[Federal Register Volume 62, Number 63 (Wednesday, April 2, 1997)]
[Notices]
[Pages 15690-15698]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-8397]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-723; FRL-5593-9]
Notice of Filing of Pesticide Petitions
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
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SUMMARY: This notice announces the initial filing of pesticide
petitions proposing the establishment of regulations for residues of
certain pesticide chemicals in or on various agricultural commodities.
DATES: Comments, identified by the docket control number PF-723, must
be received on or before May 2, 1997.
ADDRESSES: By mail submit written comments to: Public Response and
Program Resources Branch, Field Operations Divison (7505C), Office of
Pesticides Programs, Environmental 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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Connie Welch (PM 21).......... Rm. 227, CM #2, 703- 1921 Jefferson
305-6226, e- Davis Hwy,
mail:[email protected] Arlington, VA
mail.epa.gov.
Cynthia Giles-Parker (PM 22).. Rm. 229, CM #2, 703- Do.
305-5540, e-mail:
parker.cynthia@epamai.
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SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions as
follows proposing the establishment and/or amendment of regulations for
residues of certain pesticide chemicals in or on various raw
agricultural commodities under section 408 of the Federal Food, Drug,
and Comestic Act (FFDCA), 21 U.S.C. 346a. EPA has determined that these
petitions contain data or information regarding the elements set forth
in section 408(d)(2); however, EPA has not fully evaluated the
sufficiency of the submitted data at this time or whether the data
supports grantinig 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-723 (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
[[Page 15691]]
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 file format or ASCII
file format. All comments and data in electronic form must be
identified by the docket number (insert docket number) and appropriate
petition number. Electronic comments on this proposed rule 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: March 24, 1997.
Stephen L. Johnson,
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's Corporation
PP 6F4631
EPA has received a pesticide petition (PP 6F4631) from Bayer
Corporation, 8400 Hawthorne Road, Kansas City, MO 64120-0013, proposing
pursuant to section 408(d) of the Federal Food, Drug and Cosmetic Act,
21 U.S.C. 346a(d), to amend 40 CFR Part 180 by establishing tolerances
for residues of the herbicide, FOE 5043, N-(4-Fluorophenyl)-N-(1-
methylethyl)-2[[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]oxy]acetamide
in or on the raw agricultural commodities, field corn grain at 0.05
parts per million (ppm), field corn forage at 0.4 ppm, field corn
stover (fodder) at 0.4 ppm, soybean seed at 0.1 ppm, milk at 0.01 ppm,
meat at 0.05 ppm, and meat byproducts at 0.05 ppm. The proposed
analytical method is gas chromatography/mass spectrometry with selected
ion monitoring. (PM 22)
1. Chemical uses. FOE 5043 use on field corn and soybeans provides
selective weed control for a wide spectrum of annual grasses and small-
seeded broadleaf weeds, with exceptional strength on barnyard grass,
large crabgrass, fall panicum and foxtail species. Application
technique: Products containing FOE 5043 can be applied preplant
surface, preplant incorporated, or preemergence for control of emerging
weeds. Applications can be made up to 45 days before planting.
Applications may be made using standard low pressure ground herbicide
boom sprayers equipped with suitable nozzles and screens. The products
containing FOE 5043 may be applied either as a single or a split
application. Application rates range from 0.442 to 0.884 pounds active
ingredient (a.i.) of FOE 5043 per acre depending on the soil texture
and soil organic matter content. Tank mix combinations with selected
products may provide additional weed control.
2. FOE 5043 Safety. Bayer has submitted over 65 separate toxicology
studies in support of tolerances for FOE 5043. Among the submissions, a
finding of particular interest was the observation that in the long-
term data compiled for FOE 5043, provided no indications of a potential
to induce either carcinogenic or reproductive signs of toxicity. In
addition, developmental no-observed-adverse effects levels (NOAELs) of
25 milligrams body weight per day (mg/kg bwt/day) were established for
both the rat and rabbit.
The following mammalian toxicity studies have been conducted to
support the tolerance of AXIOM DF (contains FOE 5043 and metribuzin):
i. A rat acute oral study with an LD50 of 2,347 mg/kg (male)
and 2,027 mg/kg (female).
ii. A rabbit acute dermal with an LD50 of > 2,000 mg/kg.
iii. A rat acute inhalation with an LD50 of > 977 mg/m3.
iv. A primary eye irritation study in the rabbit which showed mild
irritation.
v. A primary dermal irritation study which showed no irritation.
vi. A primary dermal sensitization study which showed no
sensitization.
The following mammalian toxicity studies, derived from exposure to
the technical form of the chemical, have been conducted to support the
tolerance of FOE 5043:
i. A rat acute oral study with an LD50 of 1,617 mg/kg (male)
and 589 mg/kg (female).
ii. A rat acute dermal LD50 of 2,000 mg/kg bwt.
iii. A rat acute inhalation LC50 of 3,740 mg/m3 (male and
female).
iv. A primary eye irritation study in the rabbit which showed no
irritation.
v. A primary dermal irritation study which showed no irritation.
vi. A primary dermal sensitization study which showed no
sensitization.
vii. An acute neurotoxicity study with a no-observed effect level
(NOEL) for FOB, motor and locomotor activity of 75 mg/kg bwt/day for
males and females.
viii. A 90-day feeding study in the rat with a NOEL of 1.7 mg/kg
bwt/day.
ix. A 90-day subchronic neurotoxicity study in the rat with a
neurotoxicity and overall NOEL of 120 ppm.
x. A 24-months chronic feeding/oncogenicity study in the rat with
an overall NOEL of 1.2 mg/kg bwt/day in males and females based on
liver, kidney, hematologic and thyroid effects. There was no evidence
of an oncogenic response.
xi. A 90-day feeding study in dogs with a NOEL of 50 ppm, based on
liver hematology, and thyroid effects.
xii. A 12-month feeding study in dogs with a NOEL of 40 ppm, based
on hematology and thyroid effects.
xiii. A mouse oncogenicity study which provided no evidence of
oncogenicity.
xiv. An oral teratology study in the rat with maternal and
developmental NOAELs of 25 mg/kg bwt/day.
xv. An oral teratology study in the rabbit with maternal and fetal
NOELs of 5 and 25 mg/kg bwt/day respectively.
xvi. An two-generation reproduction study in the rat with a NOEL
for reproductive and parental toxicity of 500 and 20 ppm, respectively.
xvii. Ames assay: Negative
xviii. Unscheduled DNA synthesis: Negative
xix. Mouse Micronucleus Assay: Negative.
3. Threshold effects-- chronic effects. Based on the available
chronic toxicity data, Bayer believes the Reference Dose (RfD) for FOE
5043 should be 0.0114 mg/kg/day. The RfD for FOE 5043 is based on a 1
year chronic toxicity study in the dog with a threshold No Observed
Effect Level (NOEL) of 1.14 mg/kg/day and an uncertainty factor of 100.
Acute toxicity. EPA recently proposed a tiered approach to estimate
acute dietary exposure. The methods proposed by the EPA were reviewed
and supported by the FIFRA Scientific Advisory Panel (SAP, 1995). EPA's
Tier 1 method is based on the assumption that residue concentrations do
not vary. The analysis assumes that all residues have the same
magnitude, typically the highest field trial residue or tolerance
value. This value is assumed for all
[[Page 15692]]
points along the consumption distribution, resulting in a distribution
of dietary exposure.
For the acute analysis for FOE 5043, a Tier 1 analysis was
conducted for the overall U.S. population, infants, children 1 to 6
years of age, females 13 years and older, and males 13 years and older.
Using the NOEL of 138 mg/kg derived from the acute oral toxicity study
in rats, the following margins of exposure were calculated (margins of
exposure of 100 or more are considered satisfactory):
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Population Group Margin of Exposure
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U.S. Population-All Seasons............... 94,741
Infants................................... 64,986
Children 1 to 6........................... 76,494
Women 13 to 50 years old.................. 191,418
Men 13 years and older.................... 109,805
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4. Non-threshold Effects-- carcinogenicity. Using the Guidelines
for Carcinogen Risk Assessment, Bayer believes FOE 5043 to be in Group
E for carcinogenicity--no evidence of carcinogenicity--based on the
results of carcinogenicity studies in three species. There was no
evidence of carcinogenicity in an 18-month feeding study in mice, a 2-
year feeding study in rats, or a 1-year feeding study in dogs at the
dose levels tested. The doses tested are adequate for identifying a
cancer risk. Thus, a cancer risk assessment should not be necessary for
FOE 5043.
5. Aggregate Exposure. For purposes of assessing the potential
dietary exposure under the proposed tolerances for FOE 5043, the
estimated aggregate exposure was based on the Theoretical Maximum
Residue Concentrations (TMRC) and the proposed tolerances (The TMRC is
a worst case estimate of dietary exposure since it is assumed that 100
% of all crops for which tolerances are established are treated and
that pesticide residues are present at the tolerance levels.).
Registration for FOE 5043 and AXIOM are currently being sought on field
corn and soybeans. FOE 5043 and AXIOM are not registered for any uses.
Tolerances are proposed (pesticide petition number 6F 4631) for FOE
5043 on the following Raw Agricultural Commodities (RAC); field corn
grain (0.05 ppm), forage (0.4 ppm) and stover (fodder) (0.4 ppm),
soybean seed (0.1 ppm), milk (0.01 ppm), meat (0.05 ppm), and meat
byproducts (0.05 ppm). The TMRC is obtained by multiplying the
tolerance level for these commodities by consumption data which
estimates the amounts of corn and soybean products eaten by various
human population subgroups. Tolerances are proposed for milk, meat and
meat byproducts because residues for FOE 5043 can be transferred from
corn and soybean based feeds through livestock to humans.
This dietary exposure estimate assumes that 100% of these crops are
treated with FOE 5043 and that the residues of FOE 5043 found in these
crops would occur at the proposed tolerance levels. These assumptions
result in an overestimate of exposure. In making a safety determination
for these tolerances this conservative exposure estimate has been taken
into account.
Other potential sources of exposure of the general population to
residues of FOE 5043 are residues in drinking water and exposure from
non-occupational sources. In ongoing ground water monitoring studies,
trace levels of FOE 5043 residues (less that 1 part per billion (ppb)
total residues) have been detected in ground water. These studies are
being performed at sites with vulnerable shallow aquifers and large
amounts of irrigation are being applied monthly. The highest residue
level detected is well below the anticipated life-time Health Advisory
Level of 84 ppb. If residues of FOE 5043 do occur in ground water used
for drinking water they will be far below the level which causes
concern. Based on the available data, no significant residues of FOE
5043 are anticipated to occur in surface water used for drinking water.
Since registration is not being sought for any residential or homeowner
uses no other potential for exposure to FOE 5043 residues exists.
The toxicological profile for FOE 5043 is fundamentally
characterized by structural- and functional-related alterations in
thyroid, hematologic and hepatic parameters. These sort of changes are
not uncommon among herbicides. Since residues of FOE 5043 and its
degradates will occur in raw agricultural commodities and processed
foods in the high parts per billion or low parts per million range
there is no compelling evidence that suggests a cumulative effect
(i.e., potentiated, additive, or synergistic response) might occur or
be anticipated in the human following exposure to multiple chemical
agents with similar toxicological profiles and/or mechanisms of
toxicity.
6. Determination of safety for U.S. population--Reference dose
(RfD). Using the conservative exposure assumptions described above,
based on the completeness and reliability of the toxicity data, the
aggregate exposure to FOE 5043 will utilize 2.1% of the RfD for the
U.S. population. EPA generally has no concern for exposures below 100 %
of the RfD. Therefore, based on the completeness and reliability of the
toxicity data and the conservative exposure assessment, Bayer concludes
that there is a reasonable certainty that no harm will result from
aggregate exposure to residues of FOE 5043, including all anticipated
dietary exposure and all other non-occupational exposures.
7. Determination of Safety for Infants and Children. The
possibility of FOE 5043 induced developmental toxicity was suggested in
preliminary and non-definitive toxicity studies using rats (> 175 mg/kg
bwt/day) and rabbits (> 125 mg/kg bwt/day). However NOAELs for
developmental effects were ultimately established in the definitive
studies. Those values, as mentioned previously, were 25 mg/kg bwt/day
in the rat and 25 mg/kg bwt/day in the rabbit.
Reference Dose (RfD). Using the conservative exposure assumptions
described previously, Bayer has concluded that the percent of the RfD
utilized by aggregate exposure to residues of FOE 5043 ranges from 1.1
% for non-nursing infants, up to 5.2 % for children 1 to 6 years old.
EPA generally has no concern for exposure below 100 % of the Reference
Dose. Therefore, based on the completeness and reliability of the
toxicity data and the conservative exposure assessment, Bayer concludes
that there is a reasonable certainty that no harm will result to
infants and children from aggregate exposure to the residues of FOE
5043, including all anticipated dietary exposure and all other non-
occupational exposures.
8. Estrogenic Effects. No specific tests have been conducted with
FOE 5043 to determine whether the pesticide may have an effect in
humans that is similar to an effect produced by a naturally occurring
estrogen or other endocrine effects.
9. Chemical Residue. The qualitative nature of the residues in
plants and animals is adequately understood for the purposes of
registration. Residues of FOE 5043 do concentrate slightly (1.6x) in
the processed commodity of corn grits. No tolerance has been proposed
for residue of FOE 5043 in corn grits because anticipated residues are
less than two times the limit of quantitation for the analytical
method. There are no Codex maximum residue levels established for
residues of FOE 5043 on any crop. Bayer has submitted a practical
analytical method for detecting and measuring levels of FOE 5043 in or
on food with a limit of detection that allows monitoring of food with
residues at or above the proposed tolerance levels. EPA will provide
information on
[[Page 15693]]
this method to FDA. The method is available to anyone who is interested
in pesticide residue enforcement from the EPA's Field Operations
Division, Office of Pesticide Programs.
Fifty-five separate residue trials have been conducted with FOE
5043 on corn and soybeans. Analysis of these trials shows that the
maximum total combined residue for FOE 5043 and its major metabolites
in any commodity will be at/below 9.75 ppm. Residues occurred at this
level in soybean dry hay. However, no tolerances have been proposed for
residues of FOE 5043 on soybean hay because the proposed labels for
products containing FOE 5043 do not allow livestock to be fed with FOE
5043 treated soybean hay.
Tolerances have been requested for residues of FOE 5043 and its
major metabolites on field corn grain (0.05 ppm), forage (0.4 ppm) and
stover (fodder) (0.4 ppm) and soybean seed (0.1 ppm), milk (0.01 ppm),
meat (0.05 ppm), and meat byproducts (0.05 ppm).
The proposed tolerance levels are adequate to cover residues likely
to be present from the proposed use of FOE 5043. Therefore, no special
processing to reduce the residues will be necessary.
There is no need for tolerances in poultry or eggs since there is
no reasonable expectation of residues in these materials based on the
results of poultry metabolism studies, as well as the corn and soybean
metabolism and rotational crop studies. Calculated transfer factors are
extremely low and maximum expected residues in poultry and eggs would
be in the low parts per billion or high parts per trillion range. The
anticipated residues in poultry tissues and eggs resulting from feeding
poultry FOE 5043 treated corn and or soybeans would be far below the
limit of quantitation of the analytical residue method.
No FOE 5043 food additive tolerances are proposed for field corn
starch (wet milling), field corn refined oil (wet milling), field corn
flour (dry milling) and field corn refined oil (dry milling) because no
residues were detected above the limit of quantitation in this
processed commodity.
Additionally, no FOE 5043 food additive tolerances are proposed in
field corn grits (dry milling) field corn meal (dry milling), soybean
meal, soybean hulls, and soybean refined oil because the measured
concentration, when adjusted for the exaggerated application rate, was
less that two times the limit of quantitation.
No feed additive tolerances are proposed for FOE 5043 in the
aspirated grain fractions of corn and soybeans. With pre-plant and or
pre-emergent modes of application for AXIOM DF and FOE 5043 DF, no
residues were expected on the seed surface in the corn and soybean
magnitude of residue studies. Therefore, no aspirated grain fractions
were collected for analysis. A tolerance has not been proposed for
soybean forage because feeding soybean hay and forage (silage) to
livestock animals is not permitted by the proposed label.
Also, no feed additive tolerances are proposed for soybean meal or
hulls since the measured concentration in the soybean processing study
for these feeds, when adjusted for the exaggerated application rate,
was less that two times the limit of quantitation.
No tolerances are proposed for corn milled by-products. Table II
(September 1995) advises use residue data for corn dry-milled processed
commodities having the highest residues, excluding oils. No residues
were detected in the dry-milled processed commodities above the limit
of quantitation.
10. Environmental Fate. Laboratory studies indicate that FOE 5043
residue has the potential to be moderately mobile in soil. However the
results of field dissipation studies performed in Wisconsin and North
Carolina, both corn and/or soybean producing states, indicate that
downward movement of FOE 5043 residue is limited, with no quantifiable
residues being found below 18 inches. These studies were conducted
under conditions conducive to downward movement of FOE 5043 and
degradates (very high sand content, low organic matter, and large
volumes of applied irrigation).
FOE 5043 has been found to be stable to chemical hydrolysis in the
pH range of environmental concern. The compound is also stable in water
and soil when exposed to artificial sunlight.
Microbial degradation is the principal means of dissipation in
soil. Half-lives for aerobic microbial degradation range from 10 to 34
days in varying soil types at the anticipated field application rate.
Degradation of FOE 5043 in soil under aerobic conditions occurs by
cleavage of the thiadiazole ring to form 3-trifluoromethyl-1,3,4-
thiadiazol-2(3H)one (FOE thiadone) and the corresponding alcohol, N-(4-
flurophenyl)-2-hydroxy-N-(1-methylethyl)acetamide. The FOE thiadone is
further metabolized to CO2, and the alcohol is subsequently oxidized to
[4-flurophenyl)(1-methylethyl)amino]oxoacetic acid. Another major
degradation product of FOE 5043 is 4-fluoro-N-methylethylaniline-
sulfoacetamide which is proposed to form through the oxidation of a
cysteine conjugate intermediate. (PM 22)
PP 5F4577
EPA has received a pesticide petition (PP) 5F4577 from Bayer
Corporation, 8400 Hawthorn Rd., P.O. Box 4913, Kansas City, MO 64120-
0013 proposing, pursuant to section 408(d) of the Federal Food, Drug
and Cosmetic Act (FFDCA), 21 U.S.C. 346a, to amend 40 CFR 180.474 by
establishing tolerances for residues of the fungicide tebuconazole in
or on the raw agricultural commodities grass forage at 8.0 ppm and
grass hay at 25.0 ppm and tolerances for residues of the fungicide
tebuconazole in or on the raw agricultural commodities cattle liver at
0.2 ppm, cattle kidney at 0.2 ppm, cattle meat byproducts at 0.2 ppm,
and milk at 0.1 ppm. The proposed analytical method for determining
residues uses gas-liquid chromatography coupled with a thermionic
detector. EPA has determined that the 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. (PM 21)
Tebuconazole is a sterol demethylation inhibitor (DMI) fungicide.
It is systemic and shows activity against rusts (Puccinia spp.) and
powdery mildew infecting grasses grown for seed. Tebuconazole provides
protective activity by preventing completion of the infection process.
It is rapidly absorbed by plants and is translocated systemically in
the young growing tissues.
A. Residue Chemistry
1. Plant and livestock metabolism. Bayer believes the nature of the
residue in plants and animals is adequately understood. The residue of
concern is the parent compound only, as specified in 40 CFR 180.474.
2. Analytical method. Bayer has submitted an enforcement method for
plant commodities has been validated on various commodities. It has
undergone successful EPA validation and has been submitted for
inclusion in PAM II. The method should be adequate for grasses grown
for seed. The animal method has also been approved as an adequate
enforcement method and will be submitted to FDA for inclusion in PAM
II.
3. Magnitude of residue. Nine separate residue trials have been
conducted and submitted to the EPA with tebuconazole on grasses grown
for seed. The EPA has
[[Page 15694]]
determined that these data show that residues of
tebuconazole,-[2-(4-Chlorophenyl)ethyl]--(1,1-
dimethylethyl)-H-1,2,4-triazole-1-eth anol, are not expected to exceed
8 ppm in grass forage and 25 ppm in grass hay as a result of the
proposed use. In addition, the EPA has determined that tolerances are
needed for the following animal commodities: cattle liver, kidney and
meat byproducts at 0.2 ppm and milk at 0.1 ppm. The tolerance
expression for the animal commodities will include the HWG 2061
metabolite,-[2-(4-Chlorophenyl)-ethyl]--[(2-hydroxy-
1,1-dimethyl)ethyl]-1H-1,2,4triazole-1-ethanol, in addition to the
parent.
No processed commodities are associated with the proposed use on
grasses grown for seed. In addition, due to the nature of the crop,
rotational crops will not be an issue.
B. Toxicological Profile of Tebuconazole
1. Acute toxicity. i. Rat acute oral study with an LD50 of >
5,000 mg/kg (male) and 3,933 mg/kg (female)
ii. Rabbit acute dermal of LD50 of > 5,000 mg/kg
iii. Rat acute inhalation of LC50 of > 0.371 mg/l
iv. Primary eye irritation study in the rabbit which showed mild
irritation reversible by day 7
v. Primary dermal irritation study which showed no skin irritation
vi. Primary dermal sensitization study which showed no
sensitization
2. Genotoxicity. i. An Ames mutagenesis study in Salmonella showed
no mutagenicity with or without metabolic activation.
ii. A micronucleus mutagenesis assay study in mice showed no
genotoxicity.
iii. A sister chromatid exchange mutagenesis study using CHO cells
was negative at dose levels 4 to 30 g/mL without activation or
15 to 120 g/mL with activation.
iv. An unscheduled DNA synthesis (UDS) study was negative for UDS
in rat hepatocytes.
3. Reproductive and developmental toxicity. i. A rat oral
developmental toxicity study with a maternal NOEL of 30 milligrams per
kilogram of body weight per day (mg/kg bwtt/day) and an LEL of 60 mg/kg
bwtt/day based on elevation of absolute and relative liver weights. For
developmental toxicity, a NOEL of 30 mg/kg bwtt/day and an LEL of 60
mg/kg bwtt/day was determined, based on delayed ossification of
thoracic, cervical and sacral vertebrae, sternum, fore and hind limbs
and increase in supernumerary ribs.
ii. A rabbit oral developmental toxicity study with a maternal NOEL
of 30 mg/kg bwt/day and an LEL of 100 mg/kg bwt/day based on depression
of body weight gains and food consumption. A developmental NOEL of 30
mg/kg bwt/day and an LEL of 100 mg/kg bwt/day were based on increased
post-implantation losses, from both early and late resorptions and
frank malformations in eight fetuses of five litters.
iii. A mouse oral developmental toxicity study with a maternal NOEL
of 10 mg/kg bwt/day and an LEL of 20 mg/kg bwt/day based on a
supplementary study indicating reduction in hematocrit and histological
changes in liver. A developmental NOEL of 10 mg/kg bwt/day and an LEL
of 30 mg/kg bwt/day based on dose-dependent increases in runts/dam at
30 and 100 mg/kg bwt/day.
iv. A mouse dermal developmental toxicity study with a maternal
NOEL of 30 mg/kg bwt/day and an LEL of 60 mg/kg bwt/day based on a
supplementary study indicating increased liver microsomal enzymes and
histological changes in liver. The NOEL for developmental toxicity in
the dermal study in the mouse is 1,000 mg/kg bwt/day, the highest dose
tested (HDT).
v. A two-generation rat reproduction study with a dietary maternal
NOEL of 15 mg/kg bwt/day (300 ppm) and an LEL of 50 mg/kg bwt/day
(1,000 ppm) based on depressed body weights, increased spleen
hemosiderosis, and decreased liver and kidney weights. A reproductive
NOEL of 15 mg/kg bwt/day (300 ppm) and an LEL of 50 mg/kg bwt/day
(1,000 ppm) were based on neonatal birth weight depression.
4. Subchronic toxicity. i. 28-day feeding study in the rat with a
NOEL of 30 mg/kg/day and a LEL of 100 mg/kg/day based on changes in
hematology and clinical chemistry parameters.
ii. A 90-day rat feeding study with a no-observed-effect level
(NOEL) of 34.8 (mg/kg bwt/day) (400 ppm) and a lowest-effect-level
(LEL) of 171.7 mg/kg bwt/day (1,600 ppm) in males, based on decreased
body weight gains and histological changes in the adrenals. For
females, the NOEL was 10.8 mg/kg bwt/day (100 ppm) and the LEL was 46.5
mg/kg bwt/day (400 ppm) based on decreased body weights, decreased body
weight gains, and histological changes in the adrenals.
iii. A 90-day dog-feeding study with a NOEL of 200 ppm (73.7 mg/kg
bwt/day in males and 73.4 mg/kg bwt/day in females) and an LEL of 1,000
ppm (368.3 mg/kg bwt/day in males and 351.8 mg/kg bwt/day in females).
The LEL was based on decreases in mean body weights, body weight gains,
and food consumption, and an increase in liver N-demethylase activity.
5. Chronic toxicity i. A 2-year rat chronic feeding study defined a
NOEL of 7.4 mg/kg bwt/day (100 ppm) and an LEL of 22.8 mg/kg bwt/day
(300 ppm) based on body weight depression, decreased hemoglobin,
hematocrit, MCV and MCHC, and increased liver microsomal enzymes in
females. Tebuconazole was not oncogenic at the dose levels tested (0,
100, 300, and 1,000 ppm).
ii. A 1-year dog feeding study with a NOEL of 1 mg/kg bwt/day (40
ppm) and an LEL of 5 mg/kg bwt/day (200 ppm), based on lenticular and
corneal opacity and hepatic toxicity in either sex (the current
Reference Dose was determined based on this study). A subsequent 1-year
dog feeding study, using lower doses to further define the NOEL for
tebuconazole, defines a systemic LOEL of 150 ppm (based on adrenal
effects in both sexes) and a systemic NOEL of 100 ppm.
iii. A mouse oncogenicity study at dietary levels of 0, 20, 60, and
80 ppm for 21 months did not reveal any oncogenic effect for
tebuconazole at any dose tested. Because the maximum-tolerated-dose
(MTD) was not reached in this study, the study was classified as
supplementary. A follow-up mouse study at higher doses (0, 500, and
1,500 ppm in the diet), with an MTD at 500 ppm, revealed statistically
significant incidences of hepatocellular adenomas and carcinomas in
males and carcinomas in females. The initial and follow-up studies,
together with supplementary data were classified as core minimum.
6. Animal metabolism. A general rat metabolism study at dietary
levels of 2 and 20 mg/kg showed rapid elimination from the rat in 3
days (some 99% excreted by the feces and urine and 0.0304% in expired
air). Increased concentrations of radioactivity from the active
ingredient and metabolites were found only in the liver. The bones and
the brain were among the tissues showing the least amount of
radioactivity.
7. Metabolite toxicity. The residue of concern in plants is the
parent compound, tebuconazole, only. For animal commodities, the EPA
has determined that the tolerance expression should include the HWG
2061 metabolite, -[2-(4 -Chlorophenyl)-ethyl]--[(2-
hydroxy-1,1-dimethyl)ethyl]-1H-1,2,4triazole-1-ethanol. An acute oral
toxicity study has been submitted to the EPA on this metabolite. This
study shows an oral LD50 of > 5,000 for female rats. This value
indicates that the HWG 2061 metabolite is relatively innocuous and less
acutely toxic than tebuconazole.
[[Page 15695]]
8. Endocrine effects. No special studies investigating potential
estrogenic or endocrine effects of tebuconazole have been conducted.
However, the standard battery of required studies has been completed.
These studies include an evaluation of the potential effects on
reproduction and development, and an evaluation of the pathology of the
endocrine organs following repeated or long-term exposure. These
studies are generally considered to be sufficient to detect any
endocrine effects but no such effects were noted in any of the studies
with either tebuconazole or its metabolites.
9. Carcinogenicity. EPA's Carcinogenicity Peer Review Committee
(CPRC) has classified tebuconazole as a Group C carcinogen (possible
human carcinogen). This classification is based on the Agency's
``Guidelines for Carcinogen Risk Assessment'' published in the Federal
Register of September 24, 1986 (51 FR 33992). The Agency has chosen to
use the reference dose calculations to estimate human dietary risk from
tebuconazole residues. The decision supporting classification of
tebuconazole as a possible human carcinogen (Group C) was primarily
based on the statistically significant increase in the incidence of
hepatocellular adenomas, carcinomas, and combined adenomas/carcinomas
in both sexes of NMRI mice both by positive trend and pairwise
comparison at the highest dose tested.
C. Aggregate Exposure
1. Dietary (food) exposure. For purposes of assessing the potential
dietary exposure from food under the proposed tolerances, Bayer has
been advised that the EPA has estimated exposure based on the
Theoretical Maximum Residue Contribution (TMRC) derived from the
previously established tolerances for tebuconazole on cherries,
peaches, bananas, barley, oats, wheat, and peanuts as well as the
proposed tolerances for tebuconazole on milk at 0.1 ppm and cattle
liver, kidney and meat byproducts at 0.2 ppm. The TMRC is obtained by
using a model which multiplies the tolerance level residue for each
commodity by consumption data which estimate the amount of each
commodity and products derived from the commodities that are eaten by
the U.S. population and various population subgroups. In conducting
this exposure assessment, the EPA has made very conservative
assumptions--100% of all commodities will contain tebuconazole
residues, and those residues would be at the level of the tolerance--
which result in a large overestimate of human exposure. Thus, in making
a safety determination for these tolerances, the Agency took into
account this very conservative exposure assessment.
2. Dietary (drinking water) exposure. There is no Maximum
Contaminant Level established for residues of tebuconazole. Bayer was
advised by the Environmental Fate and Ground Water Branch's (EFGWB) May
26, 1993 memorandum for our application for use on bananas and peanuts
that all environmental fate data requirements for tebuconazole were
satisfied. The EFGWB had determined that tebuconazole is resistant to
most degradative processes in the environment, including hydrolysis,
photolysis in water and aerobic and anaerobic metabolism. Only minor
degradation occurred in soil photolysis studies. The photolytic half-
life of tebuconazole is 19 days. Laboratory and field studies have
shown that the mobility of tebuconazole in soil is minimal. Therefore,
Bayer concludes that tebuconazole bears no apparent risk to ground
water under most circumstances.
3. Non-dietary exposure. Although current registrations and the
proposed use for grasses grown for seed are limited to commercial crop
production, Bayer has submitted an application to register tebuconazole
on turf. Bayer has conducted an exposure study designed to measure the
upper bound acute exposure potential of adults and children from
contact with tebuconazole treated turf. The population considered to
have the greatest potential exposure from contact with pesticide
treated turf soon after pesticides are applied are young children.
Margins of exposure (MOE) of 1,518 8,561 for 10-year-old children and
1,364 - 7,527 for 5-year-old children were estimated by comparing
dermal exposure doses to the tebuconazole no-observable effect level of
1,000 mg/kg/day established in a subacute dermal toxicity study in
rabbits. The estimated safe residue levels for tebuconazole on treated
turf for 10-year-old children ranged from 4.8 - 27.3 g/
cm2 and for 5-year-old children from 4.4 - 24.0 g/
cm2. This compares with the average tebuconazole transferable
residue level of 0.319 g/cm2 present immediately after
the sprays have dried. Bayer concludes that these data indicate that
children can safely contact tebuconazole-treated turf as soon after
application as the spray has dried.
D. Cumulative Effects
At this time, the EPA has not made a determination that
tebuconazole and other substances that may have a common mechanism of
toxicity would have cumulative effects. Therefore, for this tolerance,
Bayer has considered only the potential risks of tebuconazole in its
aggregate exposure.
E. Safety Determination
1. U.S. population. Chronic Dietary Exposure: Based on a complete
and reliable toxicity database, the EPA has adopted an RfD value of
0.03 mg/kg/day. This RfD is based on a 1-year dog study with a NOEL of
2.96 mg/kg/day and an uncertainty factor of 100. Using the conservative
exposure assumptions described above, Bayer has been advised that the
EPA has concluded that aggregate dietary exposure to tebuconazole from
the previously established and the proposed tolerances will utilize 5.1
% of the RfD for the U.S. population (48 states) and 30.7% of the RfD
for the most highly exposed population subgroup (non-nursing infants,
<1 year="" old).="" there="" is="" generally="" no="" concern="" for="" exposures="" below="" 100="" %="" of="" the="" rfd="" because="" the="" rfd="" represents="" the="" level="" at="" or="" below="" which="" daily="" aggregate="" exposure="" over="" a="" lifetime="" will="" not="" pose="" appreciable="" risks="" to="" human="" health.="" therefore,="" bayer="" concludes="" that="" there="" is="" a="" reasonable="" certainty="" that="" no="" harm="" will="" result="" from="" aggregate="" exposure="" to="" tebuconazole.="" 2.="" acute="" dietary="" exposure.="" epa="" recently="" proposed="" a="" tiered="" approach="" to="" estimate="" acute="" dietary="" exposure.="" the="" methods="" proposed="" by="" the="" epa="" were="" reviewed="" and="" supported="" by="" the="" fifra="" scientific="" advisory="" panel="" (sap,="" 1995).="" epa's="" tier="" 1="" method="" is="" based="" on="" the="" assumption="" that="" residue="" concentrations="" do="" not="" vary.="" the="" analysis="" assumes="" that="" all="" residues="" have="" the="" same="" magnitude,="" typically="" the="" highest="" field="" trial="" residue="" or="" tolerance="" value.="" this="" value="" is="" assumed="" for="" all="" points="" along="" the="" consumption="" distribution,="" resulting="" in="" a="" distribution="" of="" dietary="" exposure.="" bayer="" has="" been="" advised="" that="" the="" epa="" conducted="" an="" acute="" dietary="" analysis="" using="" the="" noel="" of="" 10="" mg/kg/day="" for="" developmental="" toxicity="" in="" the="" mouse.="" the="" epa="" has="" calculated="" a="" high="" end="" margin="" of="" exposure="" (moe)="" value="" of="" 1,000="" for="" the="" population="" subgroup="" of="" concern="" (females="" 13+).="" in="" addition,="" bayer="" has="" calculated="" 95th="" percentile="" moe="" for="" the="" following="" population="" groups:="" overall="" u.s.="" population="" (moe="2,528)," infants="" (moe="711)," children="" 1="" to="" 6="" years="" of="" age="" (moe="1,145)" ,="" females="" 13="" years="" and="" older="" (moe="4,285)," and="" males="" 13="" years="" and="" older="" (moe="3,685)." therefore,="" since="" epa="" considers="" values="" of="" 100="" or="" more="" satisfactory,="" there="" is="" no="" concern="" from="" acute="" dietary="" exposure.="" 3.="" infants="" and="" children.="" in="" assessing="" the="" potential="" for="" additional="" sensitivity="" of="" [[page="" 15696]]="" infants="" and="" children="" to="" residues="" of="" tebuconazole,="" the="" data="" from="" developmental="" studies="" in="" both="" rat="" and="" rabbit="" and="" a="" two-generation="" reproduction="" study="" in="" the="" rat="" should="" be="" considered.="" the="" developmental="" toxicity="" studies="" evaluate="" any="" potential="" adverse="" effects="" on="" the="" developing="" animal="" resulting="" from="" pesticide="" exposure="" of="" the="" mother="" during="" prenatal="" development.="" the="" reproduction="" study="" evaluates="" any="" effects="" from="" exposure="" to="" the="" pesticide="" on="" the="" reproductive="" capability="" of="" mating="" animals="" through="" two="" generations,="" as="" well="" as="" any="" observed="" systemic="" toxicity.="" a="" developmental="" toxicity="" study="" in="" the="" rat,="" a="" developmental="" toxicity="" study="" in="" the="" rabbit,="" two="" developmental="" studies="" in="" the="" mouse="" and="" a="" 2-generation="" rat="" reproduction="" study="" have="" been="" conducted="" with="" tebuconazole.="" maternal="" and="" developmental="" toxicity="" noels="" of="" 30="" mg/kg/day="" were="" determined="" in="" the="" rat="" and="" rabbit="" studies.="" an="" oral="" mouse="" developmental="" toxicity="" study="" had="" maternal="" and="" developmental="" toxicity="" noels="" of="" 10="" mg/kg/day="" while="" the="" mouse="" dermal="" developmental="" study="" had="" a="" maternal="" noel="" of="" 30="" mg/kg/day="" and="" a="" developmental="" toxicity="" noel="" of="" 1,000="" mg/kg/day.="" the="" parental="" and="" reproductive="" noels="" in="" the="" 2-="" generation="" rat="" reproduction="" study="" were="" determined="" to="" be="" 15="" mg/kg/day="" (300="" ppm).="" in="" all="" cases,="" the="" reproductive="" and="" developmental="" noels="" were="" greater="" than="" or="" equal="" to="" the="" parental="" noels.="" this="" indicates="" that="" tebuconazole="" does="" not="" pose="" any="" increased="" risk="" to="" infants="" or="" children.="" ffdca="" section="" 408="" provides="" that="" epa="" may="" apply="" an="" additional="" safety="" factor="" for="" infants="" and="" children="" in="" the="" case="" of="" threshold="" effects="" to="" account="" for="" pre-="" and="" post-="" natal="" effects="" and="" the="" completeness="" of="" the="" toxicity="" database.="" based="" on="" current="" toxicological="" data="" requirements,="" the="" toxicology="" database="" for="" tebuconazole="" relative="" to="" pre-="" and="" post-="" natal="" effects="" is="" complete.="" further="" for="" tebuconazole,="" the="" noel="" of="" 2.96="" mg/kg/bwtt="" from="" the="" 1-year="" dog="" study,="" which="" was="" used="" to="" calculate="" the="" rfd,="" is="" already="" lower="" than="" the="" noels="" from="" the="" developmental="" studies="" in="" rats="" (30="" mg/kg="" bwt/day)="" and="" rabbits="" (30="" mg/kg="" bwt/day)="" by="" a="" factor="" of="" 10="" times.="" since="" a="" hundredfold="" uncertainty="" factor="" is="" already="" used="" to="" calculate="" the="" rfd,="" bayer="" surmises="" that="" an="" additional="" uncertainty="" factor="" is="" not="" warranted="" and="" that="" the="" rfd="" at="" 0.03="" mg/kg/bwtt/day="" is="" appropriate="" for="" assessing="" aggregate="" risk="" to="" infants="" and="" children.="" using="" the="" conservative="" exposure="" assumptions,="" bayer="" has="" concluded="" from="" the="" epa's="" recent="" chronic="" dietary="" analysis="" that="" the="" percent="" of="" the="" rfd="" utilized="" by="" aggregate="" exposure="" to="" residues="" of="" tebuconazole="" ranges="" from="" 14.2%="" for="" children="" 1="" to="" 6="" years="" old="" up="" to="" 30.7%="" for="" non-nursing="" infants.="" epa="" generally="" has="" no="" concern="" for="" exposure="" below="" 100="" %="" of="" the="" rfd.="" therefore,="" based="" on="" the="" completeness="" and="" reliability="" of="" the="" toxicity="" data="" and="" the="" conservative="" exposure="" assessment,="" bayer="" concludes="" that="" there="" is="" a="" reasonable="" certainty="" that="" no="" harm="" will="" result="" to="" infants="" and="" children="" from="" aggregate="" exposure="" to="" the="" residues="" of="" tebuconazole,="" including="" all="" anticipated="" dietary="" exposure="" and="" all="" other="" non-="" occupational="" exposures.="" f.="" international="" issues="" no="" codex="" maximum="" residue="" levels="" (mrls)="" have="" been="" established="" for="" residues="" of="" tebuconazole="" on="" any="" crops="" at="" this="" time.="" data="" have="" not="" been="" submitted="" to="" the="" joint="" meeting="" of="" the="" food="" and="" agriculture="" organization="" panel="" of="" experts="" on="" pesticide="" residues="" in="" food="" and="" the="" environment="" and="" the="" world="" health="" organization="" expert="" group="" on="" pesticide="" residues="" (jmpr)="" to="" establish="" codex="" mrls="" for="" grasses="" grown="" for="" seed.="" g.="" mode="" of="" action="" tebuconazole,="" the="" active="" ingredient="" of="" folicur="" 3.6="" f="" is="" a="" sterol="" demethylation="" inhibitor="" (dmi)="" fungicide.="" it="" is="" systemic="" and="" shows="" activity="" against="" rusts="" (puccinia="" spp.)="" and="" powdery="" mildew="" infecting="" grasses="" grown="" for="" seed.="" tebuconazole="" provides="" protective="" activity="" by="" preventing="" completion="" of="" the="" infection="" process="" by="" direct="" inhibition="" of="" sterol="" synthesis.="" it="" is="" rapidly="" absorbed="" by="" plants="" and="" translocated="" systemically="" in="" the="" young="" growing="" tissues.="" 2.="" ciba="" crop="" protection="" 6f4656/6h5746="" epa="" has="" received="" pesticide="" petitions="" (pp)="" 6f4656/6h5746="" from="" ciba="" crop="" protection,="" ciba-geigy="" corporation,="" p.o.="" box="" 18300,="" greensboro,="" nc="" 27419,="" proposing="" pursuant="" to="" section="" 408(d)="" of="" the="" federal="" food,="" drug="" and="" cosmetic="" act="" (ffdca),="" 21="" u.s.c="" 346a,="" to="" amend="" 40="" cfr="" part="" 180="" by="" establishing="" tolerances="" for="" residues="" of="" the="" fungicide="" cyprodinil="" (4-="" cyclopropyl-6-methyl-n-phenyl-2-pyrimidinamine)="" in="" or="" on="" the="" agricultural="" commodities="" almond="" nutmeats="" at="" 0.04="" ppm,="" almond="" hulls="" at="" 0.1="" ppm,="" grapes="" at="" 3.0="" ppm,="" raisins="" at="" 3.0="" ppm,="" the="" pomefruit="" crop="" grouping="" at="" 0.1="" ppm,="" apple="" pomace="" -="" wet="" at="" 0.4="" ppm,="" and="" the="" stone="" fruit="" crop="" grouping="" at="" 2.0="" ppm.="" the="" proposed="" analytical="" method="" for="" determining="" residues="" uses="" high="" performance="" liquid="" chromatography="" with="" uv="" detection.="" epa="" has="" determined="" that="" the="" 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.="" (pm="" 21)="" a.="" cyprodinil="" uses="" cyprodinil="" is="" the="" first="" fungicide="" in="" a="" new="" chemical="" class="" known="" as="" the="" anilinopyrimidine="" and="" is="" active="" against="" important="" botrytis,="" monilinia="" and="" venturia="" diseases="" of="" deciduous="" fruit="" and="" nut="" crops.="" cyprodinil="" with="" a="" unique="" mode="" of="" action,="" controls="" pathogens="" resistant="" to="" other="" chemical="" classes.="" application="" rates="" range="" from="" 0.125="" to="" 0.5="" lb="" active="" ingredient="" per="" acre="" per="" application="" depending="" upon="" disease="" and="" time="" of="" application.="" b.="" residue="" chemistry="" 1.="" metabolism.="" ciba="" believes="" the="" metabolism="" of="" cyprodinil="" has="" been="" well="" characterized="" in="" plants="" and="" animals.="" the="" metabolism="" profile="" supports="" the="" use="" of="" an="" analytical="" enforcement="" method="" that="" accounts="" for="" only="" parent="" cyprodinil.="" 2.="" analytical="" methodology.="" ciba="" has="" submitted="" a="" practical="" analytical="" method="" involving="" extraction,="" filtration,="" and="" solid="" phase="" cleanup="" of="" samples="" with="" analysis="" by="" hplc="" and="" uv.="" the="" limits="" of="" quantitation="" (loq)="" for="" various="" commodities="" are="" as="" follows:="" fruit,="" grain,="" juice="" -="" 0.02="" ppm;="" forage,="" fodder,="" straw="" -="" 0.05="" ppm;="" and="" grapes="" -="" 0.01="" ppm.="" c.="" magnitude="" of="" residue="" this="" petition="" is="" supported="" by="" field="" residue="" trials="" conducted="" on="" almonds,="" grapes,="" and="" representative="" members="" of="" the="" pome="" fruit="" and="" the="" stone="" fruit="" crop="" groupings.="" all="" samples="" were="" analyzed="" for="" parent="" residues="" of="" cyprodinil.="" residues="" found="" in="" the="" almond="" nutmeats="" and="" hulls="" were="" all="" less="" than="" respective="" loq's="" of="" 0.02="" ppm="" and="" 0.05="" ppm.="" tolerances="" at="" twice="" the="" loq="" for="" these="" commodities="" have="" been="" proposed.="" in="" grapes,="" the="" maximum="" residues="" found="" for="" fresh="" fruit="" and="" raisins="" were="" 2.0="" ppm="" and="" 2.9="" ppm,="" respectively.="" residues="" did="" not="" concentrate="" in="" grape="" juice.="" tolerances="" of="" 3.0="" ppm="" for="" grapes="" and="" raisins="" have="" been="" requested.="" in="" pome="" fruit,="" maximum="" residues="" ranged="" from="" 0.030="" ppm="" to="" 0.061="" ppm.="" the="" results="" of="" a="" processing="" study="" on="" apples="" using="" exaggerated="" rates="" showed="" concentration="" of="" residues="" in="" wet="" pomace="" with="" an="" average="" concentration="" factor="" of="" 4x.="" residues="" in="" apple="" juice="" were="" not="" detectable="" at="" the="" loq="">< 0.01="" ppm).="" tolerances="" of="" 0.1="" ppm="" for="" the="" rac="" of="" the="" pome="" fruit="" crop="" grouping="" and="" 0.4="" ppm="" for="" wet="" apple="" pomace="" have="" been="" proposed.="" in="" stone="" fruit,="" maximum="" [[page="" 15697]]="" residues="" ranged="" from="" 0.82="" ppm="" to="" 1.7="" ppm.="" a="" tolerance="" of="" 2.0="" ppm="" has="" been="" proposed="" for="" the="" stone="" fruit="" crop="" grouping.="" based="" upon="" the="" results="" of="" a="" three="" level="" dairy="" feeding="" study,="" ciba="" believes="" no="" transfer="" of="" residue="" to="" animals="" is="" expected="" through="" their="" diet="" and="" that="" tolerances="" in="" milk,="" meat,="" poultry,="" and="" eggs="" are="" not="" required.="" d.="" international="" tolerances="" there="" are="" no="" codex="" alimentarius="" commission="" (codex)="" maximum="" residue="" levels="" (mrl's)="" established="" for="" residues="" of="" cyprodinil="" in="" or="" on="" raw="" agricultural="" commodities.="" e.="" toxicological="" profile="" of="" cyprodinil="" the="" following="" mammilian="" toxicity="" studies="" have="" been="" conducted="" to="" support="" the="" tolerances="" of="" cyprodinil:="" 1.="" a="" rat="" acute="" oral="" study="" for="" cyprodinil="" with="" a="">50 of 2,796
mg/kg.
2. A rat acute dermal study for cyprodinil with a LD50 > 2,000
mg/kg.
3. A rat inhalation study for cyprodinil with a LC50 > 1.2 mg/
liter air.
4. A primary eye irritation study in rabbits showing cyprodinil as
minimally irritating.
5. A primary dermal irritation study in rabbits showing cyprodinil
as slightly irritating.
6. A skin sensitization study in guinea pigs showing cyprodinil as
a weak sensitizer.
7. A 28-day dermal study in the rat with a NOEL of 5 mg/kg based on
clinical signs.
8. A 90-day feeding study in the dog with a NOEL of 1500 ppm (37.5
mg/kg) based on reduced food intake and body weight.
9. A 90-day feeding study in the mouse with a NOEL of 500 ppm (75
mg/kg) based on liver histologic changes.
10. A 90-day feeding study in the rat with a NOEL of 50 ppm (5 mg/
kg) based on hematologic and histologic findings.
11. A 12-month feeding study in the dog with a NOEL of 2,500 ppm
(62.5 mg/kg) based on liver histologic changes.
12. An 18-month oncogenicity feeding study in the mouse with a NOEL
of 2,000 ppm (300 mg/kg). The MTD was 5,000 ppm based on reduction in
body weight gain and no evidence of oncogenicity was seen.
13. A 24-month chronic feeding/oncogenicity study in the rat with a
NOEL of 75 ppm (3.75 mg/kg) based on hematologic and histologic
findings. The MTD was 2,000 ppm based on liver histopathology and no
evidence of oncogenicity was seen.
14. An oral teratology study in the rat with a maternal NOEL of 200
mg/kg based on reductions in body weight gain and food consumption and
a fetal NOEL of 200 mg/kg based on decreased pup weight and delayed
skeletal growth at 1,000 mg/kg.
15. An oral teratology study in the rabbit with a maternal NOEL of
150 mg/kg based on reduction in body weight gain and a fetal NOEL of
400 mg/kg based on the absence of any fetal effects.
16. A 2-generation reproduction study in the rat with a systemic
NOEL of 100 ppm and a fetal NOEL of 1,000 ppm (100 mg/kg). A slight
decrease in pup weight at birth and subsequent body weight gain during
the lactation phase was observed only at the maternally toxic dose of
4,000 ppm without any effects on reproduction and fertility.
17. In vitro gene mutation test: Ames assay - negative; Chinese
hamster V79 cell test - negative; rat hepatocyte DNA repair test -
negative.
18. In vitro chromosome test: Chinese hamster ovary cell
cytogenetic test - negative.
19. In vivo mutagenicity test: mouse bone marrow test - negative.
F. Threshold Effects
1. Chronic effects. Based on the available chronic toxicity data,
Ciba Crop Protection believes the Reference dose (RfD) for cyprodinil
is 0.0375 mg/kg/day. This RfD is based on a 2-year feeding study in
rats with aNo-Observed Effect Level (NOEL) of 3.75 mg/kg/day (75 ppm)
and an uncertainly factor of 100. No additional modifying factor for
the nature of effects was judged to be necessary as liver sinusoidal
dilatation was the most sensitive indicator of toxicity in that study.
2. Acute toxicity. The risk from acute dietary exposure to
cyprodinil is considered to be very low. The lowest NOEL in a short
term exposure scenario, identified as 150 mg/kg in the rabbit
teratology study, is fortyfold higher than the chronic NOEL. Since
chronic exposure assessment did not result in any margin of exposure
less than 400 for even the most impacted population subgroup, Ciba
believes the margin of exposure is greater than 100 for any population
subgroups; EPA considers margins of exposure of 100 or more as
satisfactory.
G. Non-threshold Effects
Using the Guidelines for Carcinogenic Risk Assessment published
September 24, 1986 (51 FR 33992), Ciba believes cyprodinil to be in
Group ``E''( no evidence of carcinogenicity. There was no evidence of
carcinogenicity in an 18-month feed study in mice and a 24-month
feeding in rats. Dosage levels in both the mouse and the rat studies
were adequate for identifying a cancer risk.
H. Aggregate Exposure
1. Dietary exposure. For the purposes of assessing the potential
dietary exposure under the proposed tolerances, Ciba has estimated
aggregate exposure based upon the Theoretical Maximum Residue
Concentration (TMRC) from the requested tolerances: Almonds -- 0.04 ppm
for the raw agricultural commodity (RAC) and 0.1 ppm for hulls; Grapes
-- 3.0 ppm for the RAC and 3.0 ppm for raisins; Pome Fruit Crop
Grouping -- 0.1 ppm for the RAC and 0.4 ppm for apple wet pomace; and
Stone Fruit Crop Grouping -- 2.0 ppm for the RAC. The TMRC is a ``worst
case'' estimate of dietary exposure since it assumes 100 % of all crops
for which tolerances are established are treated and that pesticide
residues are at the tolerance levels. In conducting this exposure
assessment, Ciba has made very conservative assumptions -- 100% of all
almonds, grapes, pome fruit and stone fruit commodities will contain
cyprodinil residues at tolerance levels -- which result in an
overestimate of human exposure.
2. Drinking water exposure. Cyprodinil is rapidly degraded in the
environment via photolysis and microbial degradation; aqueous and soil
photolysis half lives for cyprodinil are 12 days and 67 days,
respectively. The aerobic metabolism half life is 25 days and the
leaching potential for cyprodinil is low (Koc = 1,550 to 2,030).
Based on these data, Ciba does not anticipate exposure to residue of
cyprodinil in drinking water.
3. Non-dietary exposure. Ciba believes that the potential for non-
occupational exposure to the general public is unlikely except for
potential residues in food crops discussed above. The proposed uses for
cyprodinil are for agricultural crops and the product is not used
residentially in or around the home.
Ciba believes that consideration of a common mechanism of toxicity
is not appropriate at this time since there is no information to
indicate that toxic effects produced by cyprodinil would be cumulative
with those of any other chemicals. Consequently, Ciba is considering
only the potential exposure to cyprodinil in its aggregate risk
assessment.
I. Safety To the U.S. Population
Reference dose. Using the conservative exposure assumptions
described above and based on the completeness and reliability of the
toxicity data base for cyprodinil, Ciba
[[Page 15698]]
has calculated aggregate exposure levels for this chemical. Based on
chronic toxicity endpoints, only 4% of the RfD will be utilized for the
U.S. general population. EPA usually 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. Ciba concludes that there is a
reasonable certainty that no harm will result from aggregate exposure
to cyprodinil residues.
J. Safety to Infants and Children
Developmental delays (reduced pup weight and ossification) were
observed in the rat teratology study and 2-generation rat reproduction
study at maternally toxic doses. The lowest NOEL for this effect was
established in the 2-generation study at 100 mg/kg (1,000 ppm). The
finding is judged to be a nonspecific, secondary effect of maternal
toxicity. No developmental toxicity was observed in the rabbit
teratology study.
Reference dose. Using the same conservative exposure assumptions as
employed for the determination in the general population, Ciba has
calculated the utilization of RfD by aggregate exposure to residues of
cyprodinil to be 12% for nursing infants less than 1 year old, 22% for
non-nursing infants less than 1 year old, 12% for children 1 to 6 years
old, and 6% for children 7 to 12 years old. Ciba believes that under
the worst case assumptions which overestimate exposure to infants and
children, there is a reasonable certainty that no harm will result to
infants and children from aggregate exposure to cyprodinil residues.
K. Estrogenic effects
Cyprodinil does not belong to a class of chemicals known or
suspected of having adverse effects on the endocrine system.
Developmental toxicity studies in rats and rabbits and a reproduction
study in rats gave no indication that cyprodinil might have any effects
on endocrine function related to development and reproduction. The
chronic studies also showed no evidence of a long-term effect related
to the endocrine system.
[FR Doc. 97-8397 Filed 4-1-97; 8:45 am]
BILLING CODE 6560-50-F
