[Federal Register Volume 62, Number 127 (Wednesday, July 2, 1997)]
[Notices]
[Pages 35804-35812]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-17176]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-740; FRL-5722-9]
Notice of Filing and Withdrawal 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, as well
as the withdrawal of a pesticide petition.
DATES: Comments, identified by the docket control number PF-740, must
be received on or before August 1, 1997.
ADDRESSES: By mail submit written comments to: Public Response and
Program Resources Branch, Field Operations Divison (7505C), Office of
Pesticides Programs, Environmental
[[Page 35805]]
Protection Agency, 401 M St., SW., Washington, DC 20460. In person
bring comments to: Rm. 1132, CM #2, 1921 Jefferson Davis Highway,
Arlington, VA.
Comments and data may also be submitted electronically by following
the instructions under ``SUPPLEMENTARY INFORMATION.'' No confidential
business information should be submitted through e-mail.
Information submitted as a comment concerning this document may be
claimed confidential by marking any part or all of that information as
``Confidential Business Information'' (CBI). CBI should not be
submitted through e-mail. Information marked as CBI will not be
disclosed except in accordance with procedures set forth in 40 CFR part
2. A copy of the comment that does not contain CBI must be submitted
for inclusion in the public record. Information not marked confidential
may be disclosed publicly by EPA without prior notice. All written
comments will be available for public inspection in Rm. 1132 at the
address given above, from 8:30 a.m. to 4 p.m., Monday through Friday,
excluding legal holidays.
FOR FURTHER INFORMATION CONTACT: The product manager listed in the
table below:
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Office location/
Product Manager telephone number Address
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James Tompkins, (PM 25)....... Rm. 237, CM #2, 703- 1921 Jefferson
305-7740; e-mail: Davis Hwy,
[email protected] Arlington, VA
l.epa.gov.
Mary L. Waller, (PM 21)....... Rm. 265, 703 308-9354; Do.
e-mail:
waller.mary@epamail.e.
George LaRocca (PM 13)........ Rm. 204, 703-305-5540, Do.
e-mail:
LaRocca.george@epamai.
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SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions as
follows proposing the establishment, amendment and/or withdrawal of
regulations for residues of certain pesticide chemicals in or on
various raw 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 grantinig 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 document control
number PF-740 (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''.
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 file format or ASCII
file format. All comments and data in electronic form must be
identified by the document control number (insert docket number) 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
requirements.
Dated: June 23, 1997.
James Jones,
Acting 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.
1. Bayer Corporation Withdrawal Of Pesticide Petition
PP 6E3182
On November 8, 1984 Bayer Corporation, P.O. Box 4913, Kansas City,
MO 64120, filed an import petition on behalf of the Ministry of
Agriculture, Fisheries and Forestry in Japan, requesting establishment
of a permanent tolerance (0.1 ppm) for the insecticide prothiophos
(Tokuthion) in/on Japanese sand pears being imported from Japan. On
March 27, 1997 Bayer notified EPA that it requests that the petition be
withdrawn without prejudice to future filing. The Agency has withdrawn
the subject petition. (PM 13).
2. Merck Research Laboratories, Inc.
PP 6F4628
EPA has received pesticide petition 6F4628 from Merck Research
Laboratories, Inc, P.O. Box 450, Hillsborough Road, Three Bridges, NJ
08887-0450, proposing pursuant to section 408 of the Federal Food, Drug
and Cosmetic Act (FFDCA), 21 U.S.C section 346a (d), to amend 40 CFR
part 180 by establishing tolerances for residues of the insecticide
Emamectin Benzoate, 4'-epi-methylamino-4'-deoxyavermectin B1 benzoate
[a mixture of a minimum of 90% 4'-epi-methylamino-4'-deoxyavermectin
B1a and a maximum of 10% 4'-epi-methylamino-4'-deoxyavermectin B1b
benzoate] and it degradates (with Merck research numbers in
parentheses) 8,9- isomer of the B1a and of the B1b component of the
parent insecticide (C-695,638); 4'-deoxy-4'-epi-amino- avermectin B1
(L-653,64); 4'-deoxy-4'-epi-(N-formyl-N-methyl)amino-avermectin B1 (L-
660,599); and 4'-deoxy-4'-epi(N-formyl)amino-avermectin B1 (L-657,831)
in or on the raw agricultural commodities cole crops vegetables
(cabbage, broccoli, cauliflower and brussels sprouts) at 0.025 parts
per million (ppm) and leafy vegetables (celery and head lettuce) at
0.025 ppm. The proposed analytical method is high performance liquid
chromatography (HPLC).
A. Residue Chemistry
1. Plant metabolism. The metabolism of emamectin benzoate in plants
has been studied in lettuce, cabbage, and sweet corn. The major portion
of the residue is parent compound and its delta 8,9-photoisomer.
Studies of the metabolism of emamectin in animals are not required
because the commodities
[[Page 35806]]
that are the subject of the petition are not significant animal feed
items.
2. Analytical method. Adequate analytical method (HPLC-fluorescence
methods) are available for enforcement purposes.
3. Magnitude of residues. Eighteen field trials have been
conducted: 10 on cabbage, 4 on broccoli, and 4 on cauliflower. These
trials were conducted in the major U.S. growing areas for these crops.
In samples taken after passage of the proposed interval between last
treatment and harvest, the highest combined residue of emamectin
benzoate and the degradates, which occurred in one cabbage sample, was
0.020 ppm (actually quantified) of the main component, an
unquantifiable amount that could be almost as high as the 0.005 limit
of quantification or as low as the 0.001 ppm limit of detection, and
undetectable amounts of the other two components, for a total somewhere
between 0.021 part per million (ppm) and 0.027 ppm (total of actually
quantified residues plus maximum possible levels of detectable but
nonquantifiable residues between 0.001 and 0.005 ppm). In all other
samples taken the combined measurable and nonquantifiable residues were
well below the 0.025 ppm level.
B. Toxicological Profile
The primary toxic effect seen in animal studies of emamectin
benzoate is neurotoxicity. No-observed-effect-levels (NOELs) for this
effect have been well-characterized in multiple studies. Emamectin
benzoate has not been shown to be oncogenic or teratogenic in animal
studies, it lacks mutagenic activity, and it is not selectively
developmentally toxic. The petition refers to toxicity data that
establish the following information about the toxicity of emamectin
benzoate:
1. Acute toxicity. Acute oral LD50: rat, 76-89 mg/kg;
CD-1 mouse 107-120 mg/kg; CF-1 mouse, 22-31 mg/kg. Acute oral
neurotoxicity: rat, No observed effect level (NOEL) = 5 mg/kg, Lowest
observed effect level (LOEL) = 10 mg/kg. Acute dermal LD50:
rat and rabbit, >2,000 mg/kg. Dermal irritation: rabbit, not irritating
to skin. Eye irritation: rabbit, severe eye irritant. Acute inhalation
4-hour LC50: rat, 2.12-4.44 mg/l.
2. Reproductive/developmental toxicity. Developmental toxicity:
rat, maternal NOEL = 2 mg/kg/day, developmental NOEL = 4 mg/kg/day,
developmental LOEL = maternally toxic 8 mg/kg/day (HDT) for
developmental delay; rabbit, maternal NOEL = 3 mg/kg/day, developmental
NOEL = 6 mg/kg/day (maternally toxic HDT). Developmental neurotoxicity:
rat, maternal NOEL = 3.6/2.5 mg/kg/day (HDT), developmental NOEL = 0.6
mg/kg/day, developmental LOEL = 3.6/2.5 mg/kg/day for signs of
neurotoxicity in pups. Two-generation reproductive toxicity: rat,
parental and reproductive NOEL = 0.6 mg/kg/day, parental LOEL = 3.6/1.8
mg/kg/day (for decreased weight gain and neuronal lesions);
reproductive toxicity LOEL = 3.6/1.8 mg/kg/day (for decreased fecundity
and signs of neurotoxicity in pups).
3. Subchronic And chronic toxicity and oncogenicity. With the
single exception of the chronic rat study, LOELS for the following
studies are based on clinical signs and/or histopathological evidence
of neurotoxicity (described further below). Subchronic (90-day)
toxicity: rat, NOEL = 0.5 mg/kg/day, LOEL = 2.5 mg/kg/day; CD-1 mouse,
NOEL = 5.4 mg/kg/day (TWA), LOEL = 0.5 mg/kg/day; dog, NOEL = 0.25 mg/
kg/day, LOEL = 0.5 mg/kg/day Subchronic (90-day) neurotoxicity; rat,
NOEL = 1 mg/kg/day, LOEL = 5 mg/kg/day. Chronic (105-week) toxicity/
oncogenicity, rat: NOEL = 0.25 mg/kg/day, LOEL = 1 mg/kg/day (based on
decreased body weight and clinical chemistry changes), neurotoxicity
NOEL = 1 mg/kg/day, not oncogenic. Chronic (79-week) toxicity/
oncogenicity, CD-1 mouse: NOEL = 2.5 mg/kg/day, LOEL = 5 mg/kg (males),
7.5 mg/kg/day (females), not oncogenic. Chronic (53-week) toxicity,
dog: NOEL = 0.25 mg/kg/day, LOEL= 0.5 mg/kg./day.
Exposure to sufficiently high doses of emamectin benzoate may be
associated with clinical signs of central nervous system (CNS) toxicity
and microscopic evidence of CNS/peripheral nervous system (PNS) damage.
Neurotoxicity has generally been the most sensitive endpoint for
toxicity in oral animal studies with emamectin benzoate. Clinical signs
of CNS toxicity resulting from emamectin benzoate exposure include
tremors, mydriasis, and changes in motor activity (e.g., lethargy,
hyperactivity, and/or ataxia). Nervous system lesions (generally focal
and of a low degree of severity) have been observed microscopically in
white and gray matter in the brain stem, spinal cord, and peripheral
nerves. Sporadic lesions of the optic nerve and/or retina have also
been seen at higher dose levels. NOELs have been determined in all
studies. The lowest toxic dose level of emamectin benzoate for CNS/PNS
lesions (0.5 mg/kg/day) was identified in a 1-year study in dogs (NOEL
of 0.25 mg/kg/day).
The CF-l mouse is uniquely sensitive to emamectin benzoate-induced
neurotoxicity. Studies have shown that a significant fraction of the
members of this strain inherit an inability to produce a P-glycoprotein
one that most strains and species do produce that functions to resist
the entrance of avermectin-type compounds into the central nervous
system. P-glycoprotein is also present in the gut of most species and
limits absorption of avermectin-type compounds following oral exposure.
In a 16-day feeding study in the CF-1 mouse, tremors were seen at 0.3
mg/kg/day of emamectin benzoate with a NOEL of 0.1 mg/kg/day. No
histopathologic evidence of neurotoxicity was seen in this study up to
the highest dose tested (0.9 mg/kg/day).
Emamectin benzoate photodegrades on plants and in soil. The major
photodegradates that are not animal metabolites were tested in a 15-day
neurotoxicity study in CF-1 mice. Only one photodegradate showed
neurotoxicity (Merck research number L-660,599, the N-formyl-N-methyl
degradate). Its NOEL was found to be 0.075 mg/kg/day, slightly lower
than the value for the parent compound in the same kind of study, and
both clinical signs and peripheral nerve lesions were observed at
levels of 0.1 mg/kg/day and higher.
4. Mutagenicity. Emamectin benzoate was tested in a battery of in
vitro and in vivo mutagenicity assays and showed no evidence of
mutagenic potential.. The photodegradates have also been tested in the
Ames bacterial mutagenicity assay and show no mutagenic potential in
this test system.
5. Endpoint selection. Merck is proposing that the 0.075 mg/kg/day
NOEL from the CF-1 mouse 15-day neurotoxicity study with the L-660,599
photodegradate be used as the basis for acute dietary risk assessment.
For evaluation of chronic dietary risks, Merck is proposing that the
one-year dog chronic study NOEL of 0.25 mg/kg/day be used. The dog
appears to be the most sensitive species to long-term exposure to
emamectin benzoate. Accordingly, chronic exposure is compared against a
RfD of 0.0025 mg/kg/day, based on the dog study results and an
uncertainty factor of 100.
C. Aggregate Exposure
1. Dietary exposure. Except for a temporary tolerance associated
with an experimental use permit, no tolerances for residues of
emamectin benzoate have been established. Merck projects that by the
year 2001, emamectin benzoate will be used on approximately 17% of the
acreage for the six crops covered by this petition. Chronic dietary
exposure analyses were conducted for the overall
[[Page 35807]]
U.S. population and 26 population subgroups. Assuming 100% of the crop
treated, chronic exposure for the overall U.S. population was estimated
to be 0.000003 mg/kg BW/day, and for the most highly exposed subgroup,
nursing females 13 years and older, 0.000004 mg/kg BW/day.
2. Nondietary exposure. No products containing emamectin benzoate
have yet been registered under the Federal Insecticide, Fungicide, and
Rodenticide Act (FIFRA) for any food or nonfood use. The environmental
fate of emamectin has been evaluated, and the compound is not expected
to contaminate groundwater or surface water to any measurable extent.
No significant nondietary, nonoccupational exposure is anticipated.
D. Cumulative Effects
Emamectin is a member of the avermectin family of natural and
synthetic compounds that includes the Merck products abamectin (a
naturally occurring compound that is the active ingredient of several
insecticides registered under FIFRA) and ivermectin (a human and animal
drug made from abamectin). Emamectin is made from abamectin but is less
similar to abamectin than is ivermectin. Other companies produce
certain other drugs that are members of the avermectin family. Some of
the effects seen in toxicity studies of abamectin and ivermectin are
similar to some of the effects seen in toxicity studies of emamectin.
See the discussion of abamectin and ivermectin in 61 FR 65043 (Dec. 10,
1996). Merck is not aware of any information indicating what, if any,
cumulative effect would result from exposure to two or more of these
compounds.
E. Safety Determination
1. U.S. population chronic risk. Chronic exposures were analyzed
with reference to the chronic effects referenced dose (RfD) NOEL of
0.0025 mg/kg/day. Assuming 100% of the crop treated, the chronic
exposure estimate was 0.1% of the RfD for the overall U.S. population,
and 0.2% of the RfD for the most highly exposed subgroup, nursing
females 13 years and older. If 25% crop treatrment is assumed, exposure
estimates were less than 0.1% of the RfD for all population groups.
2. U.S. population acute risk. Acute dietary exposures were
analyses for the overall U.S. population, and the population subgroups
(1) women 13 years and older, (2) infants, and (3) children. In
addition, Tier 2 and Tier 3 acute analyses were conducted assessing
acute exposures against the 0.075 mg/kg/day NOEL. These analyses showed
that the margins of exposure (MOEs) calculated from the proposed uses
of emamectin benzoate are acceptable whether using a highly
conservative approach (Tier 2) or a more realistic (Tier 3)
methodology. In the Tier 2 analysis, MOEs were well over 1,000 up to
the 95th percentile of exposure for all population groups. In the Tier
3 analysis and assuming 100% of the crop treated, MOEs up to the 99th
percentile of exposure were greater than 1,000. Assuming 25% of the
crop treated, MOEs were greater than 1,000 up to the 99.9th percentile
of exposure. Results of both the chronic and acute dietary exposure
analyses clearly demonstrate a reasonable certainty that no harm will
result from the use of emamectin benzoate.
3. Infants and children. It is Merck's position that the
administration of emamectin benzoate has not been shown to cause
developmental or reproductive effects at dose levels below those that
are maternally toxic. Even if it were decided to use the 0.6 mg/kg NOEL
from the rat developmental neurotoxicity study as an endpoint from
which to calculate an RfD, the resulting RfD would not yield a
different regulatory outcome unless a very high additional uncertainty
factor were also employed. Use of such an extra uncertainty factor is
not justified for several reasons. Emamectin benzoate is not a
teratogen. In developmental toxicity testing, the compound caused no
developmental effects in rabbits; in rats, it caused no malformations,
and caused skeletal effects typical of developmental delay only at
severely maternally toxic doses. Likewise, no reproductive toxicity or
toxicity to pups was seen in the two-generation reproductive toxicity
study except at parentally toxic doses. In the developmental
neurotoxicity study, tremors, hind-leg splay, and behavioral effects
were seen in pups at a dose level (3.6/2.5 mg/kg/day) at which no
maternal clinical signs were noted. However, the dams in the study were
discarded after the lactation period without gross necropsy or
microscopic examination. In studies in which rats dosed at similar
levels were examined microscopically, effects (central and peripheral
neural lesions) were seen.
The clinical signs of avermectin-family neurotoxicity seen in
neonatal rats are unlikely to be useful predictors of human risk. Young
rats are considerably more sensitive to avermectin-type compounds than
either adult rats or humans and other primates. (In neonatal rats,
unlike humans, the P-glycoprotein levels are only a small fraction of
the levels seen in adult rats.) Moreover, data from clinical experience
with ivermectin, a related human drug, and studies on ivermectin and
abamectin, a related pesticide, demonstrate that both the neonatal rat
and the CF-1 mouse overpredict the toxicity of the avermectin-type
compounds to humans and to non-human primates.
F. International Tolerances
No Codex maximum residue levels (MRLs) have been established for
residues of emamectin benzoate. (PM 13)
3. Novartis Crop Protection Inc.
PP 0E3875
EPA has received a pesticide petition (0E3875) from Novartis Crop
Protection Inc., PO Box 18300, Greensboro, NC 27419. The petition
proposes, to amend 40 CFR part 180, by establishing a permanent import
tolerance for the residues of the fungicide cyproconazole, (2RS,3RS)-2-
(4-chlorophenyl)-3-cyclopropyl-1-1(1H-1,2,4-triazole-1-yl)butan-2-ol,
(CAS #94361-06-5; PC Code 128993) in or on the raw agricultural
commodity coffee beans at 0.1 part per million (ppm). The time-limited
tolerance of 0.1 ppm in or on coffee beans established in the Federal
Register of September 27, 1995 (60 FR 49795) will expire July 1, 1997.
A. Chemical Uses
Cyproconazole, (2RS,3RS)-2-(4-chlorophenyl)-3-cyclopropyl-1-(1H-1,
2, 4-triazole-1-yl)butan-2-ol, is a broad spectrum fungicide that has
been classified as an ergosterol-biosynthesis inhibitor. It is used to
control a variety of fungi, including coffee rust, in several coffee
producing countries. Rates range from a preventative treatment of 20 g
ai/ha to a maximum curative treatment of 50 g ai/ha with a 30 day pre-
harvest interval (PHI) and annual maximum of 100 g ai/ha.
1. Cyproconazole safety. A battery of acute toxicity studies was
conducted placing technical cyproconazole in Toxicity Category III and
IV.
i. 90-day rat study. A NOEL for this study was not attained, but
the NOEL is estimated to be less than 1.0 mg/kg.
ii. 13-week feeding study in dogs. NOEL of 20 ppm (0.8 mg/kg/day)
and an LEL of 100 ppm (4 mg/kg/day) based on included slack muscle
tone, depressed body weight gain, and decreases in bilirubin, total
cholesterol, HDL-cholesterol, triglycerides, total protein, and
albumin. There were increases in platelet counts, alkaline phosphatase,
gamma glutamyl transferase, absolute
[[Page 35808]]
and relative liver weights, relative kidney weights, and relative brain
weights. Liver toxicity was indicated by hepatomegaly.
iii. 21-day dermal study. NOEL was 250 mg/kg and the LEL was 1,250
mg/kg. Effects included depressed body weight gain and food consumption
and increased levels of AST, creatinine, and cholesterol.
iv. 1-year dog study. NOEL of 30 ppm (1.0 mg/kg/day) and an LEL of
100 ppm (3.2 mg/kg/day) based on laminal eosinophilic intrahepatocytic
bodies observed in all males and two females at the high dose, and in
one male at the mid-level dose.
v. A mouse carcinogenicity study. NOEL for systemic toxicity of 15
ppm (1.8 mg/kg for males and 2.6 mg/kg for females). The LEL was 100
ppm (13.2 mg/kg for males and 17.7 mg/kg for females) based on a
significantly increased incidence of hepatic single cell necrosis and
diffuse hepatocytic hypertrophy at the two highest levels.
vi. A rat chronic/carcinogenicity study. The NOEL for systemic
toxicity was 50 ppm. The LEL was 350 ppm based on slightly decreased
body weights in the high-dose females and increased incidence of fatty
infiltration of the liver in the high-dose males.
vii. A rat developmental toxicity study. NOEL for maternal toxicity
was 6 mg/kg, and the LEL was 12 mg/kg based on decreased body weight
gain during dosing. The NOEL for developmental toxicity was 6 mg/kg.
The LEL was 12 mg/kg based on the increased incidence of supernumerary
ribs.
viii. A chinchilla rabbit developmental toxicity study. NOEL for
maternal toxicity was 10 mg/kg (equivocal). The LEL was 50 mg/kg based
on decreased body weight gain during dosing. Developmental effects were
also evaluated. Hydrocephalus internus was observed in 1 fetus at each
treatment level. Therefore, the NOEL for developmental toxicity was set
at less than 2 mg/kg, and the LEL was 2 mg/kg.
ix. A New Zealand white rabbit developmental toxicity study. NOEL
for maternal toxicity was 10 mg/kg, and the LEL was 50 mg/kg based on
decreased body weight gain. There was also evidence of developmental
toxicity. The NOEL for developmental toxicity was 2 mg/kg, and the LEL
was 10 mg/kg based on the increased incidence of malformed fetuses and
litters with malformed fetuses.
x. A rat two-generation reproduction study. systemic NOEL for
parental toxicity was set at 20 ppm (1.7 mg/kg) based on liver effects
at 10.6 mg/kg/day. For reproductive toxicity, the NOEL was set at 4 ppm
(0.4 mg/kg) and the LEL at 20 ppm (1.7 mg/kg) based on increased
gestation length in the F0 dams and decreased F1 litter sizes.
xi. Several mutagenicity studies. Mutagenicity potential of
cyproconazole was tested in several studies considered acceptable by
the Agency. Since the results of two chromosomal aberration assays
indicated the cyproconazole is clastogenic, additional mutagenicity
data were requested to address an identified heritable risk concern.
For the potential to induce chromosome aberrations in CHO cells,
cyproconazole was positive under non-activated and activated
conditions, thus supporting the evidence that cyproconazole is
clastogenic in this test system. However, cyproconazole was negative in
Salmonella, mouse micronucleus, and SHE/cell transformation assays. A
dominant-lethal assay in rats was submitted and was negative. Based on
this evidence, the concern for a possible heritable effect was not
pursued.
xii. Metabolism/pharmacokinetics studies. Cyproconazole was shown
to be extensively metabolized in the rat. Unchanged cyproconazole and
13 metabolites were isolated and identified, and 35 metabolites were
detected in the excreta. Excretion was relatively rapid with the
majority of the radioactivity appearing in the feces as a result of
biliary elimination. Residues were found in renal fat, adrenals, kidney
and liver, although no significant tissue radioactivity was observed at
168 hours post-dose.
2. Threshold effects.--i. Chronic effects. Based on available
chronic toxicity data, EPA has set the reference dose (RfD) used in the
dietary exposure analysis at 0.01 mg/kg bwt/day. This RfD is based on a
NOEL of 30.0 ppm (1.00 mg/kg bwt/day) from a 1-year dog feeding study
and an uncertainty factor of 100 to account for interspecies
extrapolation and intraspecies variability.
ii. Acute effects. The risk from acute dietary exposure to
cyproconazole is considered by Novartis to be very low. The lowest NOEL
in a short term exposure scenario, identified as 2 mg/kg in the rabbit
teratology study, is 2-fold higher than the chronic NOEL (see above).
Since chronic exposure assessment (see below), based on some worst-case
assumptions, resulted in margins of exposure in the thousands for even
the most impacted population subgroup, Novartis believes that the
margin of exposure for acute exposure would be much higher than one
hundred for any population groups; margins of exposure of 100 or more
are considered satisfactory by the Agency.
3. Non-threshold effects. The HED Carcinogenicity Peer Review
Committee has classified cyproconazole as a Group ``B2'' carcinogen
(probable human carcinogen) based on findings of liver tumors in both
sexes of mice administered adequate doses of cyproconazole, its
possible clastogenic activity, tumors in rats and mice administered
structurally related analogues and the lack of an adequate rat
carcinogenicity study. The committee assigned cyproconazole a risk
characterization value, Q1*, of 3.0 x 10-1 (mg/kg/day)-1 derived from
liver tumor data obtained in male mice.
B. Aggregate Exposure
The anticipated residue contributions (ARC) as percentages of the
RfD are <0.1% for="" the="" general="" population="" and="" all="" sub-populations="" and="" geographic="" regions.="" the="" chronic="" dietary="" exposure="" analysis="" for="" cyproconazole="" is="" calculated="" using="" anticipated="" residues="" for="" coffee="" and="" 100%="" treatment="" of="" all="" crops.="" this="" estimate="" is="" not="" a="" worst-case="" estimate="" of="" dietary="" exposure="" but="" still="" exaggerates="" exposure.="" based="" on="" this="" calculation,="" novartis="" believes="" the="" chronic="" dietary="" risk="" from="" the="" recommended="" use="" is="" far="" below="" the="" level="" which="" would="" trigger="" a="" concern.="" other="" potential="" sources="" for="" exposure="" are="" drinking="" water="" and="" non-="" occupational="" exposure.="" no="" cyproconazole-based="" products="" are="" labeled="" for="" residential="" use.="" non-occupational="" exposure="" for="" cyproconazole="" has="" not="" been="" estimated="" since="" the="" current="" registrations="" for="" cyproconazole-based="" products="" are="" limited="" to="" commercial="" and="" agricultural="" turf="" treatment.="" field="" studies="" have="" demonstrated="" that="" cyproconazole="" does="" not="" leach="" to="" groundwater="" or="" accumulate="" in="" the="" soil.="" the="" average="" half="" life="" of="" cyproconazole="" in="" field="" dissipation="" studies="" was=""><50 days.="" the="" field="" characteristics="" of="" cyproconazole,="" combined="" with="" its="" use="" pattern,="" make="" surface="" water="" contamination="" unlikely.="" thus,="" novartis="" believes="" the="" potential="" for="" non-occupational="" and="" drinking="" water="" exposure="" to="" the="" general="" population="" is="" insignificant.="" c.="" safety="" determination="" 1.="" u.s.="" population.="" all="" non-occupational="" exposure="" of="" cyproconazole="" in="" the="" u.s.="" is="" due="" to="" its="" use="" in="" the="" production="" of="" imported="" coffee="" beans.="" the="" anticipated="" residue="" contribution="" (arc)="" is="" 0.000001="" mg/kg/day="" for="" the="" general="" population="" and,="" 0.000002="" mg/kg/day="" for="" females,="" 20="" years="" old="" and="" older.="" novartis="" has="" calculated="" that="" the="" arc="" will="" consume="" 0.01%="" and="" 0.02%="" of="" the="" rfd="" for="" the="" general="" population="" and="" [[page="" 35809]]="" females="" 20="" years="" old="" or="" older,="" respectively.="" lifetime="" carcinogenic="" risk="" for="" dietary="" exposure="" based="" on="" quantitative="" risk="" assessment="" and="" a="">1* of 3.0 x 10-1 (mg/kg/day)-1, is 3.15 x
10-7. EPA generally has no concern for exposures below 100
percent of the RfD or lifetime carcinogenic risks less than 1 x
10-6. Therefore, Novartis concludes that there is a
reasonable certainty that no harm will result from aggregate exposure
to cyproconazole residues via the use on coffee beans.
The consideration of a common mechanism of toxicity is not
appropriate at this time because Novartis and EPA do not have
information to indicate that toxic effects produced by cyproconazole
would be cumulative with those of any other chemical compounds.
2. Infants and children. For dietary risk assessments, no exposure
is apportioned to infants and children because they do not normally
consume coffee. There is also no non-occupational exposure to infants
and children. Based on the completeness and reliability of the toxicity
data and the practical non-exposure to cyproconazole, Novartis
concludes that there is a reasonable certainty that no harm will result
to infants and children from the aggregate exposure of residues of
cyproconazole including all anticipated dietary exposure and all other
non-occupational exposures.
D. Estrogenic Effects
Cyproconazole does not belong to a class of chemicals known for
having adverse effects on the endocrine system. No estrogenic effects
have been observed in the various short and long term studies conducted
with various mammalian species.
E. Chemical Residue
The nature of the residue in coffee is fully understood. A
metabolism study in coffee, using triazole-labeled cyproconazole, was
submitted and was acceptable. Cyproconazole per se was the primary
component of the residue. A metabolism study in wheat was conducted to
determine the fate of the phenyl portion of cyproconazole in plants.
Results of the study have been submitted and the Agency found that
residues from the wheat metabolism study were not significantly
different from the coffee metabolism study.
Adequate enforcement methodology has been submitted to the EPA and
has passed a method validation trial by EPA's analytical laboratories.
Additional data has been submitted to demonstrate that residues of
several other pesticides registered for use on coffee do not interfere
with the method. Prior to publication in the Pesticide Analytical
Manual, Vol. II, the enforcement methodology is being made available in
the interim to anyone who is interested in pesticide enforcement when
requested from: Calvin Furlow, Public Response and Program Resource
Branch, Field Operations Division (7506C), Office of Pesticide
Programs, Environmental Protection Agency, 401 M St., SW., Washington,
DC 20460. Office location and telephone number: Rm. 1130A, CM#2, 1921
Jefferson Davis Hwy., Arlington, VA (703) 305-5937.
F. Environmental Fate
No domestic use of cyproconazole is associated with the established
tolerance in coffee.
G. International Tolerances
No international tolerances have been established under CODEX for
cyproconazole. (PM 21)
4. ZENECA Ag Products
PP 6F4790
EPA has received a pesticide petition (PP 6F4790) from ZENECA Ag
Products, 1800 Concord Pike, P.O. Box 15458, Wilmington, DE 19850-5458,
proposing to amend 40 CFR part 180 by establishing a tolerance for
residues of tralkoxydim, 2-cyclohexen-1-one, 2[1-(ethoxyimino) propyl]-
3-hydroxy-5-(2,4,6-trimethylphenyl)-(9CI) in or on the food commodities
barley grain, barley straw, barley hay, wheat grain, wheat forage,
wheat straw, and wheat hay at 0.1 parts per million (ppm). The proposed
analytical method is High Pressure Liquid Chromatography with ultra-
violet detection (HPLC-UV).
A. Residue Chemistry
1. Plant metabolism. Wheat Plant metabolism was evaluated in wheat.
14C-Tralkoxydim, labeled in the equivalent C4/C6 positions of the
cyclohexenone ring, was applied as a foliar spray to field-grown spring
wheat. A single application was made at a rate of 0.31 lb ai/acre at
Zadok's growth stage 31. A representative forage sample was harvested
22 days post-application. The remainder of the crop was harvested at
maturity, 96 days post-application, then separated into straw and grain
prior to analysis.
The total radioactive residues (TRR) in forage, straw and grain
were 0.71, 1.29 and 0.013 mg/kg tralkoxydim equivalents, respectively.
No residues of parent were detected and at least ten individual
components were initially observed, demonstrating extensive metabolism
of tralkoxydim. Characterization of the total radioactive residue in
grain by extraction indicates that no single component exceeds 0.01 mg/
kg. Also, in both forage and straw, the same complex metabolic profile
was evident. Characterization showed that none of the metabolites
exceeded 3.6% TRR (0.05 mg/kg) in any of the fractions examined.
2. Analytical method. The method of analysis uses High Pressure
Liquid Chromatography. It is method PRAM 99A and it has been validated
using independent laboratory confirmatory trials as described in US EPA
PR Notice 88-5. The method is for extraction and quantification of
tralkoxydim residues in wheat and barley crops. Grain, straw, or forage
is extracted into acetonitrile, filtered, and re-extracted into
dichloromethane. The organic layer is used for analysis. The limit of
detection of the analytical method is 0.02 ppm, while the limit of
quantification is 0.1 ppm.
3. Magnitude of residues. ZENECA requests registration of 2
concentrations of tralkoxydim, 80% and 40% for ACHIEVE 80DG and ACHIEVE
40DG, respectively. These products use the same rate of application and
demonstrate that there are no detectable residues on wheat and barley
crops when either product is used according to the label directions.
Wheat: ACHIEVE 80DG containing 80% tralkoxydim. Residue data are
available for tralkoxydim applied postemergence on wheat at the maximum
label rate of 0.25 lb ai/A. Application was made from full tillering to
first detectable node growth stage. In 1995, a total of 20 magnitude of
the residue trials were conducted on spring wheat. There were no
detectable residues (<0.02 ppm="" lod)="" on="" wheat="" grain="" or="" straw="" in="" any="" of="" the="" trials="" at="" the="" pre-harvest="" interval="" of="" 60="" days.="" there="" were="" no="" detectable="" residues="" on="" hay="" at="" the="" pre-harvest="" interval="" of="" 45="" days.="" there="" were="" no="" detectable="" residues="" on="" immature="" forage="" at="" the="" pre-harvest="" interval="" of="" 30="" days.="" two="" (2)="" winter="" wheat="" trials="" were="" conducted="" in="" 1995="" to="" determine="" forage="" residues="" of="" tralkoxydim="" in="" winter="" wheat,="" using="" achieve="" dg,="" 80%="" concentration="" (achieve="" 80dg).="" the="" product="" was="" applied="" at="" the="" maximum="" label="" rate="" at="" growth="" stages="" from="" advanced="" tillering="" to="" full="" tillering.="" the="" winter="" wheat="" forage="" data="" showed="" no="" detectable="" residues="" at="" either="" 16="" or="" 18="" days="" after="" treatment.="" these="" results="" fall="" well="" within="" the="" proposed="" forage="" pre-harvest="" interval="" of="" 30="" days.="" achieve="" 40dg="" containing="" 40%="" tralkoxydim.="" there="" were="" 3="" magnitude="" of="" the="" residue="" trials="" conducted="" on="" spring="" wheat="" in="" 1994="" and="" one="" trial="" was="" [[page="" 35810]]="" conducted="" in="" 1993.="" in="" addition,="" 6="" trials="" were="" conducted="" in="" canada="" during="" 1986="" and="" 1987.="" (note:="" the="" canadian="" trials="" were="" conducted="" using="" a="" 50%="" concentration="" of="" tralkoxydim="" at="" a="" higher="" use="" rate="" of="" 0.3="" -="" 0.6="" lb="" ai/a).="" there="" were="" no="" detectable="" residues=""><0.02 ppm="" lod)="" on="" wheat="" grain="" or="" straw="" in="" any="" of="" the="" trials="" at="" the="" pre-harvest="" interval="" of="" 60="" days.="" there="" were="" no="" detectable="" residues="" on="" hay="" at="" the="" pre-harvest="" interval="" of="" 45="" days.="" there="" were="" no="" detectable="" residues="" on="" immature="" forage="" at="" the="" pre-harvest="" interval="" of="" 30="" days.="" despite="" having="" no="" detectable="" residues="" of="" tralkoxydim="" at="" 0.02="" ppm,="" it="" is="" proposed="" that="" the="" tolerance="" level="" be="" based="" on="" the="" limit="" of="" quantification="" (loq)="" of="" the="" tolerance="" enforcement="" method,="" which="" has="" been="" validated="" to="" 0.1="" ppm="" for="" tralkoxydim.="" the="" proposed="" tolerance="" of="" 0.1="" ppm="" for="" wheat="" grain,="" forage,="" straw="" and="" hay="" is="" five="" (5)="" times="" greater="" than="" any="" residue="" that="" would="" result="" from="" the="" application="" of="" achieve="" dg="" arising="" from="" the="" proposed="" use="" pattern.="" wheat="" products="" (processing).="" the="" wheat="" processing="" study="" demonstrated="" that="" there="" are="" no="" detectable="" residues=""><0.02 ppm)="" in="" the="" bran,="" flour,="" middlings,="" shorts,="" and="" germ.="" therefore,="" no="" food="" or="" feed="" additive="" tolerances="" are="" required="" for="" processed="" wheat="" commodities.="" barley:="" achieve="" 80dg="" containing="" 80%="" tralkoxydim.="" a="" total="" of="" 12="" magnitude="" of="" the="" residue="" trials="" were="" conducted="" in="" 1995="" on="" barley="" crops="" for="" tralkoxydim="" applied="" postemergence="" at="" the="" maximum="" label="" rate="" of="" 0.25="" lb="" ai/a.="" the="" product="" was="" applied="" at="" full="" tillering="" to="" first="" detectable="" node="" growth="" stage.="" there="" were="" no="" detectable="" residues=""><0.02 ppm)="" on="" barley="" grain="" or="" straw="" at="" the="" pre-harvest="" interval="" of="" 60="" days.="" there="" were="" no="" detectable="" residues="" in="" hay="" at="" the="" pre-harvest="" interval="" of="" 45="" days.="" achieve="" 40dg="" containing="" 40%="" tralkoxydim.="" in="" 1994,="" 3="" magnitude="" of="" the="" residue="" trials="" were="" conducted="" on="" barley="" using="" achieve="" dg,="" 40%="" concentration="" (achieve="" 40dg).="" in="" addition,="" 6="" magnitude="" of="" the="" residue="" trails="" that="" were="" conducted="" in="" canada="" during="" 1986="" and="" 1987.="" (note:="" the="" canadian="" trials="" were="" conducted="" using="" a="" 50%="" concentration="" of="" tralkoxydim="" at="" a="" higher="" use="" rate="" of="" 0.3="" -="" 0.6="" lb="" ai/a).="" there="" were="" no="" detectable="" residues=""><0.02 ppm)="" on="" barley="" grain="" or="" straw="" at="" the="" pre-harvest="" interval="" of="" 60="" days.="" there="" were="" no="" detectable="" residues="" in="" hay="" at="" the="" pre-harvest="" interval="" of="" 45="" days.="" despite="" having="" no="" detectable="" residues="" of="" tralkoxydim="" at="" 0.02="" ppm,="" it="" is="" proposed="" that="" the="" tolerance="" level="" be="" based="" on="" the="" limit="" of="" quantification="" (loq)="" of="" the="" tolerance="" enforcement="" method,="" which="" has="" been="" validated="" to="" 0.1="" ppm="" for="" tralkoxydim.="" the="" proposed="" tolerance="" of="" 0.1="" ppm="" for="" barley="" grain,="" hay="" and="" straw="" is="" five="" (5)="" times="" greater="" than="" any="" residue="" that="" would="" result="" from="" the="" application="" of="" achieve="" dg="" arising="" from="" the="" proposed="" use="" pattern.="" barley="" products="" (processing).="" the="" barley="" processing="" study="" demonstrated="" that="" there="" are="" no="" detectable="" residues=""><0.02 ppm)="" in="" the="" pearled="" barley,="" flour="" and="" bran.="" therefore,="" no="" food="" or="" feed="" additive="" tolerances="" are="" required.="" animal="" products.="" based="" on="" the="" results="" of="" the="" poultry="" and="" ruminant="" metabolism="" studies,="" the="" extensive="" metabolism="" and="" rapid="" excretion="" of="" either="" tralkoxydim="" or="" any="" of="" its="" metabolites,="" and="" the="" poultry="" and="" ruminant="" consumption="" of="" commodities="" used="" in="" animal="" feed,="" there="" are="" no="" expected="" residues="" of="" tralkoxydim="" in="" meat,="" milk,="" or="" eggs.="" b.="" toxicological="" profile="" 1.="" acute="" toxicity.="" tralkoxydim="" technical="" results="" of="" the="" acute="" toxicity="" testing:="" acute="" oral="" in="" the="" rat="" ld50=""> 934 mg/kg, acute dermal
in the rat LD50 > 2,000 mg/kg, acute inhalation in the rat LD50 > 3.5
mg/L, eye irritation in the rabbit showed mild irritancy, skin
irritation in the rabbit showed a slight irritancy. Tralkoxydim is not
a skin sensitizer.
2. Genotoxicity.
------------------------------------------------------------------------
Assay Type Result
------------------------------------------------------------------------
In vitro Ames negative
Mouse lymphoma negative
Human lymphocyte negative
cytogenetics
In vivo Mouse micronucleus negative
UDS negative
------------------------------------------------------------------------
3. Reproductive and developmental toxicity. (Reproductive toxicity)
Tralkoxydim showed no evidence of reproductive toxicity to rats.
Tralkoxydim was dosed to rats at levels of 2.5 mg/kg/day (50 ppm), 10
mg/kg/day (200 ppm) and 50 mg/kg/day (1,000 ppm) in a 3 generation
reproductive toxicity study.
----------------------------------------------------------------------------------------------------------------
Study Type Reproductive Toxicity NOEL Effect Description
----------------------------------------------------------------------------------------------------------------
Rat (diet) 3 generation.................. NOEL = 10 mg/kg/day (200 LEL is 1,000 ppm based on reduced litter
ppm). weights and weight gain in pups and
bodyweight gain effects, food
consumption and reduced liver weights
in adults
----------------------------------------------------------------------------------------------------------------
(Developmental toxicity) Tralkoxydim caused no clear dose related
developmental effects in the rabbit. At a dose of 30 mg/kg/day,
tralkoxydim caused some developmental effects in the rat manifested by
skeletal defects including single misshapen centra. The NOEL for
developmental toxicity was established at 3 mg/kg/day.
----------------------------------------------------------------------------------------------------------------
Study Type Developmental Toxicity NOEL/LEL Effect Description
----------------------------------------------------------------------------------------------------------------
Rabbit (by gavage)..................... NOEL = 2.5 mg/kg/day No clear dose-related developmental
fetotoxicity LEL = 20 mg/kg/ effects. LEL effect, increased
day NOEL = 20 mg/kg/day partially ossified 2nd lumbar
maternal. transverse process.
Rat (by gavage)........................ NOEL = 3 mg/kg/day fetotoxicity LEL for maternal toxicity is 300 mg/kg/
and developmental LEL = 30 mg/ day maternal death and overt
kg/day NOEL = 30 mg/kg/day toxicity. Developmental LEL is 30 mg/
maternal. kg/day, skeletal defects includes
single misshapen centra.
[[Page 35811]]
Rat (by gavage)........................ NOEL = 3 mg/kg/day LEL = 200 mg/ LEL for fetotoxicity effect, increased
kg/day maternal, fetotoxicity post-implantation loss. Developmental
and developmental. effect fused or misshapen centra.
Maternal LEL is based on moralities &
overt signs of toxicity.
----------------------------------------------------------------------------------------------------------------
4. Subchronic toxicity. Tralkoxydim is of low subchronic toxicity
in 21-day dermal testing.
5. Chronic toxicity. Tralkoxydim is not a carcinogen in the rat.
The dose levels used in the 2 year combined chronic/oncogenicity study
on rats were as follows.
------------------------------------------------------------------------
Male rat (mg/kg/ Female rat (mg/kg/
Tralkoxydim in Diet (ppm) day) day)
------------------------------------------------------------------------
50 2.3 3.0
500 23.1 30.1
2,500 117.9 162.8
------------------------------------------------------------------------
Tralkoxydim administration was associated with an increase in the
incidence of benign Leydig cell tumors in the male rat at the top-dose
of 2,500 ppm, only. This increase represented an exacerbation of a
naturally occurring tumor type in the male rat and was considered to be
the result of a physiological response to tralkoxydim administration.
There was no evidence of a treatment-related effect or incidence of any
other tumor type (malignant or benign) in male or female rats at any
dose.
Oncogenicity - Hamster. Tralkoxydim is not an oncogen in the
hamster. The dose levels used in the combined chronic toxicity/
oncogenicity study on hamsters were as shown in the table below.
----------------------------------------------------------------------------------------------------------------
Tralkoxydim in Diet (ppm) Male hamster (mg/kg/day) Female hamster (mg/kg/day)
----------------------------------------------------------------------------------------------------------------
250 14.9 14.8
2,500 153.0 148.3
7,500 438.6 427.9
----------------------------------------------------------------------------------------------------------------
There was no increased tumor incidence or early onset of tumors in
hamsters receiving up to 7,500 ppm tralkoxydim in the diet. The NOEL
was established at 250 ppm, equivalent to 15 mg/kg bodyweight/day.
----------------------------------------------------------------------------------------------------------------
Study Type Oncogenicity NOEL/LEL Effect Description
----------------------------------------------------------------------------------------------------------------
Hamster (diet) NOEL = 250 ppm (15 mg/kg/day) LEL effect: decreased lymphocyte
LEL = 2,500 ppm numbers (in males only) and increased
liver lipofuscin pigment at 2,500 and
7,500 ppm.
----------------------------------------------------------------------------------------------------------------
The hamster instead of the mouse was selected as the second test
species for oncogenicity testing because laboratory mice developed
hepatic porphyria at low doses of tralkoxydim. Extensive mechanism data
in support of the mouse specific porphyria has been provided. The
results of these studies led ZENECA to the conclusion that the mouse
was not an appropriate second test species for chronic toxicity/
oncogenicity testing of tralkoxydim since the level of sensitivity in
the mouse precluded the administration of a dose sufficient to
determine chronic/oncogenicity effects in a lifetime feeding study.
One-Year Feeding Study - Dog. Tralkoxydim was administered to
groups of 4 beagle dogs at dose levels of 0, 0.5, 5.0, and 50 mg/kg/
day, as a daily oral dose in the food. At 50 mg/kg/day there was
hepatotoxicity (marked increase in liver weight) and an effect on the
adrenal gland (increase in weight and cortical vacuolation). At a dose
of 5 mg/kg/day, the following changes were not considered
toxicologically significant: a slight increase in adrenal weight
relative to body weight in males, and a slight adaptive effect in the
liver of one male dog considered to be abnormally susceptible. These
changes are of no toxicological significance.
The resulting NOEL from this study is 0.5 mg/kg/day. Based on the
EPA review of tralkoxydim toxicity data, the NOEL from this study was
recommended for use in establishing a provisional RfD.
The resulting RfD, with an uncertainty factor of 100 is 0.005 mg/
kg/day.
6. Animal metabolism. Tralkoxydim is well absorbed and completely
metabolized in the rat. Excretion is rapid and there is no accumulation
of tralkoxydim or metabolites. There are no significant plant
metabolites that are not animal metabolites.
7. Metabolite toxicology. Toxicity testing results for the
tralkoxydim parent compound is indicative of any metabolites, either in
the plant or animal.
C. Aggregate Exposure
1. Dietary exposure (Food). Tralkoxydim is to be used on wheat and
barley crops, only. For the purposes of assessing the potential dietary
exposure, ZENECA estimated aggregate exposure based on the Theoretical
Maximum Residue Contribution (TMRC) from the tolerances of tralkoxydim
on wheat at 0.1 ppm and barley at 0.1 ppm. This is a worst case
estimate of aggregate exposure and assumes 100% of the wheat and barley
crops in the United States will have residues of tralkoxydim at the 0.1
ppm. Dietary exposure to residues of tralkoxydim in or on food
[[Page 35812]]
will be limited to residues on wheat and barley, and food derived from
wheat and barley. Based on animal metabolism data and because there are
no residues on the crops at time of harvest or at grazing intervals, we
have concluded that there is reasonable expectation that no measurable
residues of tralkoxydim will occur in meat, milk, poultry, or eggs from
this use. Since tralkoxydim is a new herbicide, there are no other
established U.S. tolerances for tralkoxydim.
Due to no detectable residues in grain at harvest, even after
processing, the dietary risk assessment has been conducted on the basis
of the limit of quantification of 0.1 mg/kg. This is significantly
above (5 x ) the limit of detection of tralkoxydim residues of 0.02
mg/kg determined by ZENECA's analytical methods used in the magnitude
of residue studies. However, even using a tolerance level of 0.1 mg/kg
(limit of quantification) the chronic assessment for tralkoxydim
indicates less than 10% of the RfD is consumed, for any given
subpopulation, even assuming 100% market share. Based on a review of
available toxicity data for tralkoxydim, there are no toxicological
endpoints of concern for acute dietary risk.
Agricultural use of tralkoxydim on wheat and barley, therefore,
does not represent an acute or chronic risk to the U.S. population,
infants, children, or any other of the 23 subpopulations evaluated in
this assessment.
2. Drinking water. Based on the available studies, exposures are
not anticipated to residues of tralkoxydim in drinking water.
Tralkoxydim does not leach. It is unlikely that tralkoxydim would be in
drinking water. Tralkoxydim is unlikely to enter surface water bodies
to any significant degree except by direct accidental over-spray.
Should this arise, tralkoxydim will be readily degraded by one or more
of a number of contributory processes; studies have shown that
degradation in flooded anaerobic soil occurs with a half-life of
approximately 25 days, aqueous hydrolysis (pH 5) with a half-life of
less than 7 days and aqueous photolysis also with a half-life of less
than 7 days. All these processes will ensure that any tralkoxydim
entering surface water bodies will be short-lived and tralkoxydim will
not result in any significant contamination of potential drinking water
sources. Therefore, it is not appropriate to assess aggregate exposure
from drinking water.
3. Non-dietary exposure. Since tralkoxydim is not registered for
residential or turf uses, and does not represent a groundwater
contamination concern, exposures from other than dietary or
occupational sources are extremely unlikely.
D. Cumulative Effects
Tralkoxydim is a new class of chemistry for herbicides used on
wheat and barley. Although tralkoxydim is in the chemical class of
compounds called cyclohexanediones, it is the only herbicide in this
class to be used on wheat and barley crops. No evidence or information
exists to suggest that the toxic effects produced by tralkoxydim would
be cumulative with those of any other chemical compound.
E. Safety Determination
1. U.S. population. Using the conservative assumptions described
above, based on the completeness and reliability of the toxicity data,
the aggregate exposure to tralkoxydim will utilize less than 4% of the
RfD for the U.S. Population. EPA generally has no concern for exposures
below 100 percent of the RfD. There is reasonable certainty that no
harm will result from aggregate exposure to residues of tralkoxydim,
including all anticipated dietary exposure.
2. Infants and children. In assessing the potential for additional
sensitivity for infants and children to residues of tralkoxydim, the
three-generation reproductive study in rats and the developmental
toxicity studies in the rat and rabbit were considered. Tralkoxydim
showed no evidence of reproductive toxicity. Tralkoxydim caused no
developmental toxicity in the rabbit. At a dose of 30 mg/kg/day,
tralkoxydim caused some developmental effects in the rat manifested by
skeletal defects including single fused or misshapen centra. The NOEL
for developmental toxicity was established at 3 mg/kg/day.
Based on the current toxicological data requirements, the database
relative to pre- and post-natal effects for children is complete.
Further, for the chemical tralkoxydim, the NOEL at 0.5 mg/kg/day from
the dog feeding study which was used to calculate the RfD, is already
lower than the NOEL from the developmental study in rats by a factor of
approximately 10-fold. In addition, residue field trials have shown
that there are no detectable residues of tralkoxydim on wheat and
barley, indicating negligible exposure potential. Therefore, an
additional uncertainty factor is not warranted and the RfD at 0.005 mg/
kg/day is appropriate for assessing aggregate risk to infants and
children.
The percentage of the RfD that will be utilized by aggregate
exposure to tolerance level residues of tralkoxydim are: 2% for nursing
infants, 6% for children 1-6 years, and 5% for children 7-12 years.
Therefore, there is reasonable certainty that there will be no harm to
these sensitive subgroups of the U.S. population. The agricultural use
of tralkoxydim on wheat and barley does not represent an acute or
chronic risk to the U.S. population, infants, children or any of the 23
subgroups that were evaluated.
F. International Tolerances
There are no Codex Maximum Residue Levels established for
tralkoxydim. (PM 25)
[FR Doc. 97-17176 Filed 7-1-97; 8:45 am]
BILLING CODE 6560-50-F
