[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: [email protected]. 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: [email protected].

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=D[email protected]


    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