Buprofezin - Pesticide Petition Filing 8/98
[Federal Register: August 26, 1998 (Volume 63, Number 165)]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
ENVIRONMENTAL PROTECTION AGENCY
Notice of Filing of Pesticide Petitions
AGENCY: Environmental Protection Agency (EPA).
SUMMARY: This notice announces the initial filing of pesticide
petitions proposing the establishment of regulations for residues of
pesticide chemicals in or on various agricultural commodities.
DATES: Comments, identified by the docket control number PF-811, must
be received on or before September 25, 1998.
ADDRESSES: By mail submit written comments to: Public Information and
Records Integrity Branch, Information Resources and Services Divison
(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-
firstname.lastname@example.org. Following the instructions under
"SUPPLEMENTARY INFORMATION." No confidential business information
should be submitted through e-mail.
Information submitted as a comment concerning this document may be
claimed confidential by marking any part or all of that information as
"Confidential Business Information" (CBI). CBI should not be
submitted through e-mail. Information marked as CBI will not be
disclosed except in accordance with procedures set forth in 40 CFR part
2. A copy of the comment that does not contain CBI must be submitted
for inclusion in the public record. Information not marked confidential
may be disclosed publicly by EPA without prior notice. All written
comments will be available for public inspection in Rm. 119 at the
address given above, from 8:30 a.m. to 4 p.m., Monday through Friday,
excluding legal holidays.
FOR FURTHER INFORMATION CONTACT: By mail: Richard Gebken, Registration
Division, (7505C), Office of Pesticide Programs, Environmental
Protection Agency, 401 M St., SW., Washington, DC 20460. Office
location and telephone number: Rm. 200A, Arlington, VA. 22202, (703)
305-6701; e-mail: email@example.com.
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 raw
agricultural 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, as well as the public version,
has been established for this notice of filing under docket control
number PF-811 (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:
Electronic comments must be submitted as an ASCII file avoiding the
use of special characters and any form of encryption. Comment and data
will also be accepted on disks in Wordperfect 5.1/6.1 file format or
ASCII file format. All comments and data in electronic form must be
identified by the docket control number PF-811 and appropriate petition
number. Electronic comments on this notice may be filed online at many
Federal Depository Libraries.
Authority: 21 U.S.C. 346a.
List of Subjects
Environmental protection, Agricultural commodities, Food additives,
Feed additives, Pesticides and pests, Reporting and recordkeeping
Dated: August 10, 1998.
Director, Registration Division, Office of Pesticide Programs.
Summaries of Petitions
Below summaries of the pesticide petitions are printed. The
summaries of the petitions were prepared by the petitioners. 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.
AgrEvo USA Company
EPA has received a pesticide petition (PP 7F4923) from AgrEvo USA
Company, Little Falls Centre One, 2711 Centerville Road, Wilmington, DE
19808, 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 a tolerance for residues of buprofezin in or on the raw
agricultural commodities head lettuce at 5 parts per million (ppm),
leaf lettuce at 13 ppm, and the cucurbits crop group at 0.5 ppm. EPA
has determined that the petition contains data or information regarding
the elements set forth in section 408(d)(2) of the FFDCA; however, EPA
has not fully evaluated the sufficiency of the submitted data at this
time or whether the data supports granting of the petition. Additional
data may be needed before EPA rules on the petition.
A. Residue Chemistry
1. Plant metabolism. The metabolic profile of buprofezin has been
elucidated in a wide range of crops, including tomatoes, lettuce, and
cotton, and citrus. The nature of the residue in all plant species is
well defined and comparable from crop to crop.
Buprofezin was the only significant residue in tomatoes, lettuce
and cotton. Trace levels (1-6%) of two metabolites were also
identified. These metabolites correspond to the oxidative loss of N-t-
butyl (BF9), followed by opening of the heterocyclic ring with
concomitant loss of CH2-S-C=O (BF12). No other single metabolite
exceeded 7.5% of the total residue. Some of the minor components were,
however, shown to be polar conjugates of BF4 (buprofezin hydroxylated
in the t-butyl group) based on work in citrus. In the tomato study,
which was run prior to the citrus, cotton and lettuce metabolism
studies, these metabolites were not specifically looked for due to the
high percentage of the residue accounted for by the parent.
2. Analytical method. Background Metabolism studies on lettuce and
tomatoes have shown that the only significant residue in these crops is
buprofezin. Development of the analytical method took place in parallel
with the metabolism studies and the method was designed to quantify two
metabolites (BF9 and BF12) in addition to the parent compound. This
method was used for analysis of samples from the field trials on
lettuce and cucurbits, but for tolerance enforcement only the parent
compound is considered.
i. Data collection method. Samples are extracted with acetone. The
extracts are filtered and the acetone removed by rotary evaporation.
The remaining aqueous extract is acidified with hydrochloric acid and
partitioned with hexane. The hexane is applied to a Florisil column and
the residues are then eluted from the column with ether/
hexane (50/50). The acidic aqueous phase is adjusted to pH 7 and
partitioned into ethyl acetate/hexane (50/50). This organic extract is
combined with the eluate from the Florisil column, evaporated to
dryness, taken up in toluene and analyzed by GC with NP detection. The
limit of quantitation of this method is 0.01ppm in the sample.
ii. Tolerance enforcement method. The metabolism work and the field
sample analyses showed that the only significant residue in treated
crops was buprofezin. Accordingly, the method proposed for tolerance
enforcement quantifies only buprofezin. The method is identical to the
data collection method except the acid partition step was omitted. The
method was validated by an independent laboratory using lettuce, tomato
and cucumber as the test matrices.
iii. Multiresidue methods. Buprofezin was tested through protocols
D and F using tomatoes (a representative non-fatty food) and cottonseed
(a representative fatty food). Recoveries were satisfactory such that
the multiresidue methods could be used for tolerance enforcement or as
3. Magnitude of residues. --i. Residues in lettuce. Head and leaf
lettuce were treated with buprofezin in a 40SC formulation at sixteen
locations throughout the USA in 1994. APPLAUD 40 SC was applied at the
maximum application rate, minimum application interval and minimum
preharvest interval. The residues detected in lettuce consisted
entirely of buprofezin with no observed residues of metabolites greater
than the limit of quantitation. Residues on leaf lettuce ranged between
1.29 ppm and 12.60 ppm. Residues on head lettuce were lower than those
detected on leaf lettuce (removal of wrapper leaves on head lettuce
resulted in a further reduction in observed residues). With the wrapper
leaves in place, residues were between 0.29 ppm and 4.79 ppm. (With
wrapper leaves removed, the residues ranged from 0.03 ppm to 1.44 ppm.)
Tolerances are therefore proposed for residues of buprofezin in or on
head lettuce at 5 ppm, and leaf lettuce at 13 ppm.
ii. Residues in representative cucurbits crops. APPLAUD 40 SC
Insect Growth Regulator was applied to cucumbers, melons, and summer
squash at various geographic locations throughout the United States.
The product was applied four times at the maximum application rate,
minimum application interval, and minimum preharvest interval. The
residue consisted entirely of buprofezin with only a few traces of
metabolites, all below the limit of quantitation (LOQ). Residues on
cucumbers ranged between <0.01 ppm (the LOQ) and 0.30 ppm. Residues on
melons were between 0.15 ppm and 0.41 ppm. Residues on summer squash
were between 0.02 ppm and 0.11 ppm. Therefore, a tolerance of 0.5 ppm
is proposed for residues on buprofezin in or on the cucurbits crop
B. Toxicological Profile
An extensive battery of toxicology studies has been conducted with
buprofezin. These studies have been reviewed and summarized by the
Joint Meeting of the FAO Panel of Experts on Pesticide Residues in Food
and the Environment and the WHO Expert Group on Pesticide Residues
(JMPR, 1991 and 1995). They have also been reviewed by the USEPA as
part of the submission for an Experimental Use Permit. Supplemental
information on several studies (acute dermal, acute inhalation, chronic
dog, rat reproduction, and rat chronic toxicity/oncogenicity study) was
submitted with this petition. These studies indicate that buprofezin
has a relatively low degree of toxicity, is neither genotoxic nor
oncogenic, and does not cause any significant reproductive or
developmental effects. Thus, the use of buprofezin on lettuce and
cucurbits (as well as on cotton Arizona and California and citrus
California under the current section 18 emergency exemptions) will not
pose a significant risk to human health.
1. Acute toxicity. The acute rat oral LD50 for
buprofezin was 1,635 mg/kg in males and 2,015 mg/kg in females. The
acute rat dermal LD50 was ≥ 5,000 mg/kg in both
sexes. The 4-hour rat inhalation LC50 was > 4.57 mg/L.
Buprofezin was slightly irritating to rabbit eyes and skin and did not
induce dermal sensitization in guinea pigs.
2. Genotoxicty. No evidence of genotoxicity was noted in a battery
of in vitro and in vivo studies. Studies included Ames Salmonella and
mouse lymphoma gene mutation assays, a mouse micronucleus assay, an in
vitro human lymphocyte cytogenetics assay and an in vitro rat
hepatocyte UDS assay.
3. Reproductive and developmental toxicity. A developmental
toxicity study was conducted in rats at dose levels of 0, 50, 200 or
800 mg/kg/day. The (systemic) maternal NOEL for this study was 200 mg/
kg/day based on weight loss, decreased food consumption, clinical
signs, increased resorption rate, increased loss of entire litters and
one maternal death at 800 mg/kg/day. The developmental (fetal) NOEL was
also 200 mg/kg/day based on reduced fetal body weights and increased
incidence of delayed ossification at 800 mg/kg/day. Slightly reduced
ossification was also noted at 200 mg/kg/day but this was within
historical control range and thus not considered to be significant.
A developmental toxicity study was conducted in rabbits at dose
levels of 0, 10, 50 or 250 mg/kg/day. The maternal (systemic) NOEL was
50 mg/kg/day based on decreased weight gain, decreased food consumption
and the complete resorption of 2 litters at 250 mg/kg/day. No evidence
of developmental toxicity was noted; therefore the developmental
(fetal) NOEL was 250 mg/kg/day, the highest dose tested (HDT).
Two rat reproduction studies have been conducted at dietary
concentrations of 0, 10, 100 or 1,000 ppm. One was a two-generation
study that included a teratological evaluation. The other was a one-
generation reproduction study conducted to further evaluate some
possible changes noted in the first study. Based on the results from
both studies, the parental NOEL was 1,000 ppm (HDT). There were no
effects on any reproductive parameters but pup weights were decreased
at 1,000 ppm. Thus, the reproductive NOEL was 100 ppm.
4. Subchronic toxicity. A 90-day feeding study was conducted in
rats at dietary concentrations of 0, 40, 200, 1,000 or 5,000 ppm.
Effects noted at 1,000 and/or 5,000 ppm included decreased weight gain,
clinical pathology changes, increased liver and thyroid weights, and
gross and/or microscopic evidence of liver, thyroid and kidney lesions.
Only marginal effects, consisting of slightly reduced feed intake and
slightly decreased glucose levels, were noted at 200 ppm. Although the
report conservatively concluded the NOEL to be 40 ppm, the NOEL was
considered by the EPA to be 200 ppm (15 mg/kg/day).
A 90-day study was conducted in which beagle dogs were administered
buprofezin via capsule at dose levels of 0, 2, 10, 50 or 300 mg/kg/day.
Effects noted at 50 and/or 300 mg/kg/day included various clinical
signs of toxicity, substantially decreased weight gain, clinical
pathology changes, increased liver, kidney and thyroid weights, and
microscopic liver lesions. The NOEL was 10 mg/kg/day.
5. Chronic toxicity. A 2-year study was conducted in which beagle
dogs were administered buprofezin via capsule at dose levels of 0, 2,
20 or 200 mg/kg/day. Effects noted at 20 and/or 200 mg/kg/day included
weight gain, clinical pathology changes, increased liver and thyroid
weights, decreased liver function (measured by BSP clearance) and
microscopic liver lesions. Although the report concluded that the NOEL
for this study was 2 mg/kg/day, marginal effects in females at 2 mg/kg/
day were considered to be a possible effect by the EPA reviewer pending
receipt of additional historical control data. These data were
submitted with this petition and will establish that the dose of 2 mg/
kg/day is a NOEL for this study.
A 2-year rat feeding study was conducted at dietary concentrations
of 0, 5, 20, 200 or 2,000 ppm. No evidence of oncogenicity was noted at
any dose level. Effects noted at 2,000 ppm included decreased weight
gain, increased liver and thyroid weights, and an increased incidence
of non-neoplastic liver and thyroid lesions. A possible increase in
thyroid lesions was also noted at 200 ppm. According to the EPA
reviewer, the NOEL for this study was 200 ppm (10 mg/kg/day). However,
the conclusions of the original report and a subsequent
histopathological reevaluation, not yet reviewed by the Agency,
indicate that the NOEL should be considered to be 20 ppm (1 mg/kg/day).
A 2-year mouse feeding study was conducted at dietary
concentrations of 0, 20, 200, 2,000 and 5,000 ppm. Effects observed at
2,000 and/or 5,000 ppm included decreased weight gain, minor clinical
pathology changes, increased liver weights and an increased incidence
of non-neoplastic liver lesions. Increased liver weights were also
noted at 200 ppm. Thus, the NOEL was considered to be 20 ppm (1.8 mg/
kg/day). There were slightly increased incidences of liver tumors in
females at 5,000 ppm and of lung tumors in males at 200 and 5,000 ppm.
The increased incidences of these common tumors were not considered to
be treatment-related by either the study director or EPA reviewer but
the study was referred to the EPA Carcinogenicity Peer Review Group for
6. Animal metabolism. The metabolism and pharmacokinetics of
buprofezin have been evaluated in rats following single oral doses of
10 and 100 mg/kg. These studies indicate that buprofezin is rapidly
absorbed and excreted following oral administration, with >90% excreted
within 48 hours. Metabolism occurred primarily via hydroxylation of the
phenyl ring followed by conjugation and oxidation of the sulfur and
cleavage of the thiadiazinone ring.
7. Endocrine disruption. No special studies have been conducted to
investigate the potential of buprofezin to induce estrogenic or other
endocrine effects. The standard battery of required toxicity studies
has been completed. These studies include an evaluation of the
potential effects on reproduction and development and an evaluation of
the pathology of the endocrine organs following repeated or long-term
exposure. These studies are generally considered to be sufficient to
detect any endocrine effects. The only effect noted on endocrine organs
was an increased incidence of follicular cell hypertrophy and C-cell
hyperplasia of the thyroid gland in rats administered buprofezin at
dietary concentrations of 2,000 ppm for 24 months. Buprofezin also
caused mild to moderate hepatotoxic effects at this dietary
concentration. AgrEvo believes that the effect on the thyroid most
likely resulted from increased turnover of T3/T4 in the liver with a
resultant rise in TSH secretion (due to the hepatotoxicity). The rat is
known to be much more susceptible than humans to these effects due to
the very rapid turnover of thyroxine in the blood in rats (12 hours vs.
about 5 - 9 days in humans). Therefore, the thyroid pathological
changes, which have been noted following administration of high doses
of buprofezin, are considered to be of minimal relevance to human risk
assessment, particularly considering the low levels of buprofezin to
which humans are likely to be exposed.
C. Aggregate Exposure
1. Dietary exposure. Buprofezin is an insect growth regulator which
is approved for use under a section 18 emergency exemption for control
of whitefly on cotton in Arizona and California and red scale on citrus
in California. Non-crop uses of buprofezin are limited to an
Experimental Use Permit for use on ornamentals in greenhouses, thus
only dietary exposures are being considered.
2. Food. Potential dietary exposures from food commodities under
the proposed food tolerances for buprofezin and the approved section 18
temporary tolerances were estimated using the Exposure I software
system (TAS, Inc.) and the 1977-78 USDA consumption data. Two scenarios
In the first, worst-case scenario, it was assumed that all lettuce
and cucurbits contained residues at the proposed tolerance levels of:
leaf lettuce (13 ppm), head lettuce (5 ppm) and the cucurbit crop group
(0.5 ppm). In addition, since temporary tolerances have been granted
under a section 18 emergency exemption for citrus fruit (2.0 ppm),
dried citrus pulp (10.0 ppm), cotton seed (1.0 ppm), cotton gin by-
products (20 ppm), milk (0.03 ppm), and cattle, sheep, hogs, goats, and
horse meat (0.02 ppm), fat (0.02 ppm), and meat by-products (0.5 ppm),
these products were also included in the analysis. The section 18
provides for use on cotton in Arizona and California and on citrus in
California. Even though the use is restricted to Arizona and California
in these section 18s, the worst-case scenario assumed 100% of the crop
A slightly more realistic assessment was also conducted using
estimates of percent crop treated. But again, the unrealistic
assumption was made that all residues would be at the tolerance level
in all of the crops that were treated. In addition, the section 18
temporary tolerances are somewhat high, especially those for juice and
milk; permanent tolerances based upon new processing and feeding
studies will be proposed in the near future when application is made
for full registration on cotton and citrus.
3. Drinking water. Exposure to buprofezin from drinking water is
expected to be negligible. The potential for buprofezin to leach into
groundwater was assessed in various laboratory studies as well as
terrestrial field dissipation studies conducted in two locations and in
varying soil types. The degradation of buprofezin occurs rapidly with
half-lives in soil ranging from 22 to 59 days. No evidence of leaching
of parent or degradation products was observed in aged leaching or
terrestrial field dissipation studies. The major routes of degradation
result in mineralization to carbon dioxide and the formation of
"bound" residues. Buprofezin tends to bind to the top layers of soil
with low mobility. The Koc for most soils fell in the range 2,100-
4,800. The solubility in water is low which will result in minimal
field runoff and a low potential for contamination of surface water.
Therefore, the contribution of any such residues to the total dietary
intake of buprofezin will be negligible.
4. Non-dietary exposure. There is a current Experimental Use Permit
(EUP) for the use of buprofezin on ornamentals in greenhouses. Exposure
to the general population would be minimal in this use and thus was not
D. Cumulative Effects
At the present time, there are insufficient data available to
allow AgrEvo to properly evaluate the potential for cumulative effects
with other pesticides to which an individual may be exposed. For the
purposes of this assessment, therefore, AgrEvo has assumed that
buprofezin does not have
a common mechanism of toxicity with any other registered pesticides.
Therefore, only exposure from buprofezin is being addressed at this
E. Safety Determination
The toxicity and residue databases for buprofezin are considered to
be valid, reliable and essentially complete. The standard margin of
safety approach is considered appropriate to assess the risk of adverse
effects from exposure to buprofezin for both acute and chronic effects.
EPA has adopted a temporary RfD for buprofezin at 0.002 mg/kg/day. This
RfD was based on the systemic lowest effect level (LEL) of 2.0 mg/kg/
day (LDT) from a 2-year dog study and using a 1,000-fold uncertainty
factor. An extra factor of 10 was added to the standard 100-fold safety
factor since the RfD was based on a LEL (rather than a NOEL) and the
database lacked an acceptable reproductive study. Additional data have
been submitted to upgrade the reproduction study and to support the
lowest dose in the 2-year dog study as a NOAEL. With the upgrading of
these studies, the critical study for the establishment of a permanent
RfD would be the rat chronic/oncogenicity study. The NOEL for this
study is 1 mg/kg/day. Applying a standard safety factor of 100 for this
study, to account for interspecies extrapolation and intraspecies
variation, would result in a RfD of 0.01 mg/kg/day. It is this proposed
RfD which was used to assess risk to the public.
1. U.S. population. --i. Acute risk. EPA has previously selected,
in their approval of the section 18 emergency exemption use, a
developmental NOEL of 200 mg/kg/day from a rat developmental study for
the acute dietary endpoint. However, it appears that this is an
inappropriate acute endpoint since the clinical effects noted at the
higher dose (800 mg/kg/day) occurred only after at least 5 days of
dosing and the fetal effects (reduced fetal body weight and delayed
ossification) are not likely to be due to an acute (1 day) exposure.
Based on this assessment, AgrEvo has not evaluated the risk from acute
exposure to any subgroup of the population. Previously, EPA has
assessed the acute risk from use of buprofezin on citrus and cotton to
the population subgroup of females 13+ years of age. Using the
developmental NOEL of 200 mg/kg/day, the Margin of Exposure (MOE),
according to EPA calculations, was 5,000 for this subgroup.
ii. Chronic risk. Chronic dietary exposures for the US population
as a whole utilize 65% of the buprofezin RfD in the worst case scenario
of 100% of crop treated and all residues at the proposed tolerance
level (lettuce, cucurbits) and temporary tolerance level (cotton,
citrus, meat/milk commodities from the section 18s). In the more
realistic scenario, adjusting for the percent crop treated, the U.S.
population chronic dietary exposure utilizes only 1.75% of the RfD.
There is generally no concern for exposures below 100% of the RfD since
it represents the level at or below which noappreciable risks to human
health is posed. Therefore, there is reasonable certainty that no harm
would result to the U.S. population from exposure to buprofezin.
2. Infants and children. Data from rat and rabbit developmental
toxicity studies and rat multigeneration reproduction studies are
generally used to assess the potential for increased sensitivity to
infants and children. The developmental toxicity studies are designed
to evaluate adverse effects on the developing organism resulting from
pesticide exposure during prenatal development. Reproduction studies
provide information relating to reproductive and other effects on
adults and offspring from prenatal and postnatal exposure to the
No indication of increased sensitivity to infants and children was
noted in either of the developmental studies. However, in the
reproduction studies, the NOEL for pups (100 ppm) was lower than for
adults (1,000 ppm). Based on the intake of buprofezin in pups up to 8
weeks of age, the RfD for children, using a 1,000 fold safety factor,
would be 0.01 mg/kg/day. This is the same RfD that is calculated for
chronic exposure utilizing the rat chronic/oncogenicity study.
Evaluation of the dietary exposure to infants and children was
conducted utilizing the same assumptions as for the U.S. population as
a whole. Adjustment for the percent crop treated resulted in dietary
exposures that were 2.5% and 3.4% of the RfD for non-nursing infants
less than 1 year old and children (1-6 years), respectively. This
scenario still assumes that all residues in the crops that are treated
are at the tolerance level.
There is generally no concern for exposures below 100% of the RfD
since it represents the level at or below which no appreciable risks to
human health is posed. Thus, there is a reasonable certainty that no
harm will result to the most highly exposed population subgroups, non-
nursing infants, less than 1 year old, and children between 1 and 6
years of age, from exposure to buprofezin.
F. International Tolerances
Buprofezin was reviewed by the Joint Meeting of the Food and
Agriculture Organization Panel of Experts on Pesticide Residues in Food
and the Environment and the World Health Organization Expert Group on
Pesticide Residues (JMPR) to establish Codex MRLs in 1991, 1995 and
1997. Permanent MRLs were granted for cucumbers and tomatoes, and a
temporary MRL was granted for oranges, as described below. Additional
residue trial data on oranges will be available for the 1999 JMPR
meeting to determine if this MRL should also be made permanent.
Cucumber 0.3 ppm
Tomato 0.5 ppm
Oranges, Sweet, Sour 0.3 ppm (temporary).
[FR Doc. 98-22429 Filed 8-25-98; 8:45 am]
BILLING CODE 6560-50-F