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cyclanilide Pesticide Tolerance Petition 12/96

[Federal Register: December 23, 1996 (Volume 61, Number 247)] [Notices]
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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). 

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 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. 

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 
------------------------------------------------------------------------ 

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-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]