[Federal Register Volume 63, Number 37 (Wednesday, February 25, 1998)]
[Notices]
[Pages 9532-9540]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-4811]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-789; FRL-5767-5]
Notice of Filing of Pesticide Petition
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
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SUMMARY: This notice announces the initial filing of a pesticide
petition proposing the establishment of regulations for residues of a
certain pesticide chemical in or on various food commodities.
DATES: Comments, identified by the docket control number PF-789, must
be received on or before March 27, 1998.
ADDRESSES: By mail submit written comments to: Information and Records
Integrity Branch, Public Information 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-
docket @epamail.epa.gov. 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
[[Page 9533]]
``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: Joanne I. Miller, Registration Support
Branch, Registration Division (7505C), Office of Pesticide Programs,
Environmental Protection Agency, 401 M St., SW., Washington, DC 20460.
Office location, telephone number, and e-mail address: Rm. 237, Crystal
Mall #2, 1921 Jefferson Davis Highway, Arlington, VA 22202, (703) 305-
6224; e-mail: miller.joanne@epamail.epa.gov.
SUPPLEMENTARY INFORMATION: EPA has received a pesticide petition as
follows proposing the establishment and/or amendment of regulations for
residues of certain pesticide chemical 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 this petition
contains 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-789] (including comments and data submitted
electronically as described below). A public version of this record,
including printed, paper versions of electronic comments, which does
not include any information claimed as CBI, is available for inspection
from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal
holidays. The official record is located at the address in
``ADDRESSES'' at the beginning of this document.
Electronic comments can be sent directly to EPA at:
opp-docket@epamail.epa.gov
Electronic comments must be submitted as an ASCII file avoiding the
use of special characters and any form of encryption. Comment and data
will also be accepted on disks in Wordperfect 5.1/6.1 file format or
ASCII file format. All comments and data in electronic form must be
identified by the docket control number (PF-789) and appropriate
petition number. Electronic comments on this notice may be filed online
at many Federal Depository Libraries.
List of Subjects
Environmental protection, Agricultural commodities, Food additives,
Feed additives, Pesticides and pests, Reporting and recordkeeping
requirements.
Dated: February 11, 1998
Peter Caulkins,
Acting Director, Registration Division, Office of Pesticide Programs.
Summary of Petition
The petitioner summary of the pesticide petition is printed below
as required by section 408(d)(3) of the FFDCA. The summary of the
petition was prepared by the petitioner and represents the views of the
petitioner. EPA is publishing the petition summary verbatim without
editing it 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.
Valent U.S.A Corporation
PP 9F3798
EPA has received a pesticide petition (PP 9F3798) from Valent U.S.A
Corporation, 1333 North California Blvd., Suite 600, Walnut Creek,
California 94596-8025 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 extending a time-limited tolerance for residues of
lactofen, 1-(carboethoxy)ethyl 5-[2-chloro-4-(trifluoromethyl)phenoxy]-
2-nitrobenzoate and its associated metabolites containing the diphenyl
ether linkage in or on the raw agricultural commodity cottonseed at
0.05 parts per million (ppm). The tolerance would expire on December
31, 1999. The time limitation on the tolerance would allow Valent to
complete, and EPA to evaluate, additional prospective groundwater study
data. 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. Lactofen, formulated as COBRA
Herbicide, is used to control broadleaf weeds in soybeans by pre- and/
or post-emergent application and in cotton by post-directed
application. Pre-harvest intervals are extended, 45 to 70 days. Plant
metabolism protocols (cotton, peanut, soybean and tomato) have been
designed to mimic the field applications with respect to application
methods and timing. In the studies, plant material has been treated at
rates exceeding normal field application to facilitate identification
of metabolites. Postdirected application to cotton was simulated in the
field using radiocarbon labeled lactofen and demonstrated that no
radioactivity (> 0.001 ppm lactofen equivalent) was detected in the
bolls.
The lactofen molecule is rapidly degraded in the environment and in
plants. Therefore, the consistent result of all detailed plant
metabolism studies using radiolabeled lactofen has been:
i. Low concentrations of radiocarbon are distributed throughout the
plant,
ii. Much of the radiocarbon is irreversibly bound and
unextractible,
iii. Very low concentrations of radiocarbon is found in the RAC
(seeds), and
iv. Very little of the terminal residue is identifiable as finite
metabolites as a result of the extensive degradation and binding.
To demonstrate plant metabolic pathways and to validate that the
residue analytical methodology can extract, identify and quantitate
lactofen and its metabolites as aged residues, plant samples from
radiocarbon metabolism studies were analyzed soon after application,
well before normal harvest. It is from these early samples that the
definition of the regulated residue in RAC has been obtained. The
residue of concern is defined by the Agency as parent and four
degradates containing the intact diphenyl ether moiety. Parent lactofen
(PPG-844) is degraded hydrolytically to corresponding carboxylic acid-
lactate ester (PPG-947), and further to the benzoic acid (PPG-847). In
a separate pathway, the esters remain intact and the aromatic nitro
group is reduced to the corresponding aniline (PPG-1576) and the
aniline is formylated (PPG-2597). Further, there is good evidence that
these lactofen metabolites are further degraded by cleavage of the
[[Page 9534]]
diphenyl ether. The sodium salt of the benzoic acid (PPG-847) is the
commercial herbicide acifluorfen. All five of the compounds in the
regulated residue as defined have never been found in a single RAC
sample either from plant metabolism or from crop field studies. For
example, at maximum treatment rates in crop field trials, only one
soybean seed sample was found to have a residue of parent lactofen
greater than the limit of detection, but less than the limit of
quantitation and only a single cotton gin trash sample was found to
contain a finite residue of lactofen. Even at exaggerated rates in
metabolism or crop residue studies, residues are rarely above the limit
of detection for any analyte. In fact, more than one analyte has never
been found above the limit of detection in a single RAC sample from
crop field trials.
2. Analytical method. Adequate analytical methodology is available
for detecting and measuring levels of lactofen and regulated
metabolites in or on food with a limit of detection that allows
monitoring of food with residues at or above the level set in the time-
limited tolerance on cotton. The method involves extraction with
triethylamine/aqueous ethanol, partitioning, methylation of the
carboxylic acids, column clean-up, and separation and quantitation by
gas chromatography with electron capture detection. The method, RM-28D,
has been validated by an independent laboratory on both cottonseed and
peanuts and was found to be acceptable with comments for enforcement in
cottonseed by the EPA Analytical Chemistry Laboratory. In general, the
analytical method has a limit of detection of 0.005 ppm and limit of
quantitation of 0.01 ppm in crops.
3. Magnitude of residues. Lactofen is the active ingredient in
COBRA Herbicide (EPA Reg. No. 59639-34). There are existing tolerances
for lactofen on soybeans, and snap beans. A time limited tolerance
supported use on cotton, and a tolerance is pending for peanuts.
Lactofen is a broad-spectrum broadleaf herbicide with the following use
pattern on cotton:
Post-emergence directed spray applications with a single
application maximum of 0.2 lb. a.i./acre, a seasonal maximum total
application of 0.4 lb. a.i./acre, and a PHI of 70 days.
Because of relatively long pre-harvest interval, post-directed
applications, and extensive degradation, finite lactofen residues have
not been found in cottonseed or processed cottonseed commodities.
Reports covering field residue trials from twenty-one sites in all
cotton growing states, several at exaggerated rates, along with
processing studies have failed to show detectable residues of lactofen
or its regulated degradates in any sample. Consequently, a tolerance on
cottonseed is proposed at 0.05 ppm, based on the sum of the 0.01 ppm
limits of quantitation for lactofen and its four regulated metabolites
containing the diphenyl ether linkage. Field residue data for cotton
gin trash has recently been submitted. All other lactofen tolerances to
date have been established similarly at 0.05 ppm.
B. Toxicological Profile
1. Acute toxicity. Lactofen (PPG-844) Technical has been placed in
EPA Toxicity Category III for dermal toxicity and Category IV for the
other four acute toxicity tests. It has also been found to be a weak
skin sensitizer. This chemical therefore represents a minimal acute
toxicity risk.
2. Genotoxicty. Lactofen Technical has been tested and produced
negative results in genotoxicity tests including unscheduled DNA
synthesis in rat hepatocytes, DNA covalent binding in mouse liver,
chromosomal aberration in CHO cells. Lactofen technical was also
negative in an Ames assay. In repeat Ames assays, lactofen was shown to
be positive without metabolic activation at 5,000 g/plate and
above. Overall lactofen is not a genetic hazard.
3. Reproductive and developmental toxicity. Reproduction and
teratology studies indicate that adverse effects, including
embryotoxicity, occur only at doses that are also maternally toxic.
Since lactofen causes effects only at levels which also produce
systemic toxicity the compound is not a reproductive hazard.
4. Reproduction-- Rats. Groups of male and female rats were fed 0,
50, 500 or 2,000 ppm of Lactofen Technical continuously in their diets
for 2-generations. Adult systemic toxicity (mortality, reduced body
weight, increased liver and spleen weight, decreased kidney weight and
histological changes in the liver and testes) was observed at levels of
500 ppm and greater. Reproductive toxicity (lower pup survival rates,
reduced pup weight and pup organ weight effects) was also observed at
levels of 500 ppm and greater. The No-Observed Effect-Level (NOEL) for
both systemic and reproductive toxicity was 50 ppm (2.5 milligram/
kilogram/day (mg/kg/day).
5. Developmental toxicity-- Rats. Pregnant rats were administered
oral doses of 0, 15, 50 and 150 mg/kg/day Lactofen Technical on days 6-
19 of gestation. Maternal toxicity (death, abortion and reduced body
weight gain) was observed at 150 mg/kg/day. Developmental toxicity
(reduced fetal weight, slightly reduced ossification, bent ribs and
bent limb bones) was also observed at 150 mg/kg/day. The NOEL for this
study was 50 mg/kg/day.
6. Developmental toxicity-- Rabbits. 2 developmental toxicity
studies were conducted in rabbits with Lactofen Technical. In the first
study, pregnant rabbits were administered oral doses of 0, 5, 15 or 50
mg/kg/day Lactofen Technical on days 6-18 of gestation. Maternal
toxicity (clinical signs and reduced weight gain) and developmental
effects (increased embryonic death, decreased litter size and increased
post-implantation loss) were reported at 15 and 50 milligram/kilogram
(mg/kg). The Agency concluded that the data were insufficient to
establish a clear NOEL. In the second rabbit developmental toxicity
study, pregnant rabbits were exposed to 0, 1, 4 or 20 mg/kg/day oral
doses on days 6-18 of gestation. Maternal toxicity (reduced food
consumption) was observed at 20 mg/kg/day, while no developmental
effects were observed at any dose. Therefore, the maternal NOEL was 4
mg/kg/day and the developmental NOEL was greater than 20 mg/kg/day.
C. Subchronic Toxicity
1. Subchronic feeding-- Rat-- 4-week. Male and female rats were fed
diets containing Lactofen Technical at concentrations of 0, 200, 1,000,
5,000, and 10,000 ppm for four weeks. A slight increase in spleen
weight was the basis for a Lowest-Observed Effect-Level (LOEL) of 200
ppm (lowest dose tested). At doses of 1,000 ppm or higher the following
findings were reported: clinical signs of toxicity; decreased RBC,
hemoglobin, hematocrit, and increased WBC; increased relative liver and
spleen weights; and necrosis and pigmentation of hepatocytes. At 10,000
ppm severe toxic signs were observed by day 7 and all animals were dead
or killed in extremis by day 11. Hypocellularity of the spleen, thymus
and bone marrow was also observed in animals exposed to 10,000 ppm.
2. Subchronic feeding-- Rat-- 3-month. Lactofen Technical was fed
to male and female rats at dietary concentrations of 0. 40, 200, and
1,000 ppm for 13-weeks. Histopathological changes in the liver and
significant changes in clinical chemistry associated with the liver
were observed in rats exposed to 1,000 ppm Lactofen Technical dosage.
Decreased RBC, hemoglobin and hematocrit values were also observed at
1,000 ppm. The NOEL in this study was 200 ppm.
[[Page 9535]]
3. Subchronic feeding-- Dog-- 4-week. In a range finding study
Lactofen Technical was fed in the diet of dogs at 0. 1,000, 3,000, and
10,000 ppm for 4-weeks. Toxic effects noted in dogs fed 10,000 ppm
included decreased rbc count and hemocrit, and increased BUN and SGPT.
Food palatability problems led to greatly decreased feed consumption at
higher dosages. The NOEL appeared to be 1,000 ppm.
4. Subchronic feeding-- Mice-- 3-month. Groups of Male and female
mice were fed diets containing Lactofen Technical at concentrations of
0, 40, 200, 1,000, 5,000, and 10,000 for 13-weeks. At week 5, the
dosage of the 40 ppm groups was increased to 2,000 ppm. Treatment
related mortality occurred at dosages above 1,000 ppm. The LOEL was 200
ppm based on: increased WBC; decreased hematocrit, hemoglobin and RBC;
increased alkaline phosphatase, SGOT, SGPT, cholesterol and total serum
protein levels; increased weights or enlargement of the spleen, liver,
adrenals, heart and kidney; histopathological changes of the liver,
kidney, thymus, spleen, ovaries and testes. In general, effects were
slight in the 200 ppm groups, and moderate to severe in the 1,000 ppm
groups.
5. Peroxisome proliferation-- Mice-- 7-weeks. Butler et al (1988)
studied the effects of lactofen on peroxisome proliferation in mice
exposed for 7-weeks to dietary concentrations of 2, 10, 50 and 250 ppm.
Liver-weight to body-weight ratio, liver catalase, liver acyl-CoA
oxidase, liver cell cytoplasmic eosinophilia, nuclear and cellular
size, and peroxisomal staining were increased by the tumorigenic dose
of lactofen, i.e. 250 ppm. Lower doses of lactofen had little to no
effect on these parameters. Thus, this study indicates that lactofen
induces peroxisome proliferation and further, that 50 ppm (7 mg/kg/
day), a dose which is not tumorigenic, would be considered a threshold
dose in mice for peroxisome proliferation produced by lactofen.
Peroxisome Proliferation -- Chimpanzees 14-weeks: A subchronic study
conducted in chimpanzees (Couch and Erickson, 1986), indicated no
effect on clinical chemistry or histological endpoints that would
suggest liver toxicity or peroxisome proliferation at doses up to 75
mg/kg/day administered for 93 days. Therefore, Valent believes that 75
mg/kg/day is a clear NOEL for peroxisome proliferation observed in a
species closely related to man.
D. Chronic Toxicity
A complete chronic data base supported by appropriate subchronic
studies for lactofen is available to the Agency. Lactofen Technical
causes adverse health effects when administered to animals for extended
periods of time. These effects include proliferative changes in the
liver, spleen, and kidney; hematological changes; and blood
biochemistry changes. Based on the Lowest Effect Level (LEL) of 1.5 mg/
kg/day in the 18-month mouse feeding study and an uncertainty factor of
1,000, a reference dose (RfD) of 0.002 mg/kg/day has been established
for lactofen. An uncertainty factor of 1,000 was used since a clear
NOEL was not established.
1. Chronic/carcinogenicity feeding study-- Mouse-- 24-month. In a
dietary 18-month oncogenicity study in mice at dosages of 10, 50 and
250 ppm Lactofen Technical, an increase in liver adenomas and
carcinomas, cataracts and liver pigmentation was observed at 250 ppm.
The lowest dose, 10 ppm, was the LOEL based on increased liver weight
and hepatocytomegaly.
2. Chronic/carcinogenicity feeding study-- Rat-- 24-month. In a 2-
year chronic feeding/oncogenicity study of Lactofen Technical in rats
at dosages of 0, 500, 1,000 and 2,000 ppm in the diet, an increase in
liver neoplastic nodules and foci of cellular alteration was observed
in both sexes at 2,000 ppm. The NOEL for systemic toxicity is 500 ppm
based on kidney and liver pigmentation.
3 Oral toxicity study-- Dog-- 12-month. In a 1-year study in dogs
exposed to 40, 200, and 1,000 (wk.1-17) or 3,000 ppm (wk 18-52)
Lactofen Technical in their diet, the NOEL was determined to be 200 ppm
based on renal dysfunction and decreased RBC, hemoglobin hematocrit and
cholesterol observed at 1,000/3,000 ppm.
4. Carcinogenicity. The Toxicology Branch Peer Review Committee has
determined that lactofen meets the criterion for a B2 (possible human)
carcinogen since it caused an increase in liver tumors (adenomas and/or
carcinomas) in two species. Based on the mouse oncogenicity study, a
human upper-bound potency estimate (Q1*) was calculated as
0.17 (mg/kg/day).
The calculated human Q1* is based on the standard
interspecies scaling factor of BW0.67. Recent EPA guidance
indicates that BW0.75 is a more appropriate factor for
general use. This change alone would result in a reduction of the
calculated human potency factor and a reduction in the calculated
carcinogenic risk by about 20%.
More importantly, evidence summarized above suggest that
carcinogenic effects observed in rodent liver related to long term
lactofen consumption are attributable to peroxisomal proliferation as
opposed to a direct genotoxic effect. This mechanism of action would
more appropriately be regulated as a threshold effect (similar to RfD
comparisons) as opposed to a non-threshold effect with a quantitative
potency factor derived from low dose extrapolations. This change in the
hazard assessment process for lactofen would have a profound effect on
the exposure and risk assessments for this chemical.
5. Animal metabolism. Single high, single low, and repeated low
dose radiocarbon labeled lactofen metabolism studies have been
performed in male and female rats. Radiocarbon is almost completely
eliminated (>95%) in excreta within 3-days of oral dosing. Generally
about 60% of orally administered radioactivity (14C-
lactofen) is found in the feces with lactofen itself being the major
component. About 40% of radioactivity is recovered in urine and PPG-847
(hydrolyzed side chain) is the major metabolite. Other metabolites
include PPG-947, PPG-1576, and PPG-2053. Except for the formyl
derivative (PPG-2597), a minor plant metabolite, there were no plant
metabolites detected that were not also produced in mammals.
Additional pharmacokinetic studies using both radiocarbon labeled
and unlabeled lactofen were performed in rats, mice, rhesus monkeys,
and chimpanzees. Little parent was seen in the plasma of any species
tested. At steady state, the primary metabolite in the circulation of
rodents was PPG-847. In the primates, PP-2053 was the primary
circulating metabolite. Mice appeared to be least efficient in clearing
PPG-844 and other lactofen metabolites from the circulation, while
rats, and especially primates appeared to be more efficient.
6. Metabolite toxicology. A major hydrolytic metabolite of lactofen
is PPG-847, the benzoic acid. The sodium salt of this benzoic acid,
sodium 5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrobenzoate, is the
registered herbicide acifluorfen. This product has a complete data base
supporting registration with a RfD of 0.013 mg/kg/day and a Cancer
Potency Factor of 0.107 (mg/kg/day)-1. Exposure to
acifluorfen from all sources must be evaluated to perform a cumulative
risk analysis.
7. Endocrine disruption. No special studies to investigate the
potential for estrogenic or other endocrine effects of lactofen have
been performed. However, as summarized above, a large and
[[Page 9536]]
detailed toxicology data base exists for the compound including studies
acceptable to the Agency in all required categories. These studies
include evaluations of reproduction and reproductive toxicity and
detailed pathology and histology of endocrine organs following repeated
or long term exposure. These studies are considered capable of
revealing endocrine effects and no such effects were observed.
E. Aggregate Exposure
1. Dietary exposure. A chronic dietary toxicity endpoint of
concern, RfD, has been identified by the Agency based on the Lowest
Effect Level (LEL) of 1.5 mg/kg/day in the 18-month mouse feeding study
and an uncertainty factor of 1,000. The RfD is 0.002 mg/kg/day for
lactofen. An uncertainty factor of 1,000 was used since a clear NOEL
was not established. The Toxicology Branch Peer Review Committee has
determined that lactofen meets the criterion for a B2 (possible human)
carcinogen since it caused an increase in liver tumors (adenomas and/or
carcinomas) in two species. Based on the mouse oncogenicity study, a
human upper-bound potency estimate (Q1*) was calculated as
0.17 (mg/kg/day)-1. An acute or short term dietary endpoint
of concern has not been established by the Agency. Valent has chosen to
use the maternal NOEL for systemic toxicity of 4 mg/kg/day from the
rabbit developmental toxicity study for acute and short term dietary
risk analyses. Lactofen has no uses not associated with commercial
agriculture. Therefore the only potential exposure possible to the U.S.
Population is through the diet in food and drinking water. Risk
analyses via other exposure routs, inhalation, dermal, are not
necessary. Thus, only chronic and acute dietary exposure and risk
analyses are necessary.
2. Food. Lactofen is registered for use in the production of
commercial agricultural crops including soybeans, cotton, snap beans,
and conifer seedlings. Dietary exposures are expected to represent the
major route of exposure to the public.
3. Chronic. A chronic dietary assessment for lactofen has been
conducted using Anticipated Residue Contributions (ARC) for existing
and proposed uses of lactofen. This exposure/risk analysis has been
submitted to the Agency along with a detailed description of the
methodology and assumptions used. Since crop field trial data indicate
that quantifiable residues of lactofen are rarely found in raw
agricultural and processed commodities, ARCs were estimated based on
the analytical method limit of detection (LOD) for each commodity. When
available, analytical results for control samples were used to
determine the method LOD for lactofen and its related metabolites. When
all control samples contained no detectable residues, the limit of
detection was determined to be 0.005 ppm. Mean anticipated residues
were determined based on the sum of residues found above the LOD, or
when no detectable residues were present for lactofen or any
metabolite, one-half the greatest LOD for any analyte was used as the
anticipated residue level. The chronic exposure analysis also
considered the percent of crop treated with lactofen as follows: 5% of
soybeans, 2.5% of cotton, 4.5% of snap beans, and 5% of peanuts. The
soybean and cotton values are based on 1995 marketing research data
(Maritz) and the snap bean and peanut values are estimates of future
market penetration. Note that a lactofen peanut tolerance is still
pending at the Agency and no lactofen is used on this crop even though
peanuts are included in the dietary exposure assessment Dietary
exposure was calculated for the U.S. population and 26 population
subgroups. Chronic dietary exposure was less than 0.1% of the RfD for
all subpopulations.
4. Acute. A first tier acute exposure and risk analysis was
performed for lactofen assuming tolerance level residues in soybeans,
snapbeans, cotton, and peanuts (0.05 ppm) and 0.02 ppm in all meat and
milk commodities. Using the acute dietary endpoint of 4.0 mg/kg/day,
the NOEL from the rabbit developmental toxicity study, the calculated
exposures and margins of exposure (MOE) for the higher exposed
proportions of the subgroups are listed below. It should be noted that
the population sizes are small at the lower probability exposures (e.g.
99th and 99.9th percentiles) oftentimes leading
to unrealistically high calculated exposures. In all cases, margins of
exposure exceed 1,000.
Calculated Acute Dietary Exposures to Lactofen Residues in Food
--------------------------------------------------------------------------------------------------------------------------------------------------------
99th Percentile 99.9th Percentile
Population Subgroup ---------------------------------------------------------------------------------------------------
Exposure (mg/kg bw/day) MOE Exposure (mg/kg bw/day) MOE
--------------------------------------------------------------------------------------------------------------------------------------------------------
U.S. Population..................................... 0.001199 3,337 0.002211 1,809
Females 13-50....................................... 0.000464 8,619 0.000712 5,616
Children 1-6........................................ 0.001911 2,094 0.002781 1,438
Children 7-12....................................... 0.001019 3,927 0.001472 2,717
All Infants......................................... 0.002887 1,385 0.003870 1,034
Non-Nursing Infants(<1)............................. 0.002956="" 1,353="" 0.003901="" 1,025="" --------------------------------------------------------------------------------------------------------------------------------------------------------="" 5.="" drinking="" water.="" drinking="" water="" represents="" a="" potential="" route="" of="" acute="" or="" chronic="" dietary="" exposure="" for="" lactofen="" and="" should="" be="" considered="" in="" an="" aggregate="" exposure="" assessment.="" since="" lactofen="" is="" applied="" outdoors="" to="" growing="" agricultural="" crops,="" the="" potential="" exists="" for="" lactofen="" or="" its="" metabolites="" to="" leach="" into="" ground="" water="" or="" reach="" surface="" water="" that="" are="" used="" for="" drinking.="" there="" is="" no="" established="" maximum="" concentration="" level="" for="" residues="" of="" lactofen="" in="" drinking="" water="" under="" the="" safe="" drinking="" water="" act.="" 6.="" ground="" water.="" based="" on="" available="" lactofen="" studies="" used="" in="" epa's="" assessment="" of="" environmental="" risk,="" epa="" required="" a="" small="" scale="" prospective="" ground="" water="" study="" for="" lactofen.="" valent="" conducted="" a="" study="" using="" the="" maximum="" application="" rate="" applied="" to="" a="" site="" which="" was="" extremely="" vulnerable="" to="" leaching="" to="" a="" shallow="" aquifer.="" the="" water="" table="" was="" at="" a="" depth="" of="" 6="" to="" 9="" feet,="" the="" top="" two="" feet="" of="" soil="" were="" classified="" as="" loamy="" sand="" (78="" -="" 82%="" sand),="" and="" the="" deeper="" soil="" was="" classified="" as="" sand="" (88="" -="" 94%="" sand).="" the="" final="" report="" demonstrated="" that="" lactofen="" degrades="" rapidly="" without="" downward="" movement="" in="" soil="" and="" did="" not="" contaminate="" even="" shallow="" ground="" water="" beneath="" light,="" sandy="" soils.="" there="" were="" no="" detections="" of="" lactofen="">< 1="" ppb)="" in="" lysimeter="" or="" monitoring="" well="" water="" samples.="" lactofen="" degrades="" to="" acifluorfen,="" which="" was="" also="" monitored="" in="" the="" study.="" since="" acifluorfen="" results="" from="" lactofen="" degradation,="" but="" is="" not="" the="" only="" degradation="" product,="" concentrations="" are="" expected="" to="" be="" lower="" for="" acifluorfen="" than="" for="" lactofen.="" acifluorfen="" was="" found="" to="" degrade="" [[page="" 9537]]="" somewhat="" more="" slowly="" than="" lactofen,="" and="" it="" did="" not="" leach="" to="" ground="" water="" during="" the="" study.="" there="" were="" no="" detections="" of="" acifluorfen="" (=""> 1
ppb) in lysimeter or monitoring well samples.
Assuming that all ground water contains lactofen at one-half the
limit of quantitation from this study, 0.005 ppm, is non-determinate,
and overly conservative. SCI-GROW modeling, using the same
environmental fate parameters utilized below gave a Ground Water
Screening Concentration of 0.002 ppb.
7. Surface water. Potential surface water concentrations for
lactofen were estimated using GENEEC and the following conservative
use, physical property, and environmental fate parameters: use rate,
0.2 lb a.i./a; applications, 2 aerial broadcast; application interval,
14 days; KOC, 6,600; water solubility 0.945 ppm; aerobic
soil half-life, 2.2-days; hydrolysis (pH 7) half-life 11-days; and
photolysis in water half-life, 2.75-days. The maximum concentration
predicted in the hypothetical small stagnant farm pond water was 1.05
ppb and 0.17 ppb for the 4 and 56 day average GEEC, respectively.
Potential lactofen concentrations in actual drinking water would be
much lower than one-half of the quantitation limit in the ground water
study or the concentration modeled in ground water from the SCI-GROW
Ground Water Screening Concentration or the concentration modeled by
GENEEC in the hypothetical small stagnant farm pond. For this risk
analyses, the finite concentrations modeled by GENEEC are selected.
Based on this analyses, the lactofen exposure contribution from
drinking water to realistic dietary risk analyses is negligible.
Exposure to Lactofen from Drinking waterfor Adults and Children from GENEEC Modeling
----------------------------------------------------------------------------------------------------------------
Exposure (mg/kg bw/day)
-------------------------------------------------
Exposure Adult (70 kg, 2 liter/ Child (10 kg, 1 liter/
day) day)
----------------------------------------------------------------------------------------------------------------
Acute (4-day average)......................................... 0.000030 0.000105
Chronic (56-day average)...................................... 0.0000049 0.000017
----------------------------------------------------------------------------------------------------------------
1. Summary-- Aggregate chronic dietary exposure. Aggregate chronic
dietary exposure to lactofen is the sum of the contributions from food
and water as shown in the table below. It can be seen that the total
potential chronic exposure to lactofen to two representative population
subgroups is dominated by the conservative estimation of residues in
water, but even so, there is no cause for concern.
Aggregate Chronic Exposure to Lactofenfor Two Representative U.S. Populations
----------------------------------------------------------------------------------------------------------------
Exposure (mg/kg bw/day)
-------------------------------------------------
Exposure Medium U.S. Population (all Non-Nursing Infant
seasons) (less than 1 year)
----------------------------------------------------------------------------------------------------------------
Food.......................................................... 0.0000001 0.0000001
Drinking Water................................................ 0.0000049 0.000017
Sum of Chronic Exposures...................................... 0.000005 0.000017
Occupancy of RfD(percent)..................................... 0.25 0.85
----------------------------------------------------------------------------------------------------------------
2. Summary-- Aggregate acute exposure. It is possible to sum
calculated acute exposures from dietary sources as shown in the table
below. However, summation is exceedingly conservative because the
approach assumes that two low probability events occur simultaneously.
For example, it is highly unlikely that an individual in a single day
consumes the 99.9th percentile dietary exposure (one-in-a-
thousand), and also consumes all the daily drinking water from a pond
surrounded by treated cotton fields. Even so, the acute exposures shown
below that sum exposures from food and drinking water gives MOE values
at or above 1,000. These calculated acute and short term exposures are
very conservative, and are small enough to be of little significance.
Aggregate Acute Exposure to Lactofenfor Two Representative U.S. Populations(summation of low probability maximum
values)
----------------------------------------------------------------------------------------------------------------
Exposure (mg/kg bw/day)
-------------------------------------------------
Exposure Medium U.S. Population (all Non-Nursing Infant
seasons) (less than 1 year)
----------------------------------------------------------------------------------------------------------------
Food.......................................................... 0.002211 0.003901
Drinking Water................................................ 0.000030 0.000105
Sum of Acute Exposures........................................ 0.002241 0.004006
Margin of Exposure............................................ 1785 999
----------------------------------------------------------------------------------------------------------------
3. Non-dietary exposure. Lactofen is currently approved only for
the commercial production of agricultural crops including cotton,
soybeans, snap beans, and pine seedlings. The potential for non-
occupational exposure to the general public, other than through the
diet or drinking water, is therefore insignificant.
F. Cumulative Effects
Section 408(b)(2)(D)(v) requires that the Agency must consider
``available information'' concerning the cumulative effects of a
particular pesticide's residues and ``other substances that have a
common mechanism of toxicity.'' ``Available information'' in this
context includes not only toxicity, chemistry, and exposure data, but
also scientific policies and methodologies for understanding common
mechanisms of toxicity and conducting cumulative risk
[[Page 9538]]
assessments. Valent will submit information for EPA to consider
concerning potential cumulative effects of lactofen consistent with the
schedule established by EPA at (62 FR 42020; August 4, 1997) (FRL 5734-
6) and other EPA publications pursuant to the Food Quality Protection
Act.
There are several other pesticide compounds which are structurally
related to lactofen and may have similar effects on animals.
Specifically, lactofen, acifluorfen, fomesafen, oxyfluorfen, and
diclofop methyl are all diphenyl ethers and all have caused liver
tumors in rodents. These chemicals are approved for food uses in the
U.S. and could be considered in a cumulative exposure assessment. It is
premature to simply add the risk from all these chemicals. Exposure
considerations as well as toxicity endpoint, pharmacokinetic, and
pharmacodynamic considerations may indicate that it is inappropriate to
add the risks. Dietary exposures to these other diphenyl ethers are
expected to represent the major route of exposure to the public.
A major hydrolytic metabolite of lactofen representing perhaps 50%
of the applied dose in animal and environmental fate studies, is PPG-
847, the benzoic acid. The sodium salt of this benzoic acid, sodium 5-
[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrobenzoate, is the
registered herbicide acifluorfen. This product has a complete data base
supporting registration with a RfD of 0.013 mg/kg/day and a Cancer
Potency Factor of 0.107 (mg/kg/day)-1. Because lactofen and
acifluorfen have a ``common metabolite'', exposure to both acifluorfen
and lactofen from all sources must be evaluated to perform a cumulative
risk analysis.
It should be noted that acifluorfen, and the other related diphenyl
ethers, would benefit from the use of the larger interspecies scaling
factor as well as lactofen. Further, the rodent liver tumor effects of
these other diphenyl ethers may be due to peroxisome proliferation
which would more appropriately be regulated as a threshold effect. The
carcinogenic risk assessments performed to date are, therefore, highly
conservative.
G. Safety Determination
The Food Quality Protection Act introduces a new standard of
safety, a reasonable certainty of no harm. To make this determination
exposure and consequent risk to both acifluorfen and lactofen from all
sources must be evaluated.
In evaluating chronic dietary exposures, the food and water
consumed for a lifetime is assumed to contain a baseline amount of
residues. Chronic risks are evaluated by comparing a conservatively
calculated baseline exposure to the RfD. A long term exposure in mg/kg
bw/day is compared to a NOEL from an appropriate long term animal
exposure study adjusted by a safety factor. It is quite reasonable to
suppose that daily baseline exposures to two or more compounds could
occur simultaneously. That is, a consumer could have chronic dietary
exposure to lactofen residues and acifluorfen residues at the same
time, and because acifluorfen is a metabolite of lactofen, a cumulative
risk analysis is appropriate. The situation is very different for acute
dietary exposures. In an acute dietary risk analysis, exposures to
residues are related to the probability of occurrence of a daily diet
containing the residues. At its most simplified, the probability of
consuming a diet simultaneously containing both lactofen and
acifluorfen at the 99.9 th percentile diet is one in one-million. A
simple, additive cumulative risk analysis cannot take the probability
of simultaneous exposure into account and is not appropriate.
1. U.S. population --i. Chronic-- Food. Using the dietary exposure
assessment procedures described above (and performed by Valent) for
lactofen, and a recent assessment for acifluorfen published in the 61
FR 16740; (April 17, 1996) (FRL 5356-6) chronic dietary exposures
resulting from existing and proposed uses of lactofen and acifluorfen
were compared to their respective reference doses. The following
contributions to the RfD were found for the U.S. Population and all of
the subpopulations for which dietary consumption data are available:
ii. Lactofen. Exposure 0.0000001 (mg/kg bw/day) less than 0.01% for
all subpopulations.
iii. Acifluorfen. Exposure 0.0000052 (mg/kg bw/day, 61 FR 16740)
less than 0.04 % for all subpopulations.
iv. Chronic-- Drinking water-- Lactofen. Using the conservative
assumption that all drinking water contains lactofen at levels
calculated by GENEEC for a small farm pond surrounded by lactofen
treated fields, a very conservative estimate of risk can be made. Using
standard assumptions about body weight and water consumption, the adult
chronic exposure from this drinking water would be 4.9 x
10-6 mg/kg bw/day, 0.25% of the RfD.
2. Acifluorfen. Acifluorfen that may be in drinking water can be
derived directly from acifluorfen applied to crops, or may be
acifluorfen derived from degradation of lactofen. The physical
properties and soil stability of acifluorfen indicate that the compound
may dissolve in surface water, or leach to groundwater that may be used
for drinking water.
The U.S. Geological Survey is engaged in a National Water Quality
Assessment (NAWQA). This program samples both ground and surface water
and analyzes the samples for 75 pesticides and metabolites including
acifluorfen, but not lactofen. The data through August 1997 are
available from USGS, on the internet at http://water.wr.usgs.govpnsp/
gwsw1.html. The NAWQA sampling program was designed to provide an
overview of pesticide occurrence in water that could be used for
drinking water. Specific types of agriculture or specific products,
including acifluorfen, were not targeted. While the program is not
exhaustive, it probably provides a reasonably unbiased estimate of the
occurrence of agricultural chemical contaminants in potential drinking
water. A table summarizing the data for acifluorfen is presented below.
USGS NAWQA data on Acifluorfen
----------------------------------------------------------------------------------------------------------------
Number of Samples
Water Type -------------------------------------------------- Maximum Concentration
Total >0.05 ppb (ppb)
----------------------------------------------------------------------------------------------------------------
Agricultural Streams................. 1148 10 2.2
Urban Streams........................ 418 ND -
Large Streams........................ 282 6 0.44
Total Surface Water.................. 1848 16
Agricultural Shallow Ground Water.... 1069 ND --
Urban Shallow Ground Water........... 314 1 0.070
Major Ground Water Aquifer........... 965 1 0.190
[[Page 9539]]
Total Groundwater.................... 2348 2
----------------------------------------------------------------------------------------------------------------
It is noteworthy that there were only 18 detections of acifluorfen
in the nearly 4,200 samples analyzed for acifluorfen. More detections
and highest concentrations were found in surface water than in
groundwater. In light of all these monitoring data, it is unreasonable
to choose the single highest concentration value from a small
agricultural stream as representative of all drinking water.
Accordingly, using the conservative assumption that all drinking water
contains acifluorfen at 0.00044 ppm, the highest value in the USGS
NAWQA data on acifluorfen from large streams, a very conservative
estimate of risk can be made. Using standard assumptions about body
weight and water consumption, the chronic exposure from this drinking
water would be 1.26 x 10-5 mg/kg bw/day for adults, 0.1% of
the RfD of 0.013 mg/kg bw/day.
Chronic exposure to drinking water:
i. Lactofen. Less than 0.25% for the U.S. Population.
ii. Acifluorfen. Less than 0.1% for the U.S. Population.
1. Summary- cumulative aggregate chronic dietary risk-- i. U.S.
population. The aggregate chronic dietary risks from both food and
drinking water exposure expressed as a percentage of their respective
RfD values is presented below for both lactofen and acifluorfen. It is
noteworthy that the calculated exposures and consequent risks are very
small, yet dominated by the very conservative estimates of residues in
water.
ii. Lactofen. Exposure 0.000005 (mg/kg bw/day) less than 0.25% for
all subpopulations.
iii. Acifluorfen. Exposure 0.0000178 (mg/kg bw/day) less than 0.14
% for all subpopulations.
EPA generally has no concern for exposures below 100% of 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. The current and proposed uses of these two chemicals,
even when considered collectively, represent a minimal chronic
toxicological risk to the general public and it can be concluded that
there is reasonable certainty of no harm from chronic exposures..
2. Acute. Assessment of aggregate acute exposure to food and
drinking water residues of lactofen to the U.S. Population has
demonstrated that exposures are small. MOE values using very
conservative exposure assumptions and a conservative toxicity endpoint
are all greater than 1,000 and it can be concluded that there is
reasonable certainty of no harm to the U.S. Population from acute
dietary exposures to lactofen residues.
3. Carcinogenicity. Carcinogenic risks for both lactofen and
acifluorfen can be calculated from the aggregate chronic dietary
exposures presented above. Because both products are only used in
agriculture, the exposure to the general population is exclusively
dietary from potential residues in food and drinking water.
4. Food. For lactofen, carcinogenic risks from exposure to residues
in food were calculated by Valent using a potency factor
(Q1*) of 0.17 (mg/kg/day) -1. The resulting
carcinogenic risk from existing and proposed uses of lactofen was
calculated at 1.54 x 10-8 or less for several lifetime
population groups. This is approximately 65 times lower than the
acceptable level of one-in-a-million additional lifetime cancers. It
should be noted that the proposed use on peanuts, which is not being
considered in the current action, accounts for more than a third of the
exposure contributing to the calculated carcinogenic risk. Therefore,
these estimates of carcinogenic risk from lactofen residues in food are
conservative and are well within acceptable levels.
For acifluorfen, carcinogenic risks from exposure to residues in
food were published by EPA (61 FR 16740; April 17, 1996) (FRL-5356-6)
using a Q1* value of 0.107 (mg/kg/day)-1. The
resulting carcinogenic risk from existing and proposed uses of
acifluorfen is calculated at 5.6 x 10-7 or less. This is
lower than the generally acceptable level of one-in-a-million
additional lifetime cancers.
5. Drinking water. In the discussions above, very conservative
estimates of lactofen and acifluorfen residues in potential drinking
water have been presented. The estimates are conservative in that
common concentrations of the compounds in real drinking water are zero,
or orders of magnitude below the estimates. Using the conservative
exposure estimates and the corresponding cancer potency factors, the
cancer risk from drinking water is 8.5 x 10-7 and 6.7 x
10-6 or less for lactofen and acifluorfen, respectively.
6. Summary- cumulative aggregate chronic cancer risk-- i. U.S.
population. The aggregate chronic dietary risks of cancer from exposure
to food and drinking water residues is presented below for both
lactofen and acifluorfen.
ii. Lactofen. Chronic Exposure less than 0.000005 mg/kg bw/day Q*
0.17 (mg/kg bw/day)-1 Cancer Risk: 8.5 x 10-7.
iii. Acifluorfen chronic exposure. Less than 0.0000178 mg/kg bw/day
Q* 0.107 (mg/kg bw/day)-1 Cancer Risk 1.9 x
10-6.
It is noteworthy that the calculated exposures and consequent risks
are dominated by the very conservative estimates of potential residues
in water. The Agency has expressed concern about the potential for
excess oncogenic risk of acifluorfen in drinking water. To evaluate
drinking water exposures, groundwater monitoring studies have been
required for both acifluorfen and lactofen. Additional time is required
to allow registrants to complete the studies, to present real data in
potential drinking water, and for EPA to evaluate the information and
adequately address the drinking water exposure issue. The calculated
cancer risks are for lifetime exposure to levels of all potential
acifluorfen in drinking water little of which could possibly be
attributable to lactofen use on cotton. There is a reasonable certainty
of no harm during the time necessary to obtain and evaluate real
exposure data.
7. Non-dietary exposure. Lactofen and acifluorfen are currently
approved only for the commercial production of agricultural crops. The
potential for non-occupational exposure to the general public, other
than through the diet or drinking water, is therefore insignificant.
8. Infants and children -- Safety factor for infants and children.
In assessing the potential for additional sensitivity of infants and
children to residues of lactofen, FFDCA section 408 provides that EPA
shall apply an additional margin of safety, up to 10-fold, for added
protection for infants and children in the case of threshold
[[Page 9540]]
effects unless EPA determines that a different margin of safety will be
safe for infants and children. The toxicological data base for
evaluating pre- and post-natal toxicity for lactofen is complete with
respect to current data requirements. There are no special pre- or
post-natal toxicity concerns for infants and children, based on the
results of the rat and rabbit developmental toxicity studies and the
reproductive toxicity study in rats. Systemic toxicity effects, and not
reproductive or developmental toxicity determined the no effect levels
for these studies of 50, 4, and 2.5 mg/kg bw/day, respectively. Valent
concludes that reliable data support use of the standard 100-fold
uncertainty factor with respect to protection of infants and children,
and that an additional uncertainty factor is not needed to be further
protective.
Furthermore, the chronic RfD for lactofen is based on the Lowest
Effect Level (LEL) of 1.5 mg/kg/day in the 18-month mouse feeding study
with an uncertainty factor of 1,000. An additional margin of safety,
10-fold, was used since a clear NOEL was not established in the mouse
study. Thus, although an extra safety factor is not needed to further
protect infants and children, an extra 10-fold uncertainty factor has
been included because of the lack of a clear NOEL in the mouse study.
9. Chronic-- Food. Using the dietary exposure assessment procedures
described above (and performed by Valent) for lactofen, and a recent
assessment for acifluorfen published in the Federal Register (61 FR
16740; April 17, 1996) total chronic dietary exposures resulting from
existing and proposed uses of lactofen and acifluorfen were compared to
their respective reference doses. The following contributions to the
RfD were found for all of subpopulations including infants and children
for which dietary consumption data are available:
i. Lactofen. Exposure 0.0000001 (mg/kg bw/day) less than 0.01% of
RfD.
ii. Acifluorfen. Exposure 0.0000052 (mg/kg bw/day), (61 FR 16740;
April 17, 1996) less than 0.04% of RfD.
10. Chronic- drinking water- lactofen. Using the conservative
assumption that all drinking water contains lactofen at levels
calculated by GENEEC for a small farm pond surrounded by lactofen
treated fields, a very conservative estimate of risk can be made. Using
standard assumptions about body weight and water consumption, the child
chronic exposure from this drinking water would be 1.7 x
10-5 mg/kg bw/day, 0.85 percent of the RfD.
11. Acifluorfen. Using the very conservative assumption that all
drinking water contains acifluorfen at 0.00044 ppm, from the USGS NAWQA
data on acifluorfen, a very conservative estimate of risk can be made.
Using standard assumptions about body weight and water consumption, the
child chronic exposure from this drinking water would be 4.4 x
10-5 mg/kg bw/day, 0.34 percent of the RfD.
Summary - Cumulative aggregate chronic dietary risk-- Infants and
children. The aggregate chronic dietary risks from both food and
drinking water exposure expressed as a percentage of their respective
RfD values is presented below for children for both lactofen and
acifluorfen. It is noteworthy that the calculated exposures and
consequent risks are very small, yet dominated by the very conservative
estimates of residues in water.
(a) Lactofen. Less than 0.86 % for all infant and children
subpopulations.
(b) Acifluorfen. Less than 0.38 % for all infant and children
subpopulations.
EPA generally has no concern for exposures below 100% of 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. The current and proposed uses of these two chemicals,
even when considered collectively, represent a minimal chronic
toxicological risk to infants and children and it can be concluded that
there is reasonable certainty of no harm from chronic exposures.
1. Acute. Assessment of aggregate acute exposure to food and
drinking water residues of lactofen to non-nursing infants has
demonstrated that exposures are small. MOE values using very
conservative exposure assumptions and a conservative toxicity endpoint
approximate 1,000. It can be concluded that there is reasonable
certainty of no harm to infants and children from acute dietary
exposures to lactofen residues.
G. International Tolerances
There are no Codex Maximum Residue Limits (MRL) established for
lactofen on any commodity.
[FR Doc. 98-4811 Filed 2-24-98; 8:45 am]
BILLING CODE 6560-50-F
