[Federal Register Volume 61, Number 247 (Monday, December 23, 1996)]
[Notices]
[Pages 67544-67549]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-32359]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-683; FRL-5577-1]
Rhone-Poulenc Ag Company; Pesticide Tolerance Petition Filing
AGENCY: Environmental Protection Agency (EPA).
[[Page 67545]]
ACTION: Notice of filing.
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SUMMARY: This notice is a summary of a pesticide petition proposing the
establishment of a regulation for residues of cyclanilide in or on
cottonseed, cotton gin byproducts, milk, fat, meat, meat by-products,
and kidney of cattle, goats, horses, hogs and sheep. The summary was
prepared by the petitioner, Rhone-Poulenc Ag Company.
DATES: Comments, identified by the docket number [PF-683], must be
received on or before, January 22, 1997.
ADDRESSES: By mail, submit written comments to Public Response and
Program Resources Branch, Field Operations Division (7506C), Office of
Pesticide 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 22202.
Comments and data may also be submitted electronically be sending
electronic mail (e-mail) to: 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. Comments and data will also be
accepted on disks in WordPerfect in 5.1 file format or ASCII file
format. All comments and data in electronic form must be identified by
docket number [PF-683]. Electronic comments on this notice may be filed
online at many Federal Depository Libraries. Additional information on
electronic submissions can be found below this document.
Information submitted as a comments 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: Philip V. Errico, Acting Product
Manager (PM 22), Rm., 229, CM #2, 1921 Jefferson Davis Highway,
Arlington, VA., 703-305-5540, e-mail: errico.philip@epamail.epa.gov.
SUPPLEMENTARY INFORMATION: EPA has received a pesticide petition (PP)
6F4643 from Rhone-Poulenc AG Company, P.O. Box 12014, Research Triangle
Park, NC 27709 proposing pursuant to section 408(d) of the Federal
Food, Drug and Cosmetic Act, 21 U.S.C. section 346a(d), to amend 40 CFR
part 180 by establishing a tolerance for residues of the plant growth
regulator, cyclanilide [1-(2,4-dichlorophenylaminocarbonyl)-
cyclopropane carboxylic acid] determined as 2,4-dichloroaniline
(calculated as cyclanilide) in or on the raw agricultural commodities
cottonseed at 0.6 parts per million (ppm); cotton gin byproducts at 25
ppm; milk at 0.04 ppm; fat of cattle, goats, horses, hogs and sheep at
0.10 ppm; meat of cattle, goats, horses, hogs and sheep at 0.02 ppm;
meat by-products (except kidney) of cattle, goats, horses, hogs and
sheep at 0.2 ppm; and kidney of cattle, goats, horses, hogs and sheep
at 2.0 ppm. The proposed analytical method is gas chromatography.
Pursuant to the section 408(d)(2)(A)(i) of the FFDCA, as amended,
Rhone-Poulenc AG Company has submitted the following summary of
information, data and arguments in support of their pesticide petition.
This summary was prepared by Rhone-Poulenc AG Company and EPA has not
fully evaluated the merits of the petition. EPA edited the summary to
clarify that the conclusions and arguments were the petitioner's and
not necessarily EPA's and to remove certain extraneous material.
I. Petition Summary
A. Toxicology Profile
1. Acute toxicity. The acute oral toxicity study resulted in a
LD50 of 315 mg/kg for males and 208 mg/kg for females. The acute
dermal toxicity in rabbits resulted in an LD50 in either sex of
greater than 2000 mg/kg. The acute inhalation study in rats resulted in
a LC50 greater than 2.6 mg/l. Cyclanilide was not irritating to
the skin of rabbits in the primary dermal irritation study. In the
primary eye irritation study in rabbits, cyclanilide caused severe
irritation that cleared in 14 days. The dermal sensitization study in
guinea pigs indicated that cyclanilide is not a sensitizer. Based on
the results of the eye irritation study only, cyclanilide technical is
placed in toxicity Category I.
2. Mutagenicity. The compound was found to be devoid of mutagenic
activity in the Ames assay and also in the HGPRT assay using Chinese
hamster ovary cells. Positive findings (clastogenicity) were seen in
the in vitro chromosomal aberrations study with Chinese hamster ovary
cells at doses that caused significant cytotoxicity. However, no
evidence of clastogenic activity was observed in an in vivo mouse
micronucleus test at doses that produced significant toxicity. A second
group of mutagenicity studies was performed on a cyclanilide technical
product that was produced by a different manufacturing process. Results
of these tests were generally equivalent to the above studies. The
weight-of-evidence from the two mutagenicity study batteries suggest
that this material is non-genotoxic.
3. Rat metabolism. The rat metabolism study consisted of a single
oral low dose group at 5 mg/kg, a single oral high dose group at 50 mg/
kg and a repeat oral low dose group at 5 mg/kg/day for 14 days. The
results indicated that males and females did not differ in absorption
following both single oral and repeated oral dosing. A difference was
observed between the single oral high dose group and the single oral
low dose group in that the percentage of the absorbed dose was lower
for the high group. The distribution of cyclanilide 7 days after single
oral high dosing was limited since only the skin and fur, kidney, liver
and the plasma exhibited any significant amounts of radioactivity. The
distribution of cyclanilide 7 days after single oral low dosing and
repeated dosing was even more limited. Cyclanilide was eliminated
rapidly with the majority of the dose being excreted in the first 48
hours after dosing for the single oral high dose group and in the first
24 hours after dosing for the single low dose and repeated dose groups.
The percentage of radioactivity eliminated via the urine was greater
than that eliminated in the feces for the single low dose and repeated
dose groups, while the converse was observed for the single high dose
group. The major radioactive component in the urine and feces was
identified as the parent material. However, up to 31 radioactive
components were observed in the urine and up to 37 components were
observed in the feces. The second most abundant radioactive component
in the urine samples was identified as the methyl ester of cyclanilide.
The remaining metabolites were conjugates of cyclanilide.
4. Chronic effects. a. Cyclanilide was admixed in the diet to 60
Sprague-Dawley rats/sex/group at doses of 0, 50, 150, 450, and 1000
ppm. For each dose, 10 rats/sex/group were designated to be sacrificed
at one year. Nine of 60 high dose males and 4 of 60 high dose females
died during the first 12 months
[[Page 67546]]
of the study versus 4 of 60 control males and 1 of 60 control females.
By study termination at 24 months, survival in treated males and
females was comparable to controls. The study was terminated after 23
months based on survival rates. During the first week of the study, 17
of 60 males and 23 of 60 females in the high dose were reported to have
slightly increased muscle tone which was detected upon handling. Body
weights were statistically significantly lower for males treated with
450 and 1000 ppm for the first month of the study. Body weights for
females at 450 and 1000 ppm were lower than controls throughout the
first 12 month period and were 9-14% lower than controls at week 53.
During the second year of treatment, mean body weights of females given
450 or 1000 ppm were approximately 10-20% lower than controls. An
initial, transient decrease in food consumption was evident in animals
receiving the 1000 ppm concentration in the diet. Clinical chemistry
studies performed at 6, 12, 18, and 23 months revealed possible hepatic
toxicity which consisted of decreases in serum cholesterol and globulin
levels if females treated with 450 and 1000 ppm and in males treated at
1000 ppm. No effect of cyclanilide administration was evident from
hematology or urinalysis evaluations at any time point. Macroscopic and
microscopic postmortem evaluations of animals which died during the
study or were sacrificed after 12 or 23 months of treatment revealed no
effect at any dose level. No oncogenic effect was evident. Based on the
decreased body weight gains in females and decreases in serum
cholesterol and globulin levels at 450 ppm, the No Observed Effect
Level (NOEL) for dietary administration is 150 ppm (7.5 mg/kg/day).
b. Cyclanilide was administered to pure-bred Beagle dogs (5 dogs/
sex/group) via dietary admixture at dose levels of 0, 40, 160, and 640
ppm for 52 weeks. These doses were selected using a 6-week study in
which doses of 800 ppm or higher resulted in inappetence, decreased
body weight gain and elevated SGOT and SGPT. In the one-year study,
body weight gains for high dose male and female dogs were lower than
controls throughout the study. The mean body weight change for high
dose males from week 0 to 52 was 0.0 kg as compared to a 2.6 kg gain
for the control males. The mean body weight change for high dose
females from week 0 to 52 was 0.0 kg versus 2.0 kg gain for the female
controls. There were no treatment-related deaths during the study and
clinical signs were unremarkable. Mean serum alkaline phosphatase
values for the high dose males were elevated at months 3, 6 and 12 and
were slightly elevated at month 12 for the high dose females.
Elevations in mean serum aspartate aminotransferase and alkaline
phosphatase values for high dose males, resulting from 2 of the five
animals, were also seen at month 12. No effects of cyclanilide were
evident in hematology, urinalysis or organ weight data. Microscopic
findings in the liver which were only seen in high dose dogs consisted
of minimal to moderate hepatocellular degeneration and necrosis,
subacute/chronic inflammation, post-necrotic scarring, regenerative
hepatocellular hypertrophy, hyperplasia of bile ducts, vascular
hemorrhages, and brown pigment in hepatocellular and reticulendothelial
cytoplasm. In the kidneys, brown pigment in the cytoplasm of the
epithelium lining the convoluted tubules, seen in almost all dogs on
test was most severe in the high dose animals. The NOEL for this study
was determined to be 160 ppm (4 mg/kg/day).
5. Carcinogenicity a. Cyclanilide was administered for two years
admixed in the diet to 60 Sprague-Dawley rats/sex/group at doses of 0,
50, 150, 450, and 1000 ppm. Macroscopic and microscopic postmortem
evaluations of animals which died during the study or were sacrificed
after 12 or 23 months of treatment revealed no effect at any dose
level. No oncogenic effect was evident. Based on the decreased body
weight gains in females and decreases in serum cholesterol and globulin
levels at 450 ppm, the NOEL for dietary administration is 150 ppm (7.5
mg/kg/day).
b. Cyclanilide was administered chronically via dietary
administration to 60 CD 1 mice/sex/group for 18 months at dose levels
of 0, 50, 250, and 1000 ppm. There were no effects of cyclanilide on
survival, and survival rates were between 65 and 80% overall. Body
weights for high dose males and females were consistently lower than
controls throughout the study. In female mice, statistically
significantly decreased body weight gains were seen throughout week 37
and in males, body weight gain decreases were seen through week 21. At
study termination, body weight differences from controls were 6% for
males and 2% for females. Physical observations throughout the study
were unremarkable. No toxic or oncogenic effects were evident from
hematology data. Mean liver weights and liver/body weight ratios for
high dose males and females were slightly higher than control values at
study termination. Macroscopic and microscopic postmortem examinations
revealed no toxic or oncogenic effects of cyclanilide administration.
6. Teratology. a. In rats, cyclanilide was administered by gavage
at doses of 0, 3, 10, or 30 mg/kg for gestation days 6-18. Doses were
selected based on a range-finding study. In the full study, maternal
toxicity was evident at the dosage level of 30 mg/kg and consisted of
significantly reduced body weight gain (25% less than controls for
gestation days 6-16) and decreased food consumption during the
treatment period. There was no evidence of maternal toxicity at lower
doses. The administration of cyclanilide during the critical phase of
organogenesis did not affect intrauterine survival, fetal sex ratio, or
fetal weight. No treatment-related malformations or developmental
variations were noted in the study. The NOEL for maternal toxicity was
10 mg/kg/day and the NOEL for developmental toxicity was 30 mg/kg/day.
b. In rabbits, cyclanilide was administered by gavage at doses of
0, 3, 10, and 30 mg/kg for gestation days 6-19. Doses were selected
based on a range finding study. In the full study, there were 20
animals per group. Maternal toxicity in the high dose animals was
characterized by decreased food consumption, decreased body weight
gains (90% less than controls for gestation days 6-19), wobbly gait,
apparent hind limb paralysis, decreased activity, salivation,
emaciation and decreased defecation at 30 mg/kg. Mean body weight gains
during gestation days 6-19 were 22 grams for the 30 mg/kg group and 209
grams for the controls. Two females administered 30 mg/kg and one
female in the control group aborted on gestation days 18, 20, and 28,
respectively. At 30 mg/kg, a slight increase in embryo-lethality in
association with maternal toxicity was seen due to two animals that had
total litter resorption. However, this post-implantation loss was well
within historical control ranges for the laboratory. All other Cesarean
section parameters evaluated, including the mean number of corpora
lutea, implantation sites, viable fetuses, early and late resorptions,
fetal sex ratio, gravid uterus weight and fetal body weights were
generally comparable between the control and treatment groups. No
treatment-related malformations or developmental variations were noted
in the study. The NOEL for maternal toxicity was 10 mg/kg/day and the
NOEL for developmental toxicity was 30 mg/kg/day.
[[Page 67547]]
7. Reproductive effects. Cyclanilide was administered to Sprague-
Dawley rats in the feed at 0, 30, 300, and 1000 ppm to examine
reproductive performance. The pre-mating period was 10 weeks. Animals
were randomly mated within treatment groups for a three week mating
period to produce the F1 offspring. The F1 litters were culled to 8
pups on postnatal day 4 and weaned on postnatal day 21. At weaning, 10
weanlings/sex/group were necropsied, and 30/sex/group were selected as
F1 parents to produce the F2 generation. The F0 females were necropsied
with histopathology of reproductive and selected organs for high dose
and control animals. After an 11 week pre-breed period the F1 rats were
mated for 3 weeks to produce the F2 generation. At weaning of the F2
litters, 10 weanlings/sex/group were necropsied. After weaning of the
F2 litters, parental F1 animals were necropsied for histopathology of
reproductive and selected organs. Adult toxicity was observed in both
generations in both sexes at 300 and 1000 ppm with respect to body
weight and food consumption. Transient isolated cases of decreased food
consumption were seen also at 30 ppm. One male and one female in the F1
post-weaning group died at 1000 ppm. The mortality of the F1 animals
was considered a consequence of their small size due to reduced body
weights at 1000 ppm during the lactation period, and therefore,
treatment related. No treatment-related clinical signs were seen in F0,
F1 or F2 animals. Slight mineralization was seen in the kidneys of the
F1 males at 300 and 1000 ppm and in the females at 30, 300 and 1000
ppm. Administration of cyclanilide had no effect on reproductive
parameters including fertility, litter size, prenatal death, stillbirth
or sex ratios. There was no NOEL for adult toxicity in this study due
to isolated transient effects on adult food consumption and renal
histopathology in F1 females at the low dose. The adult toxicity
Lowest-Observed Effect Level (LOEL) for F1 females was 30 ppm (1.5 mg/
kg/day). The adult toxicity NOEL for F1 males was 30 ppm. The NOEL for
reproductive toxicity was at least 1000 ppm and the NOEL for postnatal
toxicity (reduced pup body weights) was 30 ppm.
8. Neurotoxicity. a. In acute neurobehavioral and motor activity
studies, 3 of 5 males and 1 of 5 females administered 150 mg/kg
exhibited a transient increase in body tone and a slight overall gait
incapacity on the day of dosing. The slight gait effects were
characterized by a knuckling of the forelimbs and exaggerated/slow
abducted movements. In motor activity tests, the total activity counts
for males and females in the 150 mg/kg group were decreased at
approximately 7 hours after dosing (peak effect time) when compared to
the controls. None of these signs were seen at day 7 or 14 or at any
time for animals receiving the next lower dose, 50 mg/kg. In addition,
there were no gross or histopathological findings in the nervous system
at any dose level. The NOEL for neurobehavioral effects following acute
oral exposure is 50 mg/kg. The temporary nature of the changes seen and
the absence of any neuropathology findings indicate that there is no
persistent neurotoxic effect of cyclanilide.
b. A 90-day study in rats was performed to examine the potential
effects of cyclanilide on behavior and neuromorphology. The doses were
0, 50, 450, and 1200 ppm in the diet and there were 12 animals/sex/
group. A functional observation battery (FOB) and motor activity test
were performed prestudy and on weeks 4, 8, and 13. At the completion of
the study, 6 rats/sex/.group were perfused for neuropathological
evaluation. Lower body weights were seen on day 7 for the males at 1200
ppm. For females treated at 1200 ppm, significantly lower body weights
were seen on days 21, 42, 52, and 70. Qualitative FOB evaluations
revealed no effects of cyclanilide. Significantly lower hind-limb splay
values were seen for females in the high dose group at week 13. In the
absence of any other differences in behavioral measures for these
animals, this finding was not considered to be of neurotoxicological
significance. Quantitative evaluations of grip strength and body
temperature were unaffected. There were no gross or histopathological
findings in the nervous system considered to be related to treatment.
The NOEL for neurotoxicity is 1200 ppm (60 mg/kg/day).
B. Aggregate Exposure
Cyclanilide is intended for use only on cotton and as a result, the
dietary exposure will be very low. Based on the results from these
studies, the nature and magnitude of the residues in cotton, meat and
milk are considered to be adequately understood. Rhone-Poulenc
sponsored a raw agricultural commodity (RAC) study at ten locations in
1993 and at twelve trial locations (representing the major cotton
production areas of picker and stripper cotton varieties) in 1994. In
1993, residues of cyclanilide in treated samples ranged from 0.06 to
0.44 ppm. In 1994, cyclanilide residues ranged from 0.06 to 0.55 ppm
in/on cotton seed and from 1.41 to 22.9 ppm in/on gin trash. The cow
feeding study determined the magnitude of cyclanilide residues in the
meat and milk of lactating dairy cattle following a 28-day oral
exposure to cyclanilide. When cyclanilide residues plateaued, average
concentrations in the milk were approximately 0.013, 0.044, and 0.19
ppm for the 1X, 3X, and 10X groups, respectively. The maximum
cyclanilide residues found in milk, kidney, liver, fat and muscle from
the 1X group were 0.040, 1.4, 0.14, 0.021, and 0.019 ppm respectively.
Rhone-Poulenc proposes the following tolerances for cyclanilide:
------------------------------------------------------------------------
Commodity Part per million (ppm)
------------------------------------------------------------------------
Cotton
Cottonseed........................... 0.6 ppm
Gin byproduct........................ 25 ppm
Dairy Cow
Milk................................. 0.04 ppm
Cattle, goats, horses, hogs and sheep
Fat.................................. 0.10 ppm
Meat................................. 0.02 ppm
Meat byproducts
Except kidney........................ 0.20 ppm
Kidney............................... 2.0 ppm
------------------------------------------------------------------------
[[Page 67548]]
These tolerances are based on the primary metabolite of
cyclanilide, 2,4-dichloroaniline, since the enforcement methods for
cyclanilide in either cotton or processed fractions or animal
substrates are ``common moiety'' methods, which hydrolyze cyclanilide
to 2,4-dichloroaniline with subsequent conversion to N-(2,4-
dichlorophenyl)-2-chloropropylamide.
Two methods have been developed for establishing and enforcing
tolerances for cyclanilide residues in cotton (RAC and Processed
Fractions) and animal substrates. In both the plant and animal methods,
cyclanilide residues are hydrolyzed with hot aqueous base to 2,4-
dichloroaniline, which is distilled from the reaction mixture,
partitioned into dichloromethane, and ultimately, reacted with 2-
chloropropionyl chloride to yield N-(2,4-dichlorophenyl)-2-
chloropropylamide. After cleanup on a Florisil column, residues are
quantified as N-(2,4-dichlorophenyl)-2-chloropropylamide using gas
chromatography equipped with a Supelco wide-bore Sup-Herb open tubular
column and electron capture detection.
In a cotton processing study, raw agricultural and processed
commodity samples were analyzed for cyclanilide residues. Total
cyclanilide residue levels in cotton raw agricultural and processed
commodity samples ranged from 0.85 - 0.91 ppm in cottonseed and 0.06 -
0.13 ppm in cottonseed hulls. There were no residues above the level of
quantification (LOQ) in any of the other processed commodities (meal,
crude oil, refined oils and soapstocks).
The Food Quality Protection Act of 1996 lists three other potential
sources of exposure to the general population that must be addressed.
These are pesticides in drinking water, exposure from non-occupational
sources, and the potential cumulative effect of pesticides with similar
toxicological modes of action. Based on the available studies and the
use pattern, Rhone-Poulenc does not anticipate residues of cyclanilide
in drinking water. There is no established Maximum Concentration Level
or Health Advisory Level for cyclanilide under the Safe Drinking Water
Act.
The potential for non-occupational exposure to the general public
is also insignificant. There are no residential lawn or garden uses
anticipated for cyclanilide products where the general population may
be exposed via inhalation or dermal routes. Rhone-Poulenc concludes
that consideration of a common mechanism of toxicity is not appropriate
at this time since there is no significant toxicity observed for
cyclanilide even at high doses, cyclanilide is the only known pesticide
member of its class of chemistry, and that there is no reliable data to
indicate that the effects noted would be cumulative with those of any
other class of compounds. Based on these points, Rhone-Poulenc has
considered only the potential risks of cyclanilide in its exposure
assessment.
C. Safety Determination
The NOEL's for cyclanilide are 7.5 mg/kg/day for the chronic rat
study, 35 mg/kg/day for the mouse oncogenicity study, and 4 mg/kg/day
for the dog 1 year chronic study. In the rat 2 generation reproduction
study, the LOEL was 1.5 mg/kg/day due to kidney effects (slight
mineralization) that was not seen in other rat studies. Using the LOEL
of 1.5 mg/kg/day and a safety factor of 300, the Reference Dose (RfD)
is estimated to be 0.005 mg/kg/day. The safety factor was chosen based
on the minimal severity of the finding which did not appear to affect
the overall health of the animal and would not be expected to
significantly affect the function of the organ.
1. DRES-U.S. Population, Infants, Children (1-6 years old) a.
General U.S. population. A chronic dietary risk assessment was
conducted using two approaches: (1) an absolute worst case scenario
using the proposed tolerances, and (2) a conservatively realistic
assessment using data from actual residue studies (anticipated
residues). These assessments incorporated either tolerance values or
anticipated residue concentrations for cyclanilide in cottonseed meal,
cottonseed oil, meat and milk. In the worst case scenario, exposure to
cyclanilide was 0.000311 mg/kg/day for the U.S. population (48 states,
all seasons). This exposure correlates to 6.2% of the calculated RfD.
The highest exposure was observed in the children sub-population (aged
1-6 years), followed by the non-nursing infants subgroup. The exposures
for these two groups were found to be 0.000995 (19.9% of the RfD) and
0.000597 mg/kg/day (11.9% of the RfD), respectively. The commodities
which were found to be significant contributors to exposure were dairy
products. The reasonably conservative analysis yielded exposure values
of 0.000022 mg/kg/day for the U.S. population (48 states, all seasons).
This correlates to 0.4% of the RfD. The highest exposure was observed
in the children sub-population (aged 1-6 years), followed by the non-
nursing infants subgroup. The exposures for these two groups were found
to be 0.000072 (1.4% of the RfD) and 0.000045 mg/kg/day (0.9% of the
RfD), respectively. Again, the commodities which were found to be
significant contributors to exposure were dairy products.
b. Infants and children. In assessing the potential for
additional sensitivity of infants and children to residues of
cyclanilide, the available developmental toxicity and reproductive
toxicity studies and the potential for endocrine modulation by
cyclanilide were considered. Developmental toxicity studies in two
species indicate that cyclanilide is not a teratogen. The 2-generation
reproduction study in rats demonstrated that there were no adverse
effects on reproductive performance, fertility, fecundity, pup
survival, or pup development. Maternal and developmental NOELs and
LOELs were comparable, indicating no increased susceptibility of
developing organisms. No evidence of endocrine effects were noted in
any study. It is therefore concluded that cyclanilide poses no
additional risk for infants and children and no additional uncertainty
factor is warranted.
2. Adequate margin of safety for infants and children. FFDCA
section 408 provides that an additional safety factor for infants and
children may be applied in the case of threshold effects. Since, as
discussed in the previous section, the toxicology studies do not
indicate that young animals are any more susceptible than adult animals
and the fact that the proposed RfD calculated from the LOEL from the 2
generation reproduction study already incorporates an additional
uncertainty factor, Rhone-Poulenc believes that an adequate margin of
safety is therefore provided by the proposed RfD. Additionally, this
LOEL is also 5X lower than the next lowest NOEL (chronic rat study,
NOEL = 7.5 mg/kg/day) in the cyclanilide toxicology data base.
3. Endocrine effects. Cyclanilide has no endocrine-modulation
characteristics as demonstrated by the lack of endocrine effects in
developmental, reproductive, subchronic, and chronic studies.
D. Other Considerations
There is an extensive residue and toxicology database to support
the registration of cyclanilide. All studies performed satisfy the
current appropriate FIFRA guidelines. Included in the data submitted
are studies which showed the nature and magnitude of cyclanilide in
cotton, wheat, ruminants and hen. The metabolism of 14C-
cyclanilide in cotton was investigated and the findings indicated that
14C-
[[Page 67549]]
cyclanilide undergoes negligible metabolism in mature cotton.
Following application to mature cotton, foliage contained approximately
27 ppm cyclanilide equivalents, while the concentration in the lint
ranged from 1.0 to 4.0 ppm, depending on whether the boll was open at
the time of foliar application. The seed, in contrast, did not contain
any detectable residue. Greater than 97% of the extractable radioactive
residues in the foliage was identified as 14C-cyclanilide. The
radioactive residues present in the lint were identified solely as the
parent material, 14C-cyclanilide.
14C-cyclanilide has been shown to be rapidly absorbed and
metabolized to a limited extent by methylation or conjugation reactions
in the rat, but is apparently unchanged in the goat and hen. The main
product eliminated in both urine and feces in the rat and goat and in
the excreta of the chicken was 14C-cyclanilide. Elimination was
observed to be rapid in all three species with very low levels of
radioactive residues being found in the tissues at the time of
sacrifice. The blood/plasma half-life (t1/2) was approximately 90 hours
in the rat. No significant sex differences were observed in the
behavior of cyclanilide in the rat.
There are no Codex tolerances for cyclanilide. There are no minor
crop uses for cyclanilide.
E. Conclusion
The request of a tolerance for cyclanilide on cotton meets the
criteria in the Food Quality Protection Act of 1996 that ``there is
reasonable certainty that no harm will result from aggregate exposure
to the chemical residue including all anticipated dietary exposures and
all other exposures for which there is reliable information.'' The
toxicology data base clearly indicates that: cyclanilide does not pose
any acute dietary risks; cyclanilide is not genotoxic; cyclanilide's
metabolism does not result in metabolites that present any chronic
dietary risk; cyclanilide is neither an oncogen, neurotoxicant,
developmental or reproductive toxicant.
An RfD of 0.005 mg/kg/day is proposed based on the LOEL in the 2
generation reproduction study. The percent of the RfD that will be
utilized by aggregate exposure to residues is extremely low under the
reasonably conservative analysis (0.4% for adults and 1.4% for children
under 6 years of age). No additional uncertainty factor for infants and
children is warranted based on the completeness and reliability of the
database, the demonstrated lack of increased risk to developing
organisms, and the lack of endocrine-modulating effects.
II. Administrative Matters
Interested persons are invited to submit comments on the this
notice of filing. Comments must bear a notation indicating the document
control number, [PF-683]. All written comments filed in response to
this petition will be available in the Public Response and Program
Resources Branch, at the address given above from 8:30 a.m. to 4 p.m.,
Monday through Friday, except legal holidays.
A record has been established for this notice under docket number
[PF-683] 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 public
record is located in Rm. 1132 of the Public Response and Program
resources Branch, Field Operations Division (7506C), Office of
Pesticide Programs, Environmental Protection Agency, Crystal Mall #2,
1921 Jefferson Davis highway, Arlington, VA.
Electronic comments can be sent directly to EPA at:
opp=Docket@epamail.epa.gov
Electronic comments must be submitted as ASCII file avoiding the
use of special characters and any form of encryption.
The official record for this rulemaking, as well as the public
version, as described above will be kept in paper form. Accordingly,
EPA will transfer all comments received electronically into printed,
paper form as they are received and will place the paper copies in the
official rulemaking record which will also include all comments
submitted directly in writing. The official rulemaking record is the
paper record maintained at the address in ``ADDRESSES'' at the
beginning of this document.
List of Subjects
Environmental Protection, Administrative practice and procedure,
Agricultural commodities, Pesticides and pests, Reporting and
recordkeeping requirements.
Dated: December 12, 1996.
Peter Caulkins,
Acting Director, Registration Division, Office of Pesticide Programs.
[FR Doc. 96-32359 Filed 12-20-96; 8:45 am]
BILLING CODE 6560-50-F
