[Federal Register Volume 64, Number 26 (Tuesday, February 9, 1999)]
[Notices]
[Pages 6351-6357]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-3146]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-856; FRL-6058-3]
Notice of Filing of Pesticide Petitions
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
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SUMMARY: This notice announces the initial filing of pesticide
petitions proposing the establishment of regulations for residues of
certain pesticide chemicals in or on various food commodities.
DATES: Comments, identified by the docket control number PF-856, must
be received on or before March 11, 1999.
ADDRESSES: By mail submit written comments to: Public Information and
Records Integrity Branch, Information Resources and Services Division
(7502C), Office of Pesticides Programs, Environmental Protection
Agency, 401 M St., SW., Washington, DC 20460. In person bring comments
to: Rm. 119, CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
Comments and data may also be submitted electronically to: opp-
[email protected]. Follow the instructions under ``SUPPLEMENTARY
INFORMATION.'' No confidential business information should be submitted
through e-mail.
Information submitted as a comment concerning this document may be
claimed confidential by marking any part or all of that information as
``Confidential Business Information'' (CBI). CBI should not be
submitted through e-mail. Information marked as CBI will not be
disclosed except in accordance with procedures set forth in 40 CFR part
2. A copy of the comment that does not contain CBI must be submitted
for inclusion in the public record. Information not marked confidential
may be disclosed publicly by EPA without prior notice. All written
comments will be available for public inspection in Rm. 1132 at the
address given above, from 8:30 a.m. to 4 p.m., Monday through Friday,
excluding legal holidays.
FOR FURTHER INFORMATION CONTACT: The product manager listed in the
table below:
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Office location/
Product Manager telephone number Address
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Joanne I. Miller (PM 23)...... Rm. 237, CM #2, 703- 1921 Jefferson
305-6224, e- Davis Hwy,
mail:miller.joanne@ep Arlington, VA
amail.epa.gov.
Sidney Jackson (PM 23)........ Rm. 233, CM #2, 703- Do.
305-7610, e-mail:
jackson.sidney@epamai
l.epa.gov.
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SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions as
follows proposing the establishment and/or amendment of regulations for
residues of certain pesticide chemicals in or on various food
commodities under section 408 of the Federal Food, Drug, and Comestic
Act (FFDCA), 21 U.S.C. 346a. EPA has determined that these petitions
contain data or information regarding the elements set forth in section
408(d)(2); however, EPA has not fully evaluated the sufficiency of the
submitted data at this time or whether the data supports granting of
the petition. Additional data may be needed before EPA rules on the
petition.
The official record for this notice of filing, as well as the
public version, has been established for this notice of filing under
docket control number [PF-856] (including comments and data submitted
electronically as described below). A public version of this record,
including printed, paper versions of electronic comments, which does
not include any information claimed as CBI, is available for inspection
from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal
holidays. The official record is located at the address in
``ADDRESSES'' at the beginning of this document.
Electronic comments can be sent directly to EPA at:
[email protected]
Electronic comments must be submitted as an ASCII file avoiding the
use of special characters and any form of encryption. Comments and data
will also be accepted on disks in Wordperfect 5.1 file format or ASCII
file format. All comments and data in electronic form must be
identified by the docket number (insert docket number) and appropriate
petition number. Electronic comments on notice may be filed online at
many Federal Depository Libraries.
List of Subjects
Environmental protection, Agricultural commodities, Food additives,
Feed additives, Pesticides and pests, Reporting and recordkeeping
requirements.
Dated: January 29, 1999.
James Jones,
Director, Registration Division, Office of Pesticide Programs.
Summaries of Petitions
Petitioner summaries of the pesticide petitions are printed below
as required by section 408(d)(3) of the FFDCA. The summaries of the
petitions were prepared by the petitioners and represent the views of
the petitioners. EPA is publishing the petition summaries verbatim
without editing them in any way. The petition summary announces the
availability of a description of the analytical methods available to
EPA for the detection and measurement of the pesticide chemical
residues or an explanation of why no such method is needed.
1. Dow AgroSciences LLC
PP 8F 3600
EPA has received a pesticide petition (8F 3600) from Dow
AgroSciences LLC, 9330 Zionsville Road, Indianapolis, IN 46268,
proposing pursuant to section 408(d) of the Federal Food, Drug, and
Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 by
establishing a tolerance for residues of the herbicide clopyralid in or
on the raw agricultural commodity sugar beet, roots at 2.0 parts per
million (ppm) and sugar beet, tops at 3.0 ppm and on the processed
agricultural commodity (PAC) sugar beet, molasses at 16.0 ppm. at sugar
beet, roots at 2.0 ppm and sugar beet, tops at 3.0 ppm and on the
processed agricultural commodity (PAC) sugar beet, molasses at 16.0
ppm. EPA has determined that the petition contains data or information
regarding the elements set forth in section 408(d)(2) of the FFDCA;
however, EPA has not fully evaluated the sufficiency
[[Page 6352]]
of the submitted data at this time or whether the data supports
granting of the petition. Additional data may be needed before EPA
rules on the petition.
A. Residue Chemistry
1. Plant metabolism. The metabolism in plants is adequately
understood. No metabolites of significance were detected in plant
metabolism studies.
2. Analytical method. There is a practical analytical method for
detecting and measuring levels of clopyralid in or on food with a limit
of quantitation (LOQ) of 0.05 ppm that allows monitoring of food with
residues at or above the levels set in these tolerances. EPA has
provided information on this method to FDA. The method is available to
anyone who is interested in pesticide residue enforcement.
3. Magnitude of residues. Tolerances for residues of the herbicide
clopyralid in or on the following raw agricultural commodities, sugar
beet roots and tops and the processed agricultural commodity molasses,
were established on August 12, 1988 (53 FR 33488, 33489) at 0.5, 0.5,
and 7.0 ppm, respectively, based upon residue data generated by Craven
Laboratories. The validity of these data were in question and Dow
AgroSciences repeated the residue studies. The last of the required
residue data using a 105 day pre-harvest interval (PHI) were submitted
to the Agency in June 1994. This pesticide petition proposes increased
tolerances based upon data using a 45 day PHI. Residues of clopyralid
were determined in roots and tops from several varieties of sugar
beets, which were harvested from plots treated at the currently labeled
season-maximum rate of 0.25 lb ae/acre in one application. Field test
plots were located at thirteen sites representing the major U.S.
production areas. Highest residues at the 45 day PHI for roots averaged
0.91 g/g with the highest individual value of 1.47 g/
g, and for tops averaged 1.52 g/g with the highest individual
value of 2.48 g/g. Based on the data, it is expected that
residues of clopyralid in or on sugar beets as a raw agricultural
commodity will not exceed proposed revised tolerances of 2 g/g
in roots and 3 g/g in tops when the PHI is 45 days or longer.
With a concentration factor of 8, the proposed tolerance for sugar beet
molasses is 16 g/g. The proposed revised tolerances would
adequately cover these anticipated residues.
B. Toxicological Profile
1. Acute toxicity. Clopyralid has low acute toxicity. The rat oral
LD50 is 5,000 milligram/kilograms (mg/kg) or greater for
males, and females. The rabbit dermal LD50 is greater than
2,000 mg/kg and the rat inhalation LC50 is greater than 1.0
mg/L air (the highest attainable concentration). In addition,
clopyralid is not a skin sensitizer in guinea pigs and is not a dermal
irritant. Technical clopyralid is an ocular irritant but ocular
exposure to the technical material would not normally be expected to
occur to infants or children or the general public. End use
formulations of clopyralid have similar low acute toxicity profiles and
most have low ocular toxicity as well. Therefore, based on the
available acute toxicity data, clopyralid does not pose any acute
dietary risks.
2. Genotoxicty. Clopyralid is not genotoxic. The following studies
have been conducted and all were negative for genotoxic responses. Ames
bacterial mutagenicity assay (with and without exogenous metabolic
activation); Host-Mediated assay In vivo cytogenetic test, rat; In vivo
cytogenetic test, mouse; In vivo dominant lethal test, rat; In vitro
unscheduled DNA synthesis assay in primary rat hepatocyte cultures; In
vitro mammalian cell gene mutations assay in Chinese hamster ovary cell
cultures (with and without exogenous metabolic activation).
3. Reproductive and developmental toxicity. Developmental toxicity
was studied using rats and rabbits. The developmental study in rats
resulted in a developmental no-observed adverse effect level (NOAEL) of
> 250 milligram/kilograms/day (mg/kg/day) (a maternally toxic dose) and
a maternal toxicity NOAEL of 75 mg/kg/day. A 1974 study in rabbits
revealed no evidence of developmental or maternal toxicity at 250 mg/
kg/day; thus the developmental and maternal NOAEL was > 250 mg/kg/day.
A more recent study in rabbits (1990) resulted in developmental and
maternal NOAELs of 110 mg/kg/day based on maternal toxicity at 250 mg/
kg/day. Based on all of the data for clopyralid, there is no evidence
of developmental toxicity at dose levels that do not result in maternal
toxicity. In a 2-generation reproduction study in rats, pups from the
high dose group which were fed diets containing clopyralid had a slight
reduction in body weight during lactation and an increase in liver
weights in F1a and F1b weanlings. The NOAEL for parental systemic
toxicity was 500 mg/kg/day. There was no effect on reproductive
parameters at > 1,500 mg/kg/day nor was there an adverse effect on the
morphology, growth or viability of the offspring; thus, the
reproductive NOAEL is > 1,500 mg/kg/day.
4. Subchronic toxicity. The following studies have been conducted
using clopyralid. In a rat 90 day feeding study, Fischer 344 rats were
fed diets containing clopyralid at doses of 5, 15, 50 or 150 mg/kg/day
with no adverse effects attributed to treatment. In a second study,
Fischer 344 rats were fed diets containing clopyralid at doses of 300,
1,500 and 2,500 mg/kg/day. Effects at the highest doses were decreased
food consumption accompanied by decreased body weights and weight gains
in both males and females. Slightly increased mean relative liver and
kidney weights were noted in males of all doses, and in females at the
top 2 doses. Because there were no other effects, the kidney and liver
weight effects were judged as being adaptive rather than directly
toxic. The no-observed adverse effect level (NOAEL) was 1,500 mg/kg/day
for males and females. The NOAEL was 300 mg/kg/day for females. In a
mouse 90 day feeding study, B6C3F1 mice were fed diets containing
clopyralid at doses of 200, 750, 2,000 or 5,000 mg/kg/day. A slight
decrease in body weight occurred at the top dose in both sexes. The
liver was identified as the target organ based on slight increases in
liver weights and minimal microscopic alterations at the higher dose
levels. The liver changes were considered to be reversible and
adaptive. The NOAEL for males was 2,000 mg/kg/day, and for females was
750 mg/kg/day. In a 180 day feeding study, beagle dogs were fed diets
containing clopyralid at doses of 15, 50 or 150 mg/kg/day; there were
no adverse effects. In a second dietary study, dogs also were fed diets
containing clopyralid at doses of 15, 50 or 150 mg/kg/day; the only
effect was an increase in the mean relative liver weight in females at
the 150 mg/kg/day. In a 21 day dermal study, clopyralid was applied by
repeated dermal application to New Zealand White rabbits at dose levels
up to 1,000 mg/kg/day. Treatment produced no systemic effects.
5. Chronic toxicity. In a chronic toxicity and oncogenicity study,
Sprague-Dawley rats were fed diets containing clopyralid at doses of 5,
15, 50 or 150 mg/kg/day. The only effect was a trend toward a decreased
body weight of female rats receiving the 150 mg/kg/day dose with a
NOAEL of 50 mg/kg/day. In a second study clopyralid was fed to Fischer
344 rats in the diet at doses of 15, 150 or 1,500 mg/kg/day. The
effects were confined almost entirely to the 1,500 mg/kg/day dose
groups and included slightly decreased food consumption and body
weights, slightly increased liver and kidney
[[Page 6353]]
weights and macroscopic and microscopic changes in the stomach. No
tumorigenic response was present. The NOAEL for this study was 150 mg/
kg/day. B6C3F1 mice were maintained for 2 years on diets formulated to
provide targeted dose levels of 10, 500 or 2,000 mg/kg/day. The only
evidence of toxicity was body weight depression in males dosed at 2,000
mg/kg/day. There was no evidence of tumorigenic response at any dose
level. Based on the chronic toxicity data, EPA has established the RfD
for clopyralid at 0.5 mg/kg/day. The RfD for clopyralid is based on a 2
year chronic oncogenicity study in rats with a no-observed-effect level
(NOAEL) of 50 mg/kg/day and an uncertainty (or safety) factor of 100.
Thus, it would not be necessary to require the application of an
additional uncertainty factor above the 100-fold factor already applied
to the NOAEL. Using its Guidelines for Carcinogen Risk Assessment
published September 24, 1986 (51 FR 33992), clopyralid would be
classified as Group E for carcinogenicity (no evidence of
carcinogenicity) based on the results of the carcinogenicity studies.
There was no evidence of carcinogenicity in 2 year feeding studies in
mice and rats at the dosage levels tested. The doses tested are
adequate for identifying a cancer risk. Thus, a cancer risk assessment
would not be appropriate.
6. Animal metabolism. Disposition and metabolism of clopyralid were
tested in male and female rats at a dose of 5 mg/kg (oral). The
majority of a radioactive dose was excreted in 24 hours of all dose
groups. Fecal elimination was minor. Detectable levels of residual
radioactivity were observed in the carcass and stomach at 72 hours
post-dose. HPLC and TLC analysis of urine and fecal extracts showed no
apparent metabolism of clopyralid.
7. Metabolite toxicology. There are no clopyralid metabolites of
toxicological significance.
8. Endocrine disruption. There is no evidence to suggest that
clopyralid is neurotoxic.
C. Aggregate Exposure
1. Dietary exposure. For purposes of assessing the potential
dietary exposure under these tolerances, exposure is estimated based on
the theoretical maximum residue contribution (TMRC) from the existing
and this proposed amended tolerance for clopyralid on food crops. The
TMRC is obtained by multiplying the tolerance level residues by the
consumption data which estimates the amount of those food products
eaten by various population subgroups. Exposure of humans to residues
could also result if such residues are transferred to meat, milk,
poultry or eggs. The following assumptions were used in conducting this
exposure assessment. 100% of the crops were treated, the raw
agricultural commodities (RAC) residues would be at the level of the
tolerance, certain processed food residues would be at anticipated
(average) levels based on processing studies and all current and
pending tolerances were included. This results in an over estimate of
human exposure and a conservative assessment of risk. Based on a NOAEL
of 50 mg/kg/day in a 2 year chronic feeding/oncogenicity study in the
rat and a hundredfold safety factor, the RfD would be 0.5 mg/kg/day.
Consequently, these tolerances have a TMRC of 0.010277 mg/kg/day and
would utilize approximately 2.1% of the RfD for the general U.S.
population.
i. Food. The Toxicology database indicates there is no concern
regarding acute and chronic dietary risk since the available data do
not indicate any evidence of significant toxicity from exposure by the
oral route.
ii. Drinking water. Another potential source of dietary exposure to
residues of pesticides are residues in drinking water. There is no
established maximum concentration level (MCL) for residues of
clopyralid in drinking water. Although there has been limited
detections at parts per billion (ppb) levels in some of the specially
designed studies under highly vulnerable test conditions, no ongoing
monitoring studies (U.S. Geological Survey, Selected Water Resources
Abstracts; Pesticides in Ground WaterDatabase - A Compilation of
Monitoring Studies: 1971-1991 National Summary; U.S. Department of
Agriculture, AGRICOLA database; and, U.S. Department of Commerce,
National Technical Information Service) have reported residues of
clopyralid in ground or surface waters.
Based on the physical and chemical characteristics of clopyralid,
such as water solubility and its stability under hydrolysis and
photolysis, it has potential for downward movement through the soil
profile. However, the behavior of the compound under field conditions
demonstrates fairly rapid degradation and limited downward movement.
Degradation based on 20 field dissipation sites indicated an average
half-life of 25 days. Degradation is driven primarily by microbial
processes. Downward movement through the soil profile was generally
confined to the upper 18 inches of the soil profile. Validated computer
modeling also predicted the maximum depth of residues to be 18-inches,
with no detections predicted at 6 months after application.
Because the laboratory derived physical/chemical properties of
clopyralid indicate a potential for downward movement, lysimeter
studies were conducted. In a U.S. study, undisturbed soil columns
(lysimeters), 8 inches in diameter, and 3 feet deep, were treated with
950 g ae/ha (about 5 x labeled use rates) in actual field conditions.
Residues of clopyralid in soil as well as soil-solution (leachate) were
collected in the closed system. The average depth of movement for the
majority of clopyralid (center of mass) was 11 inches, and no
detectable residues were observed in the leachate. In a European study,
lysimeters 1-3 ft. diameter, and 3 ft. deep, were treated with 120 and
240 g ae/ha in actual field conditions. The average center of mass was
12 inches. No detectable residues were observed in the lysimeters. The
amount of 14C in leachate accumulated over 2 years in the
degraded loess and silty sand lysimeters, was only 0.6% and 0.3% of
applied, respectively. The leachate concentrations of 14C-
labeled clopyralid in degraded loess and silty sand throughout the
first 10-16 months of the study ranged from 0.002-0.14 g/l ppb
and 0.003-0.02 ppb, respectively. A second European lysimeter study
with silty sand lysimeters treated with 120 g ae/ha revealed a 2 year
cumulative clopyralid leachate of only 0.1% of applied (0.04 ppb).
These studies demonstrate that in lysimeter test systems, under field
environmental conditions, clopyralid rapidly dissipates through
mineralization to carbon dioxide. Also the very low levels observed in
leachate demonstrate that there is very little potential for clopyralid
to leach through soil and contaminate ground water.
In summary, these data on potential water exposure indicate
insignificant additional dietary intake of clopyralid and any exposure
is more than compensated for in the conservative dietary risk
evaluation. Therefore, it is concluded that there is a reasonable
certainty of no harm even at potential upper limit exposures to
clopyralid from drinking water.
2. Non-dietary exposure. There is a non-dietary use registered
under the Federal Insecticide, Fungicide and Rodenticide Act. The use
is for weed control in residential turf and ornamentals. Potential
exposures for children from non-occupational uses is therefore limited
to turf and ornamental re-entry and this exposure is low.
[[Page 6354]]
3. Short-term or intermediate-term. The data for clopyralid does
not indicate any evidence of significant toxicity by the dermal and
inhalation routes. Consequently, there is no concern for short-term or
intermediate-term residential risk. Therefore, a short-term or
intermediate-term residential risk assessment would not be required.
4. Chronic. As part of a hazard assessment process an endpoint of
concern is determined for the chronic occupational or residential risk
assessment. However, as indicated, the exposures that would result from
the use of clopyralid are of an intermittent nature. The frequency and
duration of these exposures do not exhibit a chronic exposure pattern.
The exposure does not occur often enough to be considered a chronic
exposure; i.e., a continuous exposure that occurs for at least several
months. Therefore, it would not be appropriate to aggregate exposure
from the residential use with exposure from food and drinking water.
5. Acute. No concern would exist for an acute dietary assessment
for clopyralid because the available data indicates no evidence of
significant toxicity from a 1 day or single event exposure by the oral
route. Therefore, an acute dietary risk assessment would not be
required.
D. Cumulative Effects
The potential for cumulative effects of clopyralid and other
substances that have a common mechanism of toxicity was considered. The
mammalian toxicity of clopyralid is well defined. However, no reliable
information exists to indicate that toxic effects produced by
clopyralid would be cumulative with those of any other chemical
compound. Additionally, clopyralid does not appear to produce a toxic
metabolite produced by other substances. Therefore, consideration of a
common mechanism of toxicity with other compounds is not appropriate at
this time. Thus, only the potential exposures to clopyralid were
considered in the aggregate exposure assessment.
E. Safety Determination
1. U.S. population. Based on a NOAEL of 50.80 milligram/kilogram/
body weight/day (mg/kg/bwt/day) from a 2 year rat feeding study with a
decreased mean bwt gain effect, and using an uncertainty factor of 100
to account for the interspecies extrapolation and intraspecies
variability, a RfD of 0.5 mg/kg/bwt/day was used for this assessment of
chronic risk. As indicated, there is no endpoint of concern identified
with acute and short- or intermediate-term exposures. Based on the
known toxicity and exposure data, the proposed and existing tolerances
would utilize approximately 2.1% of the RfD for the U.S. population.
And, as indicated previously, whatever upper limit might be used for
drinking water exposure, the exposure estimate for clopyralid would not
exceed the RfD. Generally, exposures below 100% of the RfD are of no
concern because the RfD represents the level at or below which daily
aggregate dietary exposure over a lifetime will not pose appreciable
risk to human health. Thus, there is a reasonable certainty that no
harm will result from aggregate exposure to clopyralid residues.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of clopyralid, data
from developmental toxicity studies in the rat and rabbit and a 2-
generation reproduction study in the rat were considered. The
developmental toxicity studies are designed to evaluate adverse effects
on the developing organism during prenatal development resulting from
pesticide exposure to one or both parents. Reproduction studies provide
(i) information relating to effects from exposure to the pesticide on
the reproductive capability of mating animals and (ii) data on systemic
toxicity.
Developmental toxicity was studied using rats and rabbits. The
developmental study in rats resulted in a developmental NOAEL of > 250
mg/kg/day (a maternally toxic dose), and a maternal toxicity NOAEL of
75 mg/kg/day. A 1974 study in rabbits revealed no evidence of
developmental or maternal toxicity at 250 mg/kg/day; thus the
developmental andmaternal NOAEL was > 250 mg/kg/day. A more recent
study in rabbits (1990) resulted in developmental and maternal NOAEL's
of 110 mg/kg/day based on severe maternal toxicity at 250 mg/kg/day.
Based on all of the data for clopyralid, there is no evidence of
developmental toxicity at dose levels that do not result in maternal
toxicity.
In a 2-generation reproduction study in rats, pups from the high
dose group which were fed diets containing clopyralid had a slight
reduction in bwt during lactation and an increase in liver weights in
F1a and F1b weanlings. The NOAEL for parental systemic toxicity was 500
mg/kg/day. There was no effect on reproductive parameters at > 1,500
mg/kg/day nor was there an adverse effect on the morphology, growth or
viability of the offspring; thus, the reproductive NOAEL is > 1,500 mg/
kg/day.
FFDCA section 408 provides that EPA may apply an additional safety
factor for infants and children in the case of threshold effects to
account for pre- and post-natal toxicity and the completeness of the
database. Based on the current toxicological data requirements, the
database relative to pre- and post-natal effects for children is
complete. These data suggest minimal concern for developmental or
reproductive toxicity and do not indicate any increased pre- or post-
natal sensitivity. Therefore, an additional uncertainty factor is not
necessary to protect the safety of infants and children and that the
RfD at 0.5 mg/kg/day is appropriate for assessing aggregate risk to
infants and children.
The percent of the RfD that will be utilized by the aggregate
exposure from all tolerances to clopyralid will be much less than 10%
for non-nursing infants and for children (1-6 years of age). Therefore,
based on the completeness and reliability of the toxicity data and the
conservative exposure assessment, it is concluded that there is a
reasonable certainty that no harm will result to infants and children
from aggregate exposure to clopyralid residues.
F. International Tolerances
There are no Codex maximum residue levels established for
clopyralid.
2. IR4 Project
PP 8E4983, 8E5019, 8E5020,8E5021, and 8E5024
EPA has received pesticide petitions (PP 8E4983, 8E5018, 8E5019,
8E5020, 8E5021, and 8E5024) from the Interregional Research Project
Number 4 (IR-4), proposing pursuant to section 408(d) of the Federal
Food, Drug, and Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 CFR part
180 by establishing tolerances for residues of the insecticide,
tebufenozide (benzoic acid, 3,5-dimethyl-, 1-(1,1-dimethylethyl)-2-(4-
ethylbenzoyl)hydrazide) in or on the raw agricultural commodities.
1. PP 8E4983 proposed the establishment of a tolerance for
blueberries at 2.0 parts per million (ppm), and PP 8E5018 proposed a
tolerance for caneberries at 1.0 ppm. Subsequently, IR-4 amended these
tolerance proposals to include a single tolerance at 3.0 ppm for
berries (Crop Group 13) that will include both blueberries, and
caneberries under PP 8E4983.
2. PP 8E5024 proposes the establishment of tolerances for canola
seed at 1.75 ppm, and canola oil at 3.75 ppm.
3. PP 8E5019 proposes the establishment of a tolerance for
cranberries at 1.0 ppm.
[[Page 6355]]
4. PP 8E5021 proposes the establishment of a tolerance for mint at
10.0 ppm.
5, PP 8E5020 proposes the establishment of tolerances for turnips
tops at 9.0 ppm, and turnip roots at 0.25 ppm.
EPA has determined that the petitions contain data or information
regarding the elements set forth in section 408(d)(2) of the FFDCA;
however, EPA has not fully evaluated the sufficiency of the submitted
data at this time or whether the data support granting of the
petitions. Additional data may be needed before EPA rules on the
petitions.
A. Residue Chemistry
1. Plant metabolism. The metabolism of tebufenozide in plants
(grapes, apples, rice, and sugar beets) is adequately understood for
the purpose of these tolerances. The metabolism of tebufenozide in all
crops was similar and involves oxidation of the alkyl substituents of
the aromatic rings primarily at the benzylic positions. The extent of
metabolism and degree of oxidation are a function of time from
application to harvest. In all crops, parent compound comprised the
majority of the total dosage. None of the metabolites were in excess of
10% of the total dosage.
2. Analytical method. High performance liquid chromatographic
(HPLC) analytical methods using ultraviolet(UV) detection have been
validated for blueberries, raspberries, canola seed and oil,
cranberries, mint foliage and oil, and turnip roots and tops. The
methods involve extraction by blending with solvents, purification of
the extracts by liquid-liquid partitions and final purification of the
residues using solid phase extraction column chromatography. The limits
of quantitation (LOQ) is 0.005 ppm for blueberries, 0.01 ppm for canola
seed and meal, mint foliage, raspberries, and turnip roots and tops,
0.02 ppm for mint oil, 0.03 ppm for canola soapstock and oil, and 0.05
ppm for cranberries.
3. Magnitude of residues. Field residue trials were conducted with
a 70 wettable power (WP) formulation in geographically representative
regions of the U.S. A total of 8 field residue trials were conducted in
blueberries. The average blueberry residue value from all trials was
0.81 ppm.
A total of 7 field residue trials were conducted in canola. The
average canola seed residue value from all trials was 0.84 ppm. Two
processing studies were conducted. Average residues in meal, soapstock
and oil were 0.11 ppm, 0.83 ppm, and 1.75 ppm, respectively. Residues
did not concentrate in soapstock (Concentration Factor (CF) is less
than 1), and a tolerance in soapstock is not needed. For oil, the
average CF is 2.26, and the proposed tolerance is 3.75 ppm (2.26 times
1.58 ppm).
A total of 6 field residue trials were conducted in cranberries.
The average cranberry residue value from all trials was 0.30 ppm.
A total of 5 field residue trials were conducted in mint. The
average mint foliage residue value from all trials was 7.11 ppm. Mint
oil was prepared from foliage from two residue trials. The average oil
residue was 0.23 ppm. Since residues do not concentrate in oil, a
tolerance is not needed.
A total of 5 field residue trials were conducted in raspberries.
The average raspberry residue value from all trials was 0.62 ppm.
A total of 6 field residue trials were conducted in turnips. The
average residue value from all trials was 0.10 ppm for roots, and 2.27
ppm for tops.
B. Toxicological Profile
1. Acute toxicity. Results of a battery of toxicological studies
show tebufenozide has low acute toxicity. Tebufenozide Technical was
practically non-toxic by ingestion of a single oral dose in rats, and
mice (LD50 > 5,000 milligram/kilograms (mg/kg)) and was
practically non-toxic by dermal application LD50 > 5,000 mg/
kg. Tebufenozide Technical was not significantly toxic to rats after a
4 hour inhalation exposure with an LC50 value of 4.5
mg/L (highest attainable concentration), is not considered
to be a primary eye irritant or a skin irritant, and is not a dermal
sensitizer. An acute neurotoxicity study in rats did not produce any
neurotoxic or neuropathologic effects.
2. Genotoxicty. Tebufenozide technical was negative (non-mutagenic)
in an Ames assay with and without hepatic enzyme activation and in a
reverse mutation assay with E. coli. Tebufenozide technical was
negative in a hypoxanthine guanine phophoribosyl transferase (HGPRT)
gene mutation assay using Chinese hamster ovary (CHO) cells in culture
when tested with and without hepatic enzyme activation. In isolated rat
hepatocytes, tebufenozide technical did not induce unscheduled DNA
synthesis (UDS) or repair when tested up to the maximum soluble
concentration in culture medium. Tebufenozide did not produce
chromosome effects in vivo using rat bone marrow cells or in vitro
using Chinese hamster ovary cells (CHO). On the basis of the results
from this battery of tests, it is concluded that tebufenozide is not
mutagenic or genotoxic.
3. Reproductive and developmental toxicity. See discussion of
studies under section E.2. Infant and Children.
4. Subchronic toxicity-- i. The no-observed adverse effect level
(NOAEL) in a 90 day rat feeding study was 200 ppm (13 mg/kg/day for
males, 16 mg/kg/day for females). The lowest-observed adverse effect
level (LOAEL) was 2,000 ppm (133 mg/kg/day for males, 155 mg/kg/day for
females). Decreased body weight in males, and females was observed at
the LOAEL of 2,000 ppm. As part of this study, the potential for
tebufenozide to produce subchronic neurotoxicity was investigated.
Tebufenozide did not produce neurotoxic or neuropathologic effects when
administered in the diets of rats for 3 months at concentrations up to
and including the limit dose of 20,000 ppm (NOAEL = 1,330 mg/kg/day for
males, and 1,650 mg/kg/day for females).
ii. In a 90 day feeding study with mice, the NOAEL was 20 ppm (3.4
and 4.0 mg/kg/day for males and females, respectively). The LOAEL was
200 ppm (35.3 and 44.7 mg/kg/day for males and females, respectively).
Decreases in body weight gain were noted in male mice at the LOAEL of
200 ppm.
iii. A 90 day dog feeding study gave a NOAEL of 50 ppm (2.1 mg/kg/
day for males and females). The LOAEL was 500 ppm (20.1 and 21.4 mg/kg/
day for males and females, respectively). At the LOAEL, females
exhibited a decrease in rate of weight gain and males presented an
increased reticulocyte.
iv. A 10 week study was conducted in the dog to examine the
reversibility of the effects on hematological parameters that were
observed in other dietary studies with the dog. Tebufenozide was
administered for 6 weeks in the diet to 4 male dogs at concentrations
of either 0 or 1,500 ppm. After the 6 weeks, the dogs receiving treated
feed were switched to the control diet for 4 weeks. Hematological
parameters were measured in both groups prior to treatment, at the end
of the 6 weeks treatment, after 2 weeks of recovery on the control diet
and after 4 weeks of recovery on the control diet. All hematological
parameters in the treated/recovery group were returned to control
levels indicating that the effects of tebufenozide on the hemopoietic
system are reversible in the dog.
v. In a 28 day dermal toxicity study in the rat, the NOAEL was
1,000 mg/kg/day highest dose tested (HDT). Tebufenozide did not produce
toxicity in the rat when administered dermally
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for 4 weeks at doses up to and including the limit dose of 1,000 mg/kg/
day.
5. Chronic toxicity-- i. A 1 year feeding study in dogs resulted in
decreased red blood cells, hematocrit, and hemoglobin and increased
Heinz bodies, reticulocytes, and platelets at the LOAEL of 8.7 mg/kg/
day. The NOAEL in this study was 1.8 mg/kg/day.
ii. An 18 month mouse carcinogenicity study showed no signs of
carcinogenicity at dosage levels up to and including 1,000 ppm, the
HDT.
iii. In a combined rat chronic/oncogenicity study, the NOAEL for
chronic toxicity was 100 ppm (4.8 and 6.1 mg/kg/day for males and
females, respectively), and the LOAEL was 1,000 ppm (48 and 61 mg/kg/
day for males and females, respectively). No carcinogenicity was
observed at the dosage levels up to 2,000 ppm (97 mg/kg/day and 125 mg/
kg/day for males and females, respectively).
6. Animal metabolism. The adsorption, distribution, excretion and
metabolism of tebufenozide in rats was investigated. Tebufenozide is
partially absorbed, is rapidly excreted and does not accumulate in
tissues. Although tebufenozide is mainly excreted unchanged, a number
of polar metabolites were identified. These metabolites are products of
oxidation of the benzylic ethyl or methyl side chains of the molecule.
These metabolites were detected in plant and other animal (rat, goat,
and hen) metabolism studies.
7. Metabolite toxicology. Common metabolic pathways for
tebufenozide have been identified in both plants (grape, apple, rice,
and sugar beet), and animals (rat, goat, and hen). The metabolic
pathway common to both plants and animals involves oxidation of the
alkyl substituents (ethyl and methyl groups) of thearomatic rings
primarily at the benzylic positions. Extensive degradation and
elimination of polar metabolites occurs in animals such that residues
are unlikely to accumulate in humans or animals exposed to these
residues through the diet.
C. Aggregate Exposure
1. Dietary exposure--i. Food. Tolerances have been established (40
CFR 180.482) for the residues of tebufenozide, in or on a variety of
raw agricultural commodities. A permanent tolerance has been
established for the residues of tebufenozide in/on walnuts at 0.1 ppm,
and pecans at 0.05 ppm. Permanent tolerances at 0.5 ppm and 1.0 ppm
have been established for imported wine grapes, and apples,
respectively. Other proposed tolerances are pending. Risk assessments
were conducted by Rohm and Haas to assess dietary exposures and risks
from tebufenozide as follows:
ii. Acute exposure and risk. No acute endpoint was identified for
tebufenozide and no acute risk assessment is required.
iii. Chronic exposure and risk. For chronic dietary risk
assessment, it is assumed that 100% of all crops which are consumed
will contain residues of tebufenozide at the tolerance levels. The
Reference Dose (RfD) used for the chronic dietary analysis is 0.018 mg/
kg/day. Potential chronic exposures were estimated using NOVIGEN'S
Dietary Exposure Evaluation Model (DDEM Version 5.03b) which uses USDA
food consumption data from the 1989-1992 survey. The existing and
proposed tebufenozide tolerances result in a theoretical maximum
residue contribution (TMRC) that is equivalent to 34.5% of the RfD for
the U.S. population, 61.4% of the RfD for infants, 70.4% of the RfD for
non-nursing infants (> 1 year old), and 79.8% of the RfD for chlidren 1
to 6 years old. The chronic dietary risks from these uses do not exceed
EPA's level of concern.
iv. Drinking water. Submitted environmental fate studies suggest
that tebufenozide is moderately persistent to persistent and mobile,
and could potentially leach to groundwater and runoff to surface water
under certain environmental conditions. However, in terrestrial field
dissipation studies, residues of tebufenozide and its soil metabolites
showed no downward mobility and remained associated with the upper
layers of soil. Foliar interception (up to 60% of the total dosage
applied) by target crops reduces the ground level residues of
tebufenozide. There is no established Maximum Concentration Level (MCL)
for residues of tebufenozide in drinking water. No drinking water
health advisory levels have been established for tebufenozide. There is
no entry for tebufenozide in the ``Pesticides in Groundwater Database''
(EPA 734-12-92-001, September 1992).
v. Chronic exposure and risk. There are insufficient water-related
exposure data to complete a comprehensive drinking water assessment for
tebufenozide at this time. However, in order to mitigate the potential
for tebufenozide to leach into groundwater or runoff to surface water,
precautionary language has been incorporated into the product label.
Considering the precautionary language on the label and based on the
Registrant's knowledge of environmental occurrence of the chemicals,
significant exposure from residues of tebufenozide in drinking water is
not anticipated.
2. Non-dietary exposure. Tebufenozide is not currently registered
for any indoor or outdoor residential uses; therefore, no non-dietary
residential exposure is anticipated.
D. Cumulative Effects
The potential for cumulative effects of tebufenozide with other
substances that have a common mechanism of toxicity was considered.
Tebufenozide belongs to the class of insecticide chemicals known as
diacylhydrazines. The only other diacylhydrazine currently registered
for non-food crop uses is halofenozide. Tebufenozide and halofenozide
both produce a mild, reversible anemia following subchronic/chronic
exposure at high doses; however, halofenozide also exhibits other
patterns of toxicity (liver toxicity following subchronic exposure and
developmental/systemic toxicity following acute exposure) which
tebufenozide does not. Given the different spectrum of toxicity
produced by tebufenozide, Rohm Haus concludes that there is no reliable
data at the molecular/mechanistic level which would indicate that toxic
effects produced by tebufenozide would be cumulative with those of
halofenozide (or any other chemical compound).
Based on the overall pattern of toxicity produced by tebufenozide
in mammalian and insect systems, the compound's toxicity appears to be
distinct from that of other chemicals, including organochlorines,
organophosphates, carbamates, pyrethroids, benzoylureas, and other
diacylhydrazines. Thus, according to Rohm Haus, there is no evidence to
date to suggest that cumulative effects of tebufenozide and other
chemicals should be considered.
E. Safety Determination
1. U.S. population-- i. Acute exposure and risk. Since no acute
endpoint was identified for tebufenozide, no acute risk assessment is
required.
ii. Chronic exposure and risk. Using the conservative exposure
assumptions described above and taking into account the completeness
and reliability of the toxicity data, the percentage of the RfD that
will be utilized by dietary (food only) exposure to residues of
tebufenozide from existing, pending and proposed tolerances is 34.5%
for the U.S. population. Aggregate exposure (food and water) are not
expected to exceed 100%. EPA generally has no concern for exposures
below 100% of
[[Page 6357]]
the RfD because the RfD represents the level at or below which daily
aggregate dietary exposure over a lifetime will not pose appreciable
risks to human health. Rohm and Haas concludes that there is a
reasonable certainty that no harm will result from aggregate exposure
to tebufenozide residues to the U.S. population.
2. Infants and children-children-- i. In general. In assessing the
potential for additional sensitivity of infants and children to
residues of tebufenozide, data from developmental toxicity studies in
the rat and rabbit, and 2-generation reproduction studies in the rat
are considered. The developmental toxicity studies are designed to
evaluate adverse effects on the developing organism resulting from
maternal pesticide exposure during gestation. Reproduction studies
provide information relating to effects from exposure to the pesticide
on the reproductive capability of mating animals and data on systemic
toxicity.
ii. Developmental toxicity studies-- a. Rats. In a developmental
toxicity study in rats, the maternal (systemic) NOAEL was 250 mg/kg/
day. The LOAEL was 1,000 mg/kg/day based on decrease body weight and
food consumption. The developmental (pup) NOAEL as > 1,000 mg/kg/day
HDT.
b. Rabbits. In a developmental toxicity study in rabbits, the
maternal and developmental NOAELs were > 1,000 mg/kg/day HDT.
iii. Reproductive toxicity study rats. In a multigeneration
reproductive toxicity study in rats, the parental (systemic) NOAEL was
0.85 mg/kg/day. Spleenic pigmentation changes and extramedullary
hematopoiesis occurred at the LOAEL of 12.1 mg/kg/day. In addition to
these effects, decreased body weight gain and food consumption occurred
at 171.1 mg/kg/day. The reproductive (pup) NOAEL was 12.1 mg/kg/day.
The reproductive LOAEL of 171.1 mg/kg/day was based on a slight
increase in the number of pregnant females that did not deliver or had
difficulty and had to be sacrificed. Additionally at the LOAEL, in F1
dams, the length of gestation increased and implantation sites
decreased significantly. In a second study, reproductive effects were
not observed at 2,000 ppm (the NOAEL equal to 149-195 mg/kg/day) and
the NOAEL for systemic toxicity was determined to be 25 ppm (1.9-2.3
mg/kg/day).
iv. Pre- and post-natal sensitivity-- a. Pre-natal sensitivity. The
developmental NOAELs of > 1,000 mg/kg/day HDT from the developmental
toxicity studies in rats and rabbits demonstrate that there is no
developmental (prenatal) toxicity present for tebufenozide.
Additionally, these developmental NOAELs are greater than 500-fold
higher than the NOAEL of 1.8 mg/kg/day from the 1 year feeding study in
dogs which was the basis of the RfD.
b. Post-natal sensitivity. In the reproductive toxicity study in
rats, the reproductive NOAEL (12.1 mg/kg/day from the first study; 149-
195 mg/kg/day from the second study) is between 14-fold higher than the
parental NOAEL (0.85 mg/kg/day) in the first study and 83-fold higher
than the parental NOAEL (1.8-2.3 mg/kg/day) in the second study. These
data indicate that post-natal toxicity in the reproductive studies
occurs only in the presence of significant parental toxicity. These
developmental and reproductive studies indicate that tebufenozide does
not have additional post-natal sensitivity for infants and children in
comparison to other exposed groups. Because these reproductive effects
occurred in the presence of parental (systemic) toxicity and were not
replicated at the same doses in a second study, these data do not
indicate an increased pre-natalor post-natal sensitivity to children
and infants (that infants and children might be more sensitive than
adults) to tebufenozide exposure.
c. Acute exposure and risk. Since no acute endpoint was identified
for tebufenozide, no acute risk assessment is required.
d. Chronic exposure and risk. With the existing, pending and
proposed tolerances for tebufenozide, the percentage of the RfD that
will be utilized by dietary (food only) exposure to residues of
tebufenozide range from 39.9% for nursing infants less than 1 year old
to 79.8.% for children 1 to 6 years old. Aggregate exposure (food and
water) are not expected to exceed 100%. Rohm and Haas concludes that
there is a reasonable certainty that no harm will result from aggregate
exposure to tebufenozide residues to non-nursing infants.
F. International Tolerances
There are currently no CODEX, Canadian or Mexican maximum residue
levels (MRLs) established for tebufenozide in blueberries, caneberries,
canola, cranberries, mint or turnips so no harmonization issues are
required for this action.
[FR Doc. 99-3146 Filed 2-8-99; 8:45 am]
BILLING CODE 6560-50-F