerance (ppm)
0.02
0.04
0.04
0.10
0.04
0.40
1.50
0.01
0.02
0.0 1
0.04
0.02
0.02
0.05
0.03
Residue to Use in Acute ORES
Run (ppm)
0.015
0.02
0.043
0.101
0.04J
0.40J
0.16
0.01
0.02
0.01
0.04
0.02
0.02
0.05
0.03
Since residues do not concentrate in processed commodities of com, the anticipated residue of 0.015 ppm
should be used for such commodities in the ORES run (i.e,. corn oil, meaL etc.).
All residues in milk are assumed to concentrate in fat, a value of 0 ppm should be used for other milk fractions
These anticipated residues should also be used for meat, fat and meat by-products of horses, goats and sheep
in the ORES run.
Since residues do not concentrate in processed commodities of rice, the anticipated residue of 0.02 ppm should
be used for such commodities in the ORES run (i.e,. flour, etc.).
Note: As MB 46513 does not appear to be more acutely toxic than the parent, it will be
incorporated into the acute ORES run for rice. If further refinements in the acute dietary risk
assessment are required in the future, a separate ORES run for MB 46513 only will be
performed.
58
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Tabled. Summary of MB 46513 Anticipated
Assessment
Residues for Dietary Risk
Commodity
Rice Grain'
Includes processed commodities
Excludes wild rice
Meat
Liver-
Meat by-products (except liver)
Fat
Milk Far2
Hog Meat
Hog Liver
Hog Meat by-products (except liver)
Hog Fat
Poultry meat
Poultry meat by-products
Poultry fat
Eggs
Residue to Use in Chronic
ORES Run (ppm)
0.0006
0.0000039
0.000051
0.0000071
0.000062
0.00032
0.0000051
0.000067
0.0000094
0.000082
0.000012
0.000082
0.000019
0.00029
' Since residues do not concentrate in processed commodities of rice, the anticipated residue of 0.005 ppm
should be used for such commodities in the ORES run (i.e., flour, etc.).
• All residues in milk are assumed to concentrate in fit, a value of 0 ppm should be used for other milk fractions
3 These anticipated residues should also be used for meat, fat and meat by-products of horses, goats and sheep
in the ORES run.
(a) Corn and Rice RACs
For samples with residue levels below the LOQ (G.G1 ppm in cum
grain and rice grain and 0.02 ppm in forage and stover), a value of V*
LOQ used in calculating average residues. In com grain, the average
levels of fipronil were 0.005 ppm; of MB 45950, were 0.005 ppm; and
of MB 46136, were 0.005 ppm. In forage, the average levels of
fipronil were 0.013 ppm; of MB 45950, were 0.01 ppm; and of MB
46136, were 0.012 ppm. In stover, the average levels of fipronil were
0.011 ppm; of MB 45950, were 0.01 ppm; and of MB 46136, were
0.023 ppm.' The samples from the corn residue studies were analyzed
with the original version of the proposed enforcement method. This
method has been revised by addition of water to the initial extraction
solvent for dry matrices (fodder and grain). This revision was found to
result is significantly higher residues in fodder samples (Memo, G.
Kramer 4/1/96). Fipronil levels were increased by 45%; and MB
46136, by 52%. When applying these correction factors to the fodder
residues, the average levels of fipronil were 0.016 ppm; and of MB
46136, were 0.035 ppm. The total anticipated residues of fipronil and
its metabolites are thus 0.015 ppm in corn grain, 0.035 ppm in forage
59
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and 0.061 ppm in stover. In rice grain and rice straw, the average
levels of fipronil were 0.005 ppm; of MB 46513, were 0.005 ppm- of
MB 45950, were 0.005 ppm; and of MB 46136, were 0.007 ppm.'
(b) Meat, Milk & Eggs
(I) Fipronil + MB 46136 + MB 45950
Table 7. Anticipated Dietary Burden for Beef and Dairy Cattle
Feed Item
Com Grain
Com Forage
Avenge
AR/V.DM'
0.001
0.006
% in Diet1
Beef
60
40
Dairy
40
50
Total:
Anticipated Dietary Burdev*
Beef
0.0006
0.0024
0.0030
Dairy
0.0004
0.0031
0.0035
Average AR/%DM = average of anticipated residues in feed items divided by the % dry matter (%DM) for the
feed item. %DM: 88% for com grain and 40% for forage. Note: The ARs incorporate projected market
share (7%).
The % of each feed type assumed to be included in the diet was based on information contained in the revised
Table I of the OPPTS Test Guidelines Series 860.
The anticipated dietary burden is calculated by multiplying the average AR/*/»DM by the % of the feed item in
the diet.
The dosing levels used in the ruminant feeding study correspond
to 13X, 43 X and 143X the anticipated dietary burden for beef
cattle (0.0030 ppm, Table 7) and 1IX, 37X and 123X the
anticipated dietary burden for dairxcattle..[0.0035 ppm. Table 7}.
Based on this information, and based on the residues found in
meat, meat by-products, fat afid milk in the ruminant feeding
study, the anticipated residues in livestock commodities to be
used in the chronic dietary risk assessments are shown below:
meat 0.0005 ppm
liver , 0.0016 ppm
meat by-products (except liver) 0.0004 ppm
fat 0.0050 ppm
milk fat 0.011 ppm
Note: The milk fat residue is based on the average residues in
whole milk (0.042 ppm, after plateauing) found in the 0.43 ppm
dose group multiplied by a concentration factor of 3IX.
60
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Feed Item
(~nm drain
Table 8. Anticipated Dietary Burden for Poultry and Swine
Average
AR/V.DM'
nnoi
% in Diet*
Poultry
SO
Swine
Sf)
Anticipated Dietary Burden3
Poultry
A OAnfl
Swine
ft Af)AO
Average AR/%DM = average of anticipated residues in feed items divided by the % dry matter (%DM) for the
feed item. %DM: 88% for corn grain. A dry matter correction was not performed for poultry. Note: The
ARs incorporate projected market share (7%).
The % of each feed rype assumed to be included in the diet was based on information contained in the revised
Table I of the OPPTS Test Guidelines Series 860.
The anticipated dietary burden is calculated by multiplying the average AR/%DM by the % of the feed item in
the diet.
The dosing levels used in the ruminant feeding study correspond
to SOX, 162X and S40X the anticipated dietary burden for swine
(0.0008 ppm, Table 8). Based on this information, and based on
the residues found in meat, meat by-products, and fat in the
ruminant feeding study, the anticipated residues in swine
commodities to be used in the chronic dietary risk assessments
are shown below:
meat
liver
meat by-products (except liver)
fat
0.00014 ppm
0.00042 ppm
0.00011 ppm
0.0013 ppm
The dosing levels used in the poultry feeding study correspond to
12X, 39X and 129X the anticipated dietary burden for poultry
(0.0008 ppm, Table 8).' Based1 on this information, and based on
the residues found in meat, liver, eggs, and fat in the poultry
feeding study, the anticipated residues in poultry commodities to
be used in the chronic dietary risk assessments are shown below:
meat
eggs -
meat by-products
fat
0.00018 ppm
0.0011 ppm
0.00074 ppm
0.0018 ppm
61
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(ii) MB 46513-CHRONIC
Table 9. Anticipated Dietary Burden for Beef and Dairy Cattle
Feed Item
Rice grain
Rice straw
Average
AR/%DM'
0.0006
0.0006
% in Diet*
Beef
40
10
Dairy
40
10
Total:
Anticipated Dietary Burden J
Beef
0.00025
0.00006
0.00031
Dairy
0.00025
0.00006
0.00031
1 Average AR/%DM = average of anticipated residues in feed items divided by the % dry matter (%DM) for the
feed item. %OM: 88% for rice grain and 90% for straw. Note: The ARs incorporate projected market
share (11%).
2 The % of each feed type assumed to be included in the diet was based on information contained in the revised
Table I of the OPPTS Test Guidelines Series 860.
1 The anticipated dietary burden is calculated by multiplying the average AR/%DM by the % of the feed item in
the diet.
The dosing levels used in the ruminant metabolism study
correspond to 32,OOOX the anticipated dietary burden for beef and
dairy cattle (0.00031 ppm, Table 9). Based on this information,
and based on the residues found in meat, meat by-products, fat
and milk in this study, the anticipated residues in livestock
commodities to be used in the chronic dietary risk assessments
are shown below:
meat
liver
meat by-products (except liver)"'
fat
milk fat
0.0000039 ppm
0.000051 ppm
OTOOOG071 ppm
0.000062 ppm
0.00032 ppm
Note: The milk fat residue is based on thee residues in whole
milk (0.337 ppm) multiplied by a concentration factor of 31X.
Table 10. Anticipated Dietary Burden for Poultry and Swine.
Feed Item
Ripp orain
Average
AR/%DM'
noon*
% in Diet1
Poultry
(SO
Swine
6*
Anticipated Dietary Burden1
Poultry
noo/m
Swine
QJ1QO41
Average AR/%DM = average of anticipated residues in feed items divided by the % dry matter (%DM) for the
feed item. %DM: 88% for rice grain. A dry matter correction was not performed for poultry. Note: The
ARs incorporate projected market share (11 %).
The % of each feed type assumed to be included in the diet was based on information contained in the revised
Table I of the OPPTS Test Guidelines Series 860.
The anticipated dietary burden is calculated by multiplying the average AR/%DM by the % of the feed item in
the diet.
62
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The dosing levels used in the ruminant metabolism study
correspond to 24,OOOX the anticipated dietary burden for swine
(0.00041 ppm, Table 10). Based on this information, and based
on the residues found in meat, meat by-products, and fat in the
ruminant metabolism study, the anticipated residues in swine
commodities to be used in the chronic dietary risk assessments
are shown below:
meat 0.0000051 ppm
liver 0.000067 ppm
meat by-products (except liver) 0.0000094 ppm
fat 0.000082 ppm
The dosing level used in the poultry metabolism study
corresponds to 30,OOOX the anticipated dietary burden for poultry
(0.00033 ppm, Table 10). Based on this information, and based
on the residues found in meat, liver, eggs, and fat in the poultry
metabolism study, the anticipated residues in poultry
commodities to be used in the chronic dietary risk assessments
are shown below:
meat 0.000012 ppm ,
liver 0.000082 ppra
meat by-products 0.000019 ppm
fat 0.00029 ppm
b. Dietary Exposure (Drinking Water Source)
HED does not have monitoring data available to perform a quantitative
drinking water risk assessment for fipronil at this time. The Environmental
Fate and Effects Division (EFED) provided ground and surface water
exposure estimates for use on com and rice (RED, GML, 11/20/97; personal
communication from Jim Hetrick to George Kramer, 1/7/98 and 1/9/98).
Whichever use scenario provided more conservative estimates was used.
L Ground Water (tiered assessment)
The environmental fate data for fipronil indicate a moderate to high
persistence and relatively low mobility in terrestrial environments.
Based on the SCI-GRO model, acute drinking water concentration in
shallow ground water on highly vulnerable sites are not likely to
exceed the following:
63
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Fipronil
MB 46 136
MB 45950
Total:
Com (ppb)
0.055
0.001
0.00036
0.05636
Rice (ppb)
0.00804
0.00038
0.000685
0.009105
MB 465 13
Com (ppb)
0.00026
Rice (ppb)
0.004138
Chronic concentrations are not expected to be higher than acute values.
Highly vulnerable sites are those with low organic matter, coarse
textured soils (e.g., sands and loamy sands) and shallow ground water.
The fate data for fipronil and its degradates indicate a higher potential
mobility on coarse-textured soils (sand or loamy sands).
ii. Surface Water (tiered assessment)
Based on the environmental fate assessment, fipronil and its degradates
(MB 46513, MB 46136, and MB 45950) can potentially move into
surface waters. Since fipronil is used as an in-furrow application on
field com, the runoff potential of fipronil residues is expected to be
lower than for unincorporated surface application techniques. Since
photodegradation is a major route of degradation for fipronil, its
dissipation is expected to be dependent on physical components of the
water (i.e., sediment loading) which affect sunlight penetration. The
maximum fipronil concentration fb"r acute (peak concentration) and
chronic (56-day average) based on the Tier 1 GENEEC surface water
modeling is shown in Table 11 below.
Table 11 - Surface water concentrations for Fipronil based on GENEEC modeling
Fipronil
MB 46 136
MB 45950
Total:
Corn-
Acute
Peak EEC (ppb)
2.05
0.168
0.039
2.257
Chronic
56-day EEC (ppb)
0.78
0.062
0.019
0.861
Rice
Acute
Peak EEC (ppb)
1.45
0.061
0.1296
1.6406
Chronic
56-day EEC (ppb)
0.40
0.004
0.013
0.417
64
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Table 12 - Surface water concentrations for MB 46513 based on GENEEC modeling
MB 465 13
Com
Acute
Peak EEC (ppb)
0.014
Chronic
56-day EEC (ppb)
0.009
Rice
Acute
Peak EEC (ppb)
0.359
Chronic
56-day EEC (ppb)
0 066
c. Dietary Risk Assessment and Characterization
L Chronic Risk (TMRC, ARC)
A chronic dietary risk assessment is required for fipronil (+ MB 46136
and MB 45950). The RfD used for the chronic dietary analysis for
parent fipronil and 2 metabolites is 0.0002 mg/kg bwt/day. The RfD
used for the photodegradate MB 46513 is 0.00002 mg/kg bwt/day.
The analysis evaluates individual food consumption as resorted by
respondents in the USDA 1977-78 Nationwide Food Consumption
Survey (NFCS) and accumulates exposure to the chemical for each
commodity.
Chronic dietary exposure estimates (DRES) for fipronil (+ 2
metabolites) and MB 46513 are summarized in Attachments 2 & 3
(runs dated 12/5/97). The DRES analysis utilized the anticipated
residues calculated from field-trial data for all rice, corn and animal
commodities. The proposed fipronil tolerances result in an
Anticipated Residue Contribution (ARC) that is equivalent to the
following percent of the RfD:
Subgroups
U.S. Population (48 states)
Hispanics
Non-Hispanic Others
Nursing Infants (< 1 year old)
Non-Nursing Infants (< 1 year old)
Females (13+ years, pregnant)
Females (13+ years, nursing)
Children (1-6 years old)
Children (7-12 years old)
Females (20+ years, not pregnant, not nursing)
Fipronil + MB
46 136 + MB 45950
4.8%
6.2%
5.8%
2.8%
11.2%
3.3%
4.2%
11.4%
7.6%
3.0%
MB 46513
1.7%
2.9%
3.9%-
2.3%
5.5%
1.2%
1.6%
3.8%
2.3%
1.2%
Total
6.5%
8.1%
9.7%
5.1%
16.7%
4.5%
5.8%
15.2%
9.9%
4.2%
65
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HED does not consider the chronic dietary risk to exceed the level of
concern.
ii. Carcinogenic Risk
Flpronil + MB 46136 + MB 45950
Dietary risk concerns due to long-term consumption of fipronil
residues are adequately addressed by the DRES chronic exposure
analysis using the RfD.
MB 46513
Dietary risk concerns due to long-term consumption of MB 46513
residues are adequately addressed by the DRES chronic exposure
analysis using the RfD.
iii. Acute Dietary Risk
An acute dietary risk assessment is required for fipronil and MB
46513, The NOEL of 2.5 mg/kg was selected as the endpoint to be~
used for fipronil and all its metabolites (Note: 2 mg/kg was the
endpoint selected for MB 46513 for acute dietary risk assessments).
Since the photodegradate MB 46513 does not appear to be acutely
significantly more acutely toxic than the parent, it will be incorporated
into the acute DRES run for rice. If further refinements in the acute
dietary risk assessment are required in the future, a separate DRES run
for MB 46513 only will be performed. HED's detailed acute analysis
estimate ths distributios of single-day exposures for the overall U.S.
population and certain subgroups."-The analysis evaluates individual
food consumption as resorted by respondents in the USDA 1977-78
Nationwide Food Consumption Survey (NFCS) and accumulates
exposure to the chemical for each commodity. Each analysis assumes
uniform distribution of fipronil in the commodity supply.
66
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f
Table 13 - Acute Risk for Fipronil and all Metabolites
Subgroup
Genera] U.S.
Population
Infants (< 1 year)
Children ( 1 -6 years)
Females (13+ years)
Males (13+ years)
RfD
(mg/kg/day)
0.025
0.025
0.025
0.025
0.025
Acceptable
MOE
100% RfD
100% RfD
100% RfD
100% RfD
100% RfD
Exposure
(mg/kg/day)
0.0018
0.003
0.003
0.0012
0.0014
%RfD
7
12
12
5
6
iv. Drinking Water Risk (Acute and Chronic)
Fipronil [+ MB 45950, MB 456136, and MB 465l3(acute only)]
OPP has calculated drinking water levels of concern (DWLOCs) for
acute exposure to fipronil (plus MB 45950, MB 46136, and MB
46513) in surface and ground water for the U.S. population and
children (1-6 yrs) as per current guidance (Standard Operating
Procedures for Drinking Water Exposure and Risk Assessments,
11/26/97 and Interim Guidance for Conducting Drinking Water
Exposure Estimates, 12/2/97). They are 810 and 220 ppb,
respectively. For chronic (non-cancer) exposure to fipronil (plus MB
45V5U and MB 46136) in surface and ground water, the drinking water
levels of concern are 6.67 and 1.7? ppb for U.S. population, children
(1-6 years old), respectively. To calculate the DWLOC for acute
exposure relative to an acute toxicity endpoint, the acute dietary food
exposure (from the DRES analysis) was subtracted from acute RfD to
obtain the acute exposure to fipronil (plus MB 45950 and MB 46136)
in drinking water. To calculate the DWLOC for chronic (non-cancer,
cancer) exposure relative to a chronic toxicity endpoint, the chronic
dietary food exposure (from DRES) was subtracted from the chronic
RfD to obtain the acceptable chronic (non-cancer) exposure to fipronil
(plus MB 45950 and MB 46136) in drinking water. DWLOCs were
then calculated using default body weights and drinking water
consumption figures.
Estimated maximum concentrations of fipronil (plus MB 45950, MB
46136, and MB 46513) in surface and ground water are 2.271 and
0.05662 ppb (with 0.00026 ppb from MB 46513 included),
respectively. The estimated average concentration of fipronil (plus
MB 45950 and MB 46136) in surface water is 0.861 ppb. Chronic
67
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concentrations in ground water are not expected to be higher than the
acute concentrations. Note: For the purposes of the screening-level
assessment, the maximum and average concentrations in ground water
are not believed to vary significantly. The maximum estimated
concentrations of fipronil (plus MB 45950 and MB 46136) in surface
and ground water are less than OPP's levels of concern for fipronil
(plus MB 45950 and MB 46136) in drinking water as a contribution to
acute aggregate exposure. The estimated average concentrations of
fipronil (plus MB 45950 and MB 46136) in surface and ground water
are less than OPP's levels of concern for fipronil (plus MB 45950 and
MB 46136) in drinking water as a contribution to chronic aggregate
exposure. Therefore, taking into account the present uses and uses
proposed in this action, OPP concludes with reasonable certainty that
residues of fipronil (plus MB 45950 and MB 46136) in drinking water
(when considered along with other sources of exposure for which OPP
has reliable data) would not result in unacceptable levels of aggregate
human health risk at this time.
OPP bases this determination on a comparison of estimated
concentrations of fipronil (plus MB 45950 and MB 46136) in surface
waters and ground waters to back-calculated "levels of concern" for
fipronil (plus MB 45950 and MB 46136) in drinking water. These
levels of concern in drinking water were determined after OPP has
considered all other non-occupational human exposures for which it
has reliable data, including all current uses, and uses considered in this
action. The estimates of fipronil (plus MB 45950 and MB 46136) in
surface and ground waters are derived from water quality models that
use conservative assumptions (health-protective) regarding the
pesticide transport from the point of application to surface and-groiiiid
water. Because OPP considers the'aggregate risk resulting from
multiple exposure pathways associated with a pesticide's uses* levels
of concern in drinking water may vary as those uses change. If new
uses are added in the future, OPP will reassess the potential impacts of
fipronil (plus MB 45950 and MB 46136) on drinking water as a part of
the aggregate risk assessment process.
MB 46513 (chronic only)
For chronic (non-cancer) exposure to MB 46513 in surface and ground
water, the drinking water levels of concern are 0.69 and 0.19 ppb for
U.S. population, children (non-nursing infants, < 1 year old ),
respectively. To calculate the DWLOC for chronic (non-cancer,
cancer) exposure relative to a chronic toxicity endpoint, the chronic
dietary food exposure (from DRES) was subtracted from the RfD to
obtain the acceptable chronic (non-cancer) exposure to MB 46513 in
drinking water. DWLOCs were then calculated using default body
68
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weights and drinking water consumption figures.
Estimated maximum concentrations of MB 46513 in ground water is
0.00026 ppb. The estimated average concentration of MB 46513 in
surface water is 0.009 ppb. Chronic concentrations in ground water
are not expected to be higher than the acute concentrations. Note: For
the purposes of the screening-level assessment, the maximum and
average concentrations in ground water are not believed to vary
significantly. The estimated average concentrations of MB 46513 in
surface and ground water are less than OPP's levels of concern for MB
46513 in drinking water as a contribution to chronic aggregate
exposure. Therefore, taking into account the present uses and uses
proposed in this action, OPP concludes with reasonable certainty that
residues of MB 46513 in drinking water (when considered along with
other sources of exposure for which OPP has reliable data) would not
result in unacceptable levels of aggregate human health risk at this
time.
OPP bases this determination on a comparison of estimated
concentrations of MB 46513 in surface waters and ground waters to
back-calculated "levels of concern" for MB 46513 in drinking waters
These levels of concern in drinking water were determined after OPP
has considered all other non-occupational human exposures for which
it has reliable data, including all current uses, and uses considered in
this action. The estimates of MB 46513 in surface and ground waters
are derived from water quality models that use conservative
assumptions (health-protective) regarding the pesticide transport from
ths point of-application-to surface and gro'dnd^wstsri ^Because QPP ^
considers the aggregate risk resulting from multiple exposure pathways
associated with a pesticide's uses, levels of concern in drinking water
may vary as those uses change. If new uses are added in the future,
OPP will reassess the potential impacts of MB 46513 on drinking
water as a part of the aggregate risk assessment process.
d. Statement of the adequacy of the dietary exposure database to assess
infants' and children's exposure
The dietary (food and water) exposure database for fipronil is adequate to
assess infants' and children's exposure.
69
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4. Occupational and Residential Exposure and Risk
Assessment/Characterization
a. Occupational and Residential Exposure
i. Summary of Use Patterns and Formulations: Occupation and
Residential
(a) Occupational
Occupational exposure is expected as a result of the application
methods associated with the use of fipronil on rice. Broadcast
applications are made using groundboom and aerial equipment. Seed
treated with fipronil may be use in lieu of the broadcast uses. Fipronil
is to be soil incorporated within 48 hours. Exposure to daggers
assisting aerial applicators is also expected in cases where pilots do not
use mechanical flaggers. These exposures are addressed using
surrogate data available in the Pesticide Handlers Exposure Database
(PHED - Ver 1.1). Surrogate data are not available to assess the
commercial seed treatment facility personnel. This is a data gap.
The information in Table 14, below is taken from Icon 6.2 FS, Icon 80
WG, Icon 6.2 SC, and other sources as cited.
Table 14. Registration Request for Use of Icon (6.2 FS, 80 WG, and 6.2 SC) in/on rice.
Factors
\_,4i>i/ tW U**B "ii ^4*hvCf ""*'""
Pests
Application methods
Application rate
Maximum number of applications
Percent absorption
Average acreage of application per day
Manufacturer
Comments
• Rjgg- --"•—• -' - - - •— - - -- -- ••'- -—--~ --
In furrow, preplan! incorporated, or as a seed
treatment to control rice weevil and chinch bugs.
Aerial, and groundboom application or as a seed
treatment (SC formulation only).
Regardless of formulation: 0.025 to 0.05 Ibs ai/A.
One application at planting.
Endpoint is derived from a dermal study. Therefore,
adjustment for dermal absorption is not necessary.
Aerial - 480, and Ground boom - 80 acres'
Rhone Pouienc Ag Company.
' The estimate of maximum acreage used in (his assessment of worker exposure is representative of the maximum standard acreage for
Aerial and Ground boom on rice.
Toxicity endpoints are established for the active ingredient for short-
term, intermediate-term, and chronic occupational or residential
70
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exposure. The short- and intermediate-term endpoints-are derived
from a 21 day dermal toxicity study in rabbits. The NOEL was 5
mg/kg/day and the LOEL was 10 mg/kg/day based on decreased body
weight gain and food consumption. For acute oral (non-dietary)
toxicity, a NOEL of 2.5 mg/kg/day was selected from an acute
neurotoxicity study in rats. The LOEL of 1.5 mg/kg/day was based on
reduced hind limb splay.
Risk assessments are required for short-term and intermediate-term
exposures reflecting the seasonal use of fipronil. Chronic exposures
are not expected as a result of the rice use, hence a chronic exposure
assessment is not required.
Although the potential for exposure via inhalation to sprays and
particulates is low, the amount available for this route of exposure is
presented under iL Handlers Exposures and Assumptions.
Estimates assume the use of a respirator as per labeled PPE
requirements.
TYPE OF TOXICITY
Acute OraJ
Acute Dermal
' - Acute Inhaiatroii
Primary Eye
Primary Dermal
Dermal Senshiation
TOXICITY CATEGORY
Active ingredient
III
II
II
III
IV
non-sensitizing
Icon 6.2 FS
II
III
—--11- - -
HI
III
non-sensitizing
(b) Residential
Three fipronil products are conditionally registered by Rhone-Merial
for flea and tick control, Frontline® Spray Treatment (65331-1), Top
Spot™ for Cats (65331-2) and Dogs (65331-3). Fipronil is used to
control fleas and ticks on dogs and cats and is applied as a ready-to-use
pump spray (Frontline) to the fur of the animal or as a ready-to-use,
pour-on, spot treatment made along the back of the animal between the
shoulder blades (Top-Spot). The dosage per pound of the animal's
body weight is approximately 5 mg. Repeated applications if
necessary may be made once every one to three months during flea or
tick season.
71
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ii. Handler Exposures and Assumptions: Occupation and Residential
(a) Occupational
HED*s exposure assessment is based on the assumptions in Table 15.
Table 15. Assumptions for Worker Exposure Assessments
Factors
Applicator body weight
Mixer/loader body weight
Application rate (Seed Treatment Aerial and Groundboom)
Acres treated per day (Aerial)
Acres treated per day (Groundboom)
Acres planted per day (grain drill)
Applicator unit exposure from PHED (Aerial application; liquid;
closed cab; with long-pants, long-sleeved shirt and no gloves).
Flagger unit exposures from PHED (granulars and sprays; with
coveralls over short-pants, short-sleeved shirt, and gloves).
Applicator unit exposure from PHED (Groundboom application;
liquid; open cab; with coveralls over short-pants, short-sleeved shirt,
and gloves). Inhalation assumes the use of a respirator.
Mixer/loader unit exposure from the Pesticide Handlers Exposure
Database (PHED), (In support of Aerial and Groundboom application;
liquid; open mixing; with coveralls over short pants, short-sleeved
shin, and gloves). Inhalation assumes tlje use a respirator.
Mixer/loader unit exposure from the Pesticide Handlers Exposure
Database (PHED), (In support of Aerial and Groundboom application;
dry flowable; open mixing; with coveralls over short pants, short-
sleeved shirt, and gloves). Inhalation assumes the use of a respirator.
. Mixer/loader unit exposure from the Pesticide Handlers Exposure
Database (PHED), Loading treated seed in to grain drills and aircraft
using open mixing/loading; assuming loading treated seed is similar to
loading granular formulations. (Long sleeved shirt, long pants, no
gloves and no respirator).
Quantities/Units
70kg
70kg
0.025 - 0.05 Ib ai/A
480 acres
80 acres
40 acres'
Dermal - 5.0 ug/lb ai handled1
Inhalation - 0.1 ug/lb ai handled2
Dermal (granular) - 1 .7 ug/Ib ai
handled2
Inhalation (granular) - not enough
replicates
Dermal (spray) - 7.4 ug/Ib ai
handled2
.Inhalation (spray) - 0.035 ug/lb ai
handled2
1 1.0 ug/lb ai handled2 Inhalation -
0.1 ug/lb ai handled2
Dermal - 18.0 ug/lb ai handled2
Inhalation - 0. 1 ug/lb ai handled2
Dermal - 48.0 ug/lb ai handled2
Inhalation -0.1 ug/lb ai handled2
Dermal - 8.4 ug/lb ai handled2
Inhalation - 1.7 ug/lb ai handled2
72
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Personal proteaive equipment (PPE), per label.
For all labels: Coveralls over
short-sleeved shin and short pants;
chemical-resistant gloves and
respirators.
1 Standard assumptions of the acreage treated per day given the crop (rice), application method and ground
speed.
2 Source: Pesticide Handlers Exposure Database Vl.l, Surrogate Exposure Guide (May 97)dermal unit
exposures were adjusted to reflect coveralls over short pants and short sleeved shin (50%) except for aerial
applicators. Inhalation unit exposure were adjusted for 90 percent respiratory protection for use of respirator
except granular flagger and pilots.
(b) Residential
Merial has submitted several non-dietary exposure studies to support
the use of fipronil on dogs and cats for the control of fleas and ticks.
Two studies address the application of fipronil: 1) Dermal and
Inhalation Exposure of Commercial Pet Groomers During Application
of Frontline Spray Treatment, and 2) Dermal Exposure of Commercial
Pet Groomers During the Application of Frontline Top Spot The
applicator studies will be used to address the commercial use of
fipronir as well as to estimate exposure to adults treating pets in the -
home. The applicator studies are acceptable in accordance with the -
requirements outlined in Subdivision U Pesticide Assessment
Guidelines.
t
UL Post-Application Exposures and Assumptions: Occupational and
k OertfpatioB aad Residential •-- ~ - ,,
(a) Occupational
Rice is harvested mechanically resulting in low postapplication
exposure. Postapplication exposure is also mitigated via soil
incorporation as required after the application of fipronil. The
photodegradate (MB46513) is not expected to play a significant role in
postapplication exposure since fipronil is soil incorporated. Its
behavior in aquatic environments following field flooding is not
known to HED.
(b) Residential
Merial has submitted several non-dietary exposure studies to support
the use of fipronil on dogs and cats for the control of fleas and ticks.
Four studies address the dislodgeable residues of fipronil from dogs
and cats following the application of both the spray treatment and the
top spot treatment (MRID#s 44433301 thru 44433309). The
73
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dislodgeable data, coupled with a screening-level assessment, will be
used to address non-dietary, dermal and oral (hand-to-mouth) exposure
for toddlers. While there are no established guideline study
requirements for dislodgeable residues from animal fur, the
dislodgeable data are useful for conducting a Tier 2 screening level
assessment.
iv. Mixer/Loader/Application Exposure Assessment Formulas and
Exposure Tables: Occupation and Residential
(a) Occupational
Table 16; 17, 18 below, summarizes the HED estimates for total
worker exposure for applicators and mixer/loaders in the proposed use
of fipronil, on rice. These estimates are based on the assumptions
outlined in Table 15.
Table 16. Worker Exposure to Icon SO WG Insecticide
Job Functioa
Flaggers
Mixer/loaders
Applicators
Average Dermal Daily Dos*
for Icon 80 WG mf ai/kf
bw/day
Sprays -0.001 3 -0.0025
Aerial - 0.01 - 0.02
Groundboom - 0.001 - 0.003
Aerial -0.001 -0.002
Groundboom -0.0003 - 0.0006
Dermal Short A
Intermediate-Term MOE
Sprays -2,000 -4,000
Aerial -250-500
Groundboom - 1,700 - 5,000
Aerial -2,500 -5,000
Groundboom - 8000 - 17,000
MOE - NOEyADDXwhere NOEL - 5 mg/kg/day)
•
.The exposure estimates in Table 16 are based on treatment of 480 acres per day by aerial and 80 acres per day
by ground boom equipment
The following calculations were used to determine the expected worker exposures resulting from the handling
and application of fipronil (Icon 80 WG) to rice.
Table 17. Worker Exposure to Icon 62 SC Insecticide
Job Functtoa*
Mixer/loaders
Applicators
Average Dermal Dairy Dose
for Icon 6.2 SC mg ai/kf
bw/day
Aerial - 0.003 - 0.006
Groundboom -0.0005 - 0.00 1
Aerial- 0.00 1 -0.002
Groundboom -0 0003 - 0.0006
Dermal Short A Intermediate-Term
Aerial -800 - 1, 700
Groundboom - 5,000 - 10,000
Aerial - 2,500 - 5,000
Groundboom - 8.000 - 17.000
MOE = NOEL/ADD (where NOEL - 5 mg/kg/day)
74
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The exposure estimates in Table 17 are based on treatment of 480 acres per day by aerial and 80 acres per day
by ground boom.
The following calculations were used to determine the expected worker exposures resulting from the handling
and application of fipronil to rice.
•Flayers addressed in Table 16.
Table 18. Worker Exposure to (con 6.2 FS Insecticide
Job Function
Flaggers
Mixer/loaders
Applicators
Loading treated seed
Avenge Dermal Daily Dose
for Icon 6.2 FS mg ai/kf
bw/day
Granular (seed) -.0.0003-
0.0006
Aerial - 0.01 - 0.02
Groundboom -0.001 - 0.003
Aerial -0.00 1-0.002
Groundboom -0.0003 - 0.0006
Aerial -0.001 -0.003
Grain drill -0.0001 - 0.0002
Dermal Short &
Intermediate-Term MOE
8,000-17,000
Aerial - 250 - 500
Groundboom - 1,700 - 5000
Aerial -2500- 5000
Groundboom - 4000 - 8000
Aerial -1700 -5000
Grain drill - 25,000 - 50,000
MOE = NOEL/ ADD (where NOEL - 5 mg/kg/day)
The exposure estimates in Table 1 8 are based on treatment of 480
acres per day by aerial and 80 acres per day by ground boom. It is
expected that a grower can plant 40 acres per day using a grain drill.
Aircraft are expected to plant 480 acres per day. The following
calculations were used to determine the expected worker exposures
resulting from the handling and application of fipronil to rice.
Flaggers
0.05 tbt. at applitdfaert * 480 of aertt triattdlday = 24 Ibt ail day
,0017 mgllb ai handltd (framlarJ'HED, Vtrtiom 1.1) » 24 Ibt ailday * 0.041 mg ail day
0.041 mg
70 kg bw
^
0.05 ibt. ai applitdlacrt « 480 of acrtt trtatidlday - 24 Ibt ailday
.00074 mgtlb ai kandltd (PHED-spray, Vtniott 1.1) * 24 Ibt ailday =» 0.018 mg ailday
0.018 mg ailday
70 kg bw .
75
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Icon 6.2 FS and 80 WG
Groundboom
0.05 Ibs. ai appliedlacrt * 80 of acres trtattdlday = 4 Ibs at/day
.048 mg/lb ai handled (PHED, Version 1.1) * 4 Ibs ail day - 0.192 mg ail day
0.192 mg at/day - „_, ... . ,,
- = - — = 0.003 mg at/kg b ft I day
70 kg bw
Aircraft.
0.05 Ibs. ai applitdlaert * 480 of acres trtattdlday * 24 /** ail day
.048 mg/lb ai handled (PHED, Version 1.1) » 24 /A* artfe? » 1.152 mg ailday
1.152 (it* ailday «.»..- ... . ,.
- - - — = 0.016 mg ailkg b\rlday
70 kg bw
Icon 6.2 SC
Groundboom
0.05 /&*. ai appliedlacrt * 80 of acres trtattdlday * 4 /** at/day
0.018 >ȣ//* a; handled (PHED, Version 1.1) * 4 /&* ai/tfoy = 0.072 mg
0.072 m* at/day - .... ... . . .
- 2 - — = 0.001 mg atlkg bw/day
70 kg b*
'•••--• Aircraft -—-
0.05 Ibs. ai applitdlaert * 480 of acres trtattdlday = 24 /A* ailday
0.018 *i;//* ai handttd (PHED, Version 1.1) » 24 U« ai/dar = 0.432 m*
0.432 wf ailday „ ..-^ ... . . .
- = - - ^ 0.006 mg ailkg bvlday
70 kg bw
Icon 6.2 FS, Icon 6.2 SC, and 80 WG
Spray
Groundboom
0.05 Ibs. ai applitdlaert * 80 of acrtt trtattdlday = 4 Ibs ailday
0.011 mg/lb ai handled (PHED, Version 1.1) * 4 Ibs ailday - 0.044 *f ailday
0.044 mg ai/day = fc
70 *j frw
76
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Aircraft
0.05 Ibs. ai applitdlacrt * 480 of acrts trtattdlday = 24 Ibt ail day
0.005 mgllb ai handltd (PHED, Vtrtion 1.1) * 24 Ibs ailday = 0.12 mg ailday
°-'2lnga^ay - 0.0017 mg ai,kg b»,day
70 kg bw
Note: For granular formulations which have seed treatments (FS formulation
only), this subset deals with the loading of treated seed only. The actual seed
treatment process is a data gap. Subdivision U Guideline requirements for
Dermal Exposure at Indoor Sites (233) and Inhalation Exposure at Indoor
Sites (234) are required as a condition of this registration.
Pouring treated seed
Grain drill
0.05 Ibs. ai applitdlacrt * 40 of acrts trtattdlday =. 2 Ibg ailday
0.0084 mgllb ai handltd (PHED, Vtrsion 1.1) * 2 Ibs ailday = 0.0161 mg ailday
0.0168 mg at/day - «--- ... . ,.
= = 0.0002 mg ai/kg bwlday
70 kg bw
Flying the Seed On
0.05 Ibs. ai applitdlacrt * 480 of acrts trtattdlday = 24 Ibs ailday
0.0084 mgllb ai handled (PHED, Vtrsion 1.1) * 24 lb* ait day = 0.2016 mg ailday
0.2016.mg ailday „ -.., ... . .,
s — - 0.003 *f atlkg tow/day
70 kg bw
(b) Residential
In the study entitled Dermal and Inhalation Exposure of Commercial
Pet Groomers During Application of Frontline Spray Treatment
(MRID 44433302), 16 groomer/applicators each treating 8 dogs (of
varying coat lengths and body weights) at a commercial pet grooming
facility. Label instructions direct the user.to spray Frontline on a
gloved hand, then to rub the pesticide into the animal's fur and to
continue until the animal's hair is damp fo thoroughly wet. Latex
gloves were worn by the study cohorts.
The arithmetic mean representing total dermal exposure was 0.024
77
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mg/kg/day. To estimate an adult treating a pet in a residential
situation, the professional groomer mean exposure was divided by 8
(0.003 mg/kg/day). To estimate chronic professional exposure (26
weeks during peak flea season) the mean exposure was estimated by
assuming 1.7 animals treated (0.005 mg/kg/day and 0.00005
mg/kg/day (1% dermal absorption since oral endpoint used)) which
represents the median number of dogs treated daily by veterinary and
commercial users using the Frontline spray product. This value was
substantiated by a survey of professional groomers and veterinarians
submitted by Merial.
In the study entitled Dermal Exposure of Commercial Pet Groomers
During Application of Frontline Top-Spot Treatment (MRID 444333-
03), 16 groomer/appiicators each treating 8 dogs (of varying coat
lengths and body weights) at a commercial pet grooming facility.
Label instructions direct the user to snap open the plastic pipette and
pour the liquid containing 9.7% fipronil along a thin line between the
animals shoulder blades. Latex gloves were worn by the study cohorts.
The arithmetic mean representing total dermal exposure was 0.0014
mg/kg/day. To estimate an adult treating a pet in a residential
situation, the professional groomer mean exposure was divided by S
(0.00018 mg/kg/day). To estimate chronic professional exposure (26
weeks during peak flea season) the professional groomer mean
exposure was also divided by 8 reflecting the median number of dogs
treated daily by veterinary and commercial users using the Top Spot
product (0.0000018 mg/kg/day adjusted for 1% dermal absorption).
This value was substantiated by a survey of professional groomers and
veterinarians submitted by Merial.
v. Post-Application Exposure Assessment: Occupation and
Residential
(a) Occupational
The petitioner did not provide post-application exposure sampling
data. However, postapplication exposure is mitigated by the fact that it
is soil incorporated at planting and the crop is harvested mechanically.
(b) Residential
Approximately 135 mg of fipronil top-spot was applied to dogs having
similar weights and varying coat lengths and approximately 50 mg of
fipronil was applied to cats having similar weights and presumably
similar coat lengths. The studies using Frontline spray treatment were
also conducted in a similar manner. Dye free cotton gloves were worn
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1
by the investigators to dislodge residues by stroking the animals 5
times from the head to the tail along the lay of the coat. A total of 22
cats and 32 dogs were treated. In most cases, post application sample
periods was structured as follows: 1, 2, 4, 8 and 12 hours; and 1, 2, 4,
7, 14, 21 and 28 days. The half-lives of dislodgeable residues from the
animals were approximately 5 to 6 days. In general, dislodgeable
residues represented less than one percent of the applied dose. The
exceptions were during the periods measure shortly after treatment (1 -
12 hours) in which some percent dislodgeable residues were greater
than one percent (up to 1 .45%). Coefficients of variability were
approximately 30 to 45% which is not surprising given the variability
of animals coats, where the animal was stroked (although all sides
were stroked), and in the case of the spray treatment, initial deposition
and efficiency of the spray treatment itself.
For use in the Tier 2 screening level assessment 1% dislodgeability
will be used for an extreme exposure, 0.5% dislodgeability for short
term exposure (approximate average of 1 - 8 days post application
percents) and 0.4% dislodgeability for intermediate term exposure
(average of 1 to 29 days post application percents).
The post application exposure assessment for toddlers assumes the
dermal exposure one might expect if a child hugs the dog and a non-
dietary oral (hand-to-mouth) dose if the child also pets the dog.
The following dermal algorithm was used:
AR x ASA x PR x T x HSA = mg/kg/day
BW(kg)
Where:
AR = Amount of ai applied to treat a 30 pound dog (135 mg)
ASA » Animal Surface Area (6000 cm2)
DR = Percent Dislodgeable Residue from animal fur
T - Transfer factor ( 1 0%)
HSA = Human Surface Area (696 cm2) consisting of '/j arms, '/i hands
and Vi torso with 90% clothing protection.
Body Weight (15 kg)
The respective dermal exposures for 1%, 0.5% and 0.4% Dislodgeable
rates are 0.001 mg/kg/day, 0.0005 mg/kg/day, and 0.0004 mg/kg/day.
It should be noted that this scenario is similar to that of the
professional groomers in the applicator studies who picked wet dogs
up after treatment. Those groomers treated eight dogs each and a
homeowner was assumed to treat one. The homeowner dermal doses
79
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for the spray treatment were 0.003 mg/kg/day.
The following non-dietary (hand-to-mouth) algorithm was used:
AR x ASA x PR x T x HSA = mg/kg/day
BW(kg)
Where:
AR = Amount of ai applied to treat a 30 pound dog (135 mg)
ASA = Animal surface area (6000 cm2)
DR = Percent Dislodgeable Residue from animal fur
T = Transfer factor (10%)
HSA = Human Surface Area (89 cm2) consisting of/a of one hand
SE = Saliva Extraction (20%) based on hand rinse efficiency.
BW = Body Weight (15 kg)
The respective non-dietary, oral (hand-to-mouth) ingestion estimates
for 1%, 0.5% and 0.4% Dislodgeable rates are 0.00003 mg/kg/day,
0.00001 mg/kg/day, and 0.00001 mg/kg/day.
Table 19 - Margins of Exposure for the Use of Fipronil to Control Fleas and Ticks on Dogs and
Cats
Receptor
Pro-groomer
spray
Pro-groomer
top-spot
Homeowner
spray
Homeowner
top-spot
Toddler
Short-Term
MOE
210+
3,600
1,700
28,000
5,000
extreme
10,000
Intermediate
Term MOE
210+
3,600
-
- -
10,000
Chronic
MOE
380*
•
11,000*
—
—
Non-Dietary
Oral MOE
—
—
—
—
17,000
extreme
50,000
* It is current HED policy to not amortize doses related to chronic exposure. Rather, an average
is to be assumed for the period of concern. For this, the median of 1.7 animals for the spray and
1 animal for the spot treatment was used.
SO
-------
1
+ The values for short-term and intermediate term exposure arc based on very high end
assumptions (the treatment of 8 dogs/day without wash-up in between, or the option groomers
have of changing smocks between treatments). Rather, 3 to 5 dogs are more likely to be a high
estimate for professional veterinarian or groomer personnel.
b. Occupation and Residential Risk Assessment/Characterization
i. Risk from Dermal and Inhalation Exposures Equations and
Tables
As presented in Tables 16-19, MOEs are greater than 250 for all
handling activities associated with use on rice and greater than 210 for
all handling activities associated with use on pets. Post-application
reentry exposure for rice is expected to result in lower exposures and
thus, higher MOE's. As presented in Table 19, MOEs are greater than
5000 for all post-application exposures associated with use on pets.
An MOE of 100 accounts for interspecies extrapolation and
intraspecies variability. FFDCA section 408 provides that EPA shall
apply an additional 10-fold margin of safety for infants and children in
the case of threshold effects to account for pre-and post-natal toxicity
and the completeness of the data base unless EPA determines that a
different margin of safety will be safe for infants and children.
However, the FQPA Safety Factor Committee recommended
(document dated 13-MAY-1998) that the 10X factor for enhanced
sensitivity to infants and children (as required by FQPA) should be
removed for fipronil
Chronic exposure is not expected for use of fipronil on rice, hence a
chronic risk assessment will not be done. However, the use of fipronil
by veterinary personnel during flea season is likely to result in chronic
exposure. Thus, a chronic exposure assessment was conducted for this
scenario, resulting in MOEs greater than 350 for all handling activities.
Also, the Hazard I.D. committee does not consider workers to be at
risk from inhalation exposure due to the low exposure to the chemical
by this route. Consequently, an inhalation worker risk assessment will
not be done. However, unit exposure are presented in table 6 showing
inhalation exposures are likely to be much lower than dermal
exposure.
ii. Risk from Post-Application Exposures
The default dermal toxicity REI is 24 hours based on fipronil technical
being in Acute Dermal Toxicity Category II. Due to the fact that the
product is soil incorporated at planting, postapplication exposure is not
81
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expected. (Assumes that the tox category is II based on the handler
PPE which is coveralls over short pants and short sleeved shirt).
iii. Restricted Entry Interval (REI)
Based on the Tox Category, the appropriate REI is 24 hours.
iv. Incident Reports
No incidents have been reported in humans, however, target species
incident reports through December 1996 are as follows (From Memo
of Virginia A. Dobozy, 4/1/97; D233461):
Product
Frontline* Spray
Treatment
Frontline" Top
Spot™ for Cats
Frontline* Top
Spot™ for Dogs
Total Frontline*
Products
Estimated No. of
Treatments Sold*
5,433,744
1,387,410
3,960,810
10, 781,964
No. of 6(aX2) Reports Submitted
to EPA
21
15
13
49
% of 6(aX2) Reports vs.
No. of Treatments Sold
0.0004
0.00 II
0.0003
0.0005
* Treatments sold estimated using the average weight of a cat = 8 Ibs. and the average weight of a dog » 30 Ibs.
Also, the incident reports from the time of registration until March 17,
1997 for the three fipronil veterinary products, Frontline® Spray
Treatment (65331-1), Top Spot™Tor Cats (65331-2) and Dogs
(65331-3), were evaluated. See April 16,1997 Memo from Virginia
Dobozy to Richard Griffin (HED) and Rick Keigwin (RD). At that
time, the following number and type of incidents were reported to the
OPP Incident Data System for the three fipronil products.
Type of
Reaction
Dermal
irritation
Systemic
reaction
Death
Frontline Spray "
Cats
1
9
-
Dogs
10
4
-
Top Spot for Cats
Cats
21
13
1
Dogs
-
-
-
Top Spot for Dogs
Cats
-
-
-
Dogs
30
2
-
82
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Based on that review, the following recommendations were made:
1) The number and type of adverse reactions were not excessive or
unexpected. Most of the incident reports involved skin irritations which
were reported in the studies done prior to registration. The labels for Top
Spot™ state that pets may experience some temporary irritation at the site
of product application.
2) There were three reports of systemic reactions when Frontline® Spray
was misused and instilled into cats' ears. If reports of this misuse continue,
label revisions should be considered to warn against this practice.
It was additionally noted that a relatively large percentage (12.5%) of the
adverse reactions were reported in Bichon Prise's, a relatively uncommon
breed.
Review of Incidents from March 17.1997 to April 13.1998 (From Memo of
Virginia A. Dobozy, 4/29/98; D241621):
Estimates of the number and type of adverse reactions reported to the OPP
Incident Data System for the three fipronil veterinary products since March
17,1997 are as follows.
Type of
Reaction
Dermal
irritation
/
Systemic
reaction
Death"
Frontline® Spray
• Cats (i Of
-
9
6
Dogs (8)*
7
3
3
Top Spot™ for Cats
Cats (101)*
74
27
10
Dogs
-
-
Top Spot™ for Dogs
Cats
-
-
-
Dogs(2i5)-
183
32
17
a Number of animals affected; more than one type of reaction could be reported for each animal
b If dermal irritation or systemic reactions were observed prior to death, they were also counted in these categories.
There were also four rabbits treated with Top Spot™ for Cats; most
developed neurological signs of toxicity.
The majority of the deaths were investigated and the cause of death
attributed to a reason other than fipronil exposure. In some cases where the
cause was not identified, a necropsy was not conducted, although the
registrant offered to cover the cost. One adult cat and three kittens died
after they were exposed to Frontline Spray and were then confined in a
83
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carrier or under blankets, respectively. The inhalation of the product vapors
may have contributed to these deaths; no necropsies were done. Follow-up
results for two incidents are still pending. In 1005336, the New Jersey EPA
forwarded a preliminary investigation into the report of one dog which died
and another which was blinded. In 1005627-022 (complaint 9717074), a 9
month-old Siberian Husky was found dead 48 hours after application of the
product. Results of the histopathology are pending.
As demonstrated in the above table, the majority of the adverse reactions in
both cats and dogs were of a dermatological nature. In cats treated with Top
Spot™, there was a spectrum of reactions in the incident reports from
simple irritation and/or hair loss at the application site to severe moist
dermatitis and ulcerated areas that extended beyond the application site.
However, it is the general impression of this reviewer that dogs are more
severely affected than cats. For dogs, there was a spectrum of reactions
similar to cats. However, pruritis seemed to be more frequently reported
and the areas affected more extensive. Several veterinarians described the
skin as appearing to be "chemically burned". Skin sloughing also occurred
more frequently in dogs. Many animals had multiple monthly applications
before the reaction was observed. In many instances, the registrant
attributed the reaction to individual sensitivity. Advise given by the
registrant (from the incident reports) included bathing (even though the
label states that the product remains effective after bathing), treatment of the
dermal lesions and use of Frontline Spray in the future. For both cats and
dogs, there is a problem with differentiating the contribution of the fipronil
products to the dermal effects and the contribution of the flea allergy
dermatitis (FAD), if present. However, with FAD, the majority of the
lesions are on the lower back and hindquarters, whereas with the fipronil
incidents most of the lesions £t least originated with the site of application.
Review of Registrant's Analysis
Merial Limited submitted an analysis titled "Frontline® Products Reports of
Suspected Adverse Events Analysis of Breed, Age and Sex Distribution of
Dogs and Cats." A total of 344 reports received as of December 23,1997
were analyzed according to breed, sex and age for each of the three
products. Doses of product sold from product launch through September
30,1997 are: 7.8, 16.4 and 5.2 million for Frontline® Spray, Top Spot™ for
Dogs and Top Spot™ for Cats. The number of suspected adverse events
(SAE) as a function of doses sold are 0.00029%, 0.00126% and 0.0022%,
respectively, per million. According to the registrant's analysis, there were
no breed, age or sex sensitivities that would warrant specific mention on
Frontline product labels. The breeds with the largest percentage of reactions
were Retriever (Golden): 7.7%; German Shepherd: 6.8%; and Retriever (No
Desc.), mixed breed and Bichon Frise: all 5.3%. According to the American
Kennel Club list of the most popular breeds for 1997, Labrador Retriever
•
-------
was number 1, German Shepherd number 3 and Golden Retriever number 4.
It is not surprising that there are a large percentage of reactions in these
breeds. However, the Bichon Frise is a relatively uncommon breed.
Therefore, as noted in the previous review, it appears to be over-
represented. It can be argued that this breed is especially susceptible to
dermatological conditions, however other susceptible breeds, such as the
West Highland White terrier, do not have an increased sensitivity to
Frontline products.
Discussion/Recommendations
1 . The rates of suspected adverse events proposed by the registrant are
underestimates, given the denominator used for the calculations. The use of
"doses sold" overestimates the amount of product actually used. Below is a
comparison of the rates reported by the registrant based on doses sold
through December 31, 1996 and December 23, 1997.
December 31. 1996 December 23. 1997
Frontline® Spray 0.0004 0.00029
Top Spot™ for Cats 0.0011 0.00126
Top Spot™ for Dogs 0.0005 0.0022
It appears that there has been an increase in the rate for dogs exposed 'o Top
Spot™ for Dogs. However, the rate of suspected adverse events is - i
extremely low and should not affect the conversion of the time limited
registration to an unlimited registration. To monitor the trend with these
products, it is recommended that the registrant submit similar rates for all
three products at the end of 1 998.
2. The severity of the dermal reactions seen in some dogs and cats is of
concern. The label statement under HAZARDS TO DOMESTIC
ANIMALS, "Pets may experience some temporary irritation at the site of
product application", does not adequately describe the severe reactions. The
registrant should add the following label statement: "If signs persist, or
become more severe within a few days of application, consult a veterinarian
immediately."
3. Based on the incident data to date, the Bichon Frise breed may be over-
represented. It is recommended that the registrant submit individual
incident reports on this breed rather than include them with the summary
reporting which will be required as of June 16, 1998 under the final 6(aX2)
Rule.
4. Misuse of the products on rabbits or instillation of the products into the
ears for treatment of ear mites should be monitored. If such misuse
-------
continues, the label should be revised to warn against these practices.
c. Statement of the adequacy of the residential exposure data base to
assess infants' and children's exposures
The residential (food and water) exposure database for fipronil is adequate
to assess infants' and children's exposure.
5. Aggregate Exposure and Risk Assessment/Characterization
a. Acute Aggregate Exposure and Risk
Using refined exposure assumptions (anticipated residues for blended
commodities), a high-end exposure estimate (food only) of was calculated
for these subgroups: females 13+ years, for the general U.S. population,
infants (< 1 year), children (1-6 years), and males 13+. The following table
shows the high end exposure and total dietary (food only) percents of the
acute RfD for these population subgroups:
Subgroup
General U.S.
Population
Infants (< 1 year)
Children (1-6 years)
Females ( i J-T years)
Males (13+ years)
RfD
(mg/kg/day)
0.025
0.025
0.025
f* *
-------
resulting from multiple exposure pathways associated with a pesticide's
uses, levels of concern in drinking water may vary as those uses change. If
new uses are added in the future, OPP will reassess the potential impacts of
fipronil on drinking water as a part of the aggregate acute risk assessment
process.
b. Short- and Intermediate-Term Aggregate Exposure and Risk
An aggregate systemic (oral) and dermal exposure risk assessment is not
appropriate due to differences in the toxicity endpoints observed between
the oral (neurotoxicity and alterations in clinical chemistry and thyroid
parameters) and dermal (decreases in body weight gain and food
consumption) routes. An aggregate oral and inhalation risk is not required
due to the lack of exposure potential via the inhalation route based on the
current use pattern.
c. Chronic Aggregate Exposure and Risk
Chronic dietary exposure estimates for fipronil and MB 46513 utilized
anticipated residues and a projected market share and are thus highly
refined. For the U.S. population, 6.5% of the RfD is occupied by dietary-
(food) exposure. Though fipronil is currently registered for residential uses,
no chronic residential exposure is anticipated. The estimated average
' concentrations of fipronil in surface and ground water are less than OPP's
levels of concern for fipronil in drinking water as a contribution to chronic
aggregate exposure. Therefore, OPP concludes with reasonable certainty
that residues of fipronil in drinking water do not contribute significantly to
the aggregate chronic human health risk at me present time considering me
present uses and uses proposed in this action.
OPP bases this determination on a comparison of estimated concentrations
of fipronil in surface waters and ground waters to levels of concern for
fipronil in drinking water. The estimates of fipronil in surface and ground
waters are derived from water quality models that use conservative
assumptions regarding the pesticide transport from the point of application
to surface and ground water. Because OPP considers the aggregate risk
resulting from multiple exposure pathways associated with a pesticide's
uses, levels of concern in drinking water may vary as those uses change. If
new uses are added in the future, OPP will reassess the potential impacts of
fipronil on drinking water as a part of the aggregate chronic risk assessment
process.
-------
6. Other Food Quality Protection Act (FQPA) Considerations
a. Cumulative Risk
Fipronil is structurally similar to other members of the pyrazole class of
pesticides (i.e., tebufenpyrad, pyrazolynate, benzofenap, etc.). Further,
other pesticides may have common toxicity endpoints with fipronil.
Section 408 of FQPA requires that, when considering whether to establish,
modify, or revoke a tolerance, the Agency considers "available information"
concerning the cumulative effects of a particular pesticide's residues and
"other substances that have a common mechanism of toxicity." While the
Agency has some information in its files that may be helpful in determining
whether a pesticide shares a common mechanism of toxicity with any other
substances, EPA does not at this time have the methodology to resolve the
scientific issues concerning common mechanism of toxicity in a meaningful
way. EPA has begun a pilot process to study this issue further through the
examination of particular classes of pesticides. The Agency hopes that the
results of this pilot process will enable it to develop and apply policies for
evaluating the cumulative effects of chemicals having a common
mechanism of toxicity. At present, however, the Agency does not know
how to apply the information in its files concerning common mechanism-
issues to most risk assessments. There are pesticides as to which the
common mechanism issues can be resolved. These pesticides include
pesticides that are lexicologically dissimilar to existing chemical substances
(in which case the Agency can conclude that it is unlikely that a pesticide
shares a common mechanism of activity with other substances) and
pesticides that produce a common toxic metabolite (in which case common
EPA does not have, at this time, available data to determine whether fipronil
has a common mechanism of toxicity with other substances or how to
include this pesticide in a cumulative risk assessment For the purposes of
this tolerance action, therefore, EPA has not assumed that fipronil has a
common mechanism of toxicity with other substances.
«
On this basis, the registrant must submit, upon EPA's request and according
to a schedule determined by the Agency, such information as the Agency
directs to be submitted in order to evaluate issues related to whether fipronil
share(s) a common mechanism of toxicity with any other substance and, if
so, whether any tolerances for fipronil need to be modified or revoked.
b. Endocrine Disruption
EPA is required to develop a screening program to determine whether
certain substances (including all pesticides and inerts) "may have an effect
-------
1
in humans that is similar to an effect produced by a naturally occurring
estrogen, or such other endocrine effect...". The Agency is currently
working with interested stakeholders, including other government agencies,
public interest groups, industry and research scientists in developing a
screening and testing program and a priority setting scheme to implement
this program. Congress has allowed 3 years from the passage of FQPA
(August 3, 1999) to implement this program. At that time, EPA may require
further testing of this active ingredient and end use products for endocrine
disrupter effects.
c. Determination of Safety
US Population, Infants, and Children
Using refined exposure assumptions (anticipated residues for blended
commodities), a high-end exposure estimate (food only) of was calculated
for these subgroups: females 13+ years, for the general U.S. population,
infants (< 1 year), children (1-6 years), and males 13+. The total dietary
(food only) percents of the acute RfD for these population subgroups ranged
from 6-12%. This MOE calculation was based on an acute neurotoxicity
study (MRID* 44431801) NOEL in rats of 2.5 mg/kg/day for fiproml and
2.0 mg/kg/day for MB 46513 (MRID 44262808). Despite the potential for
exposure to fipronil in drinking water, HED does not expect the acute
aggregate exposure to exceed OPPs level of concern. The small percent of
the acute dietary RfD calculated for females 13+ years old provides
assurance that there is a reasonable certainty of no harm for both females
13+ years and the pre-natal development of infants.
Using highly refined exposure assumptions, HED has concluded that the
percentage of the RfD that will be utilized by chronic dietary (food only)
exposure to residues of fipronil ranges from 5.1% for nursing infants less
than one year old, up to 16.7% for non-nursing infants less than one year
old. Despite the potential for exposure to fipronil in drinking water, HED
does not expect the chronic aggregate exposure to exceed 100% of the RfD.
There are uses of fipronil that result in residential exposure, but is not
expected to result in chronic exposure. HED concludes that there is a
reasonable certainty that no harm will result to infants and children from
chronic aggregate exposure to fipronil residues.
7. Data Requirements
a. Toxicology
There are currently no toxicology data gaps for fipronil, its metabolites or
the photodegradate. The Registrant should submit a developmental
neurotoxicity (or other) study on the photodegradate (MB 46513) if one is
*> 89
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completed.
b. Chemistry
i. The petitioner should submit one additional rice residue trial located in
region 5.
ii. To provide for the periodic evaluation of the anticipated residues, the
Agency will require under Section 408(bX2XE) residue data be
submitted every five years as long as the proposed tolerances remain in
force.
iii. Storage stability data for the photodegradate MB 46513 should be
submitted.
c. Occupational and Residential Exposure
i. In regards to seed treatments (FS formulation only), Subdivision U
Guideline requirements for Dermal Exposure at Indoor Sites (233) and
Inhalation Exposure at Indoor Sites (234) are required as a condition of
this registration.
ii. In regards to pet-care products, HED recommends that the petitioner
be required to submit: 1) rates of suspected adverse events for all three
pet-care products at the end of 1998; 2) add the following label
statement: " If signs persist, or become more severe within a few days
of application, consult a veterinarian immediately;" 3) individual
incident reports on the Bichon Frise breed rather than include them
with the summary reporting which will be required as of June 16,1998
under the final 6(aX2) Rule and; 4f monitoring of misuse of the
products on rabbits or instillation of the products into the ears for
treatment of ear mites and if such misuse continues, then the label
should be revised to warn against these practices.
ATTACHMENTS
I. Acute ORES analyses for Fipronil [+ MB 45950, MB 456136, and MB 46513].
II. Chronic ORES analyses for Fipronil [+ MB 45950 and MB 456136].
III.. Chronic ORES analyses for MB 46513
cc: PP#7F04832, G. Kramer, M. Copley, J. Evans
ROI: Team (5/20/98), M. Morrow (5/21/98)
G.F. Kramer:804V:CM#2:(703) 305-5079: 7509CRAB1
»
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0.0400 BEEF-MEAT BTP 0000000
0.0400 BEEF-MEAT BTP 0000000
0.0400 BEEF-OTH ORGAN 0000000
0.0400 BEEF-OTH ORGAN 0000000
0.0400 BEEF-DRIED 0000000
•0.4000 BEEF-FAT 0000000
0.4000 BEEF-FAT 0000000
0.4000 BEEF-FAT 0000000
0.4000 BEEF-FAT 0000000
0.4000 BEEF-FAT 0000000
0.4000 BEEF-FAT 0000000
0.0400 BEEF-K1DNET 0000000
0.1000 BEEF-LIVER
0.1000 BEEF-LIVER
0.0400 BEEF-LEAN
0.0400 BEEF-LEAN
0.0400 BEEF-LEAN 0000000
0.0400 BEEF-LEAN 0000000
0.0400 BEEF-LEAN 0000000
0.0400 GOAT-NEAT BY? 0000000
0.0400 GOAT-OTH ORGAN 0000000
0.4000 GOAT-FAT 0000000
0.4000 60AT-FAT
0.0400 GOAT-KIDNEY
0.1000 GOAT-LIVER
0.0400 GOAT-LEAN
0.0400 GOAT-LEAN
0.0400 NORSK
0.0400 SHEEP-MEAT BYT
0.0400 SHEEP-OTN ORGAN 0000000
0.4000 SWEEP-FAT
0.0400 SNEEP-K1DNEY
0.1000 SNBP-LIVER
0.0400 SHEEP-LEAN . 0000000
0.0400 SHOP-LEAN 0000000
0.0100 PORK-MEAT BYP 0000000
0.0100 PORK-OTN ORGAN 0000000
0.0100 PORK-OTH ORGAN
0.0400 PORT-FAT
0.0400 PORK-FAT
0.0400 PORK-FAT 0000000
0.0400 PORK-FAT 0000000
0.0400 PORK-FAT 0000000
0.0100 PORK-KIDNEY 0000000
0.0200 PORK-LIVER 0000000
0.0200 PORK-LIVER 0000000
0.0100 PORK-LEAN 0000000
0.0100 PORK-LEAN 0000000
-------
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9388
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TOLERANCE ASSESSMENT SUMMARY FOR Mpronil
USING ANTICIPATED RESIDUES
CASUELL f938>
ANALYSIS FOR POPULATION SUB-GROUP: U.S. POPULATION
DATE: 12/05/97
STATES
EXISTING ANTICIPATED RESIDUES (Will SHED ONLY)
RESULT IN AN ARC OF: 0.000000
THE EXISTING ARC IS EQUIVALENT TO: 1.240
PROPOSED HEW ANTICIPATED RESIDUES (CURRENT PETITION ONLY)
RESULT IN AN ARC OF: <0. 000001
THESE NEW ANTICIPATED RESIDUES WILL OCCUPY: 0.475
IF THE NEW ANTICIPATED RESIDUES (CURRENT PETITION ONLY)
ARE APPROVED THE RESULTANT ARC WILL K: 0.000000
THE NEW ARC WILL OCCUPY 1.715
NO OTHER PENDING ANTICIPATED RESIDUES ARE IN THE FILE
ANALYSIS FOR POPULATION SUB -CROUP: NON-NURSING INFANTS « 1 YEAR OLD)
EXISTING ANTICIPATED RESIDUES (PUBLISHED ONLY)
RESULT IN AN ARC Of:
THE EXISTING ARC IS EQUIVALENT TO:
0.
1.540
PROPOSED NEW ANTICIPATED RESIDUES (CURRENT PETITION ONLY)
RESULT IN AN ARC OF: <0.000001
THESE NEW ANTICIPATED RESIDUES WILL OCCUPYt 3.960
IF THE NEW ANTICIPATED RESIDUES (CURRENT PETITION ONLY)
ARE APPROVED THE RESULTANT ARC WILL BE: 0.000001
THE NEW ARC WILL OCCUPY 5.520
NO OTHER PENDING ANTICIPATED RESIDUES ARE IN THE FILE
NG/KG/DAY
X OF THE ADI.
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X OF THE ADI.
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X Of THE ADf.
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