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clofencet Pesticide Tolerance Petition 12/96

[Federal Register: December 12, 1996 (Volume 61, Number 240)] [Notices]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-678; FRL-5576-2]

Clofencet; 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 clofencet, [MON 21200], in or on 
wheat as a primary application; in or on the cereal grains group (excluding 
rice, wild rice and sweet corn) and soybeans as rotational crops; and in 
animal products. This summary was prepared by the petitioner, Monsanto 
Company.

DATES: Comments, identified by docket number [PF-678], must be received on or 
before January 13, 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 by 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 
5.1 file format or ASCII file format. All comments and data in electronic form 
must be identified by the docket number [PF-678]. Electronic comments on this 
proposed rule may be filed online at many Federal Depository Libraries. 
Additional information on electronic submissions can be found below in this 
document.

Information submitted as 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. 

FOR FURTHER INFORMATION CONTACT: By mail: Robert J. Taylor, Product Manager 
(PM) 25, Registration Division, (7505C), Office of Pesticide Programs, 
Environmental Protection Agency, 401 M St., SW., Washington, DC 20460. Office 
location and telephone number: Rm. 241, CM #2, 1921 Jefferson Davis Highway, 
Arlington, VA 22202, 703-305-6027, e-mail: taylor.robert@epamail.epa.gov.

SUPPLEMENTARY INFORMATION: EPA has received a pesticide petition (PP 4F4346) 
from the Monsanto Company, 700 14th St., NW., Suite 1100, Washington, DC 20005 
proposing pursuant to section 408(d) of the Federal Food, Drug and Cosmetic 
Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 by establishing 
tolerances for residues of the plant growth regulator (hybridizing agent) 
clofencet, [MON 21200], 2- (4-chlorophenyl)-3-ethyl-2,5- dihydro-5-oxo-4-
pyridazinecarboxylic acid, potassium salt in or on the raw agricultural 
commodities from direct treatment with clofencet: wheat grain at 250 parts per 
million (ppm), wheat hay at 40 ppm, wheat straw at 50 ppm and wheat forage at 
10 ppm. Secondary residues in the animal product commodities of cattle, goats, 
hogs, horses and sheep: fat at 0.04 ppm, kidney at 10 ppm, meat at 0.15 ppm, 
meat by-products (except kidney) at 0.5 ppm and milk at 0.02 ppm. Secondary 
residues in the animal product commodities of poultry: eggs at 1 ppm, fat at 
0.04 ppm, meat at 0.15 ppm, and meat by- products at 0.2 ppm. Rotational crop 
tolerances in the raw agricultural commodities: soybeans at 30 ppm, soybean 
hay at 10 ppm and soybean forage at 10 ppm. The cereal grain crop group 
(except rice, wild rice and sweet corn) grown as rotational crops: grain at 20 
ppm, straw at 4 ppm, forage at 4 ppm, stover (fodder) at 1 ppm and hay at 15 
ppm. The proposed analytical method for primary and rotational crops includes 
derivatization of clofencet to its methyl ester followed by analysis via gas 
chromatography with electron capture detection. For rotational crops, it is 
necessary to first hydrolyze clofencet-sugar conjugates to clofencet before 
proceeding with derivatization. The proposed method for animal tissues 
includes derivatization of clofencet to its methyl ester followed by analysis 
via HPLC with UV detection. For milk and eggs, analysis is achieved by 
extraction, concentration and direct analysis via HPLC with UV detection.

Pursuant to the section 408(d)(2)(A)(i) of the FFDCA, as amended, Monsanto has 
submitted the following summary of information, data and arguments in support 
of their pesticide petition. This summary was prepared by Monsanto 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. Monsanto Petition Summary

1. Clofencet uses. Clofencet is the active ingredient in Genesis Chemical 
Hybridizing Agent (CHA), which is used in the production of hybrid wheat seed. 
Clofencet prevents normal pollen development in wheat without affecting female 
fertility. This allows for efficient cross-pollination of the treated female 
line by an untreated male pollinator line grown in close proximity, to produce 
hybrid wheat seed. By using this technique, hybrid wheat with greater yield 
potential, drought resistance and disease resistance may be produced. It is 
important to note that clofencet will not be sold directly to the wheat 
grower; rather it will be a tool utilized by specially trained seed company 
personnel to produce hybrid wheat seed which will ultimately be purchased by 
the wheat grower for planting. 

The proposed use pattern of Genesis is a single postemergent application at 
the appropriate stage of growth, namely stages 7 to 9 (Feekes scale) or stages 
32 to 39 (Zadoks scale). The maximum proposed application rate in the United 
States is 10 pounds active ingredient per acre. Due to seed production 
considerations, Genesis will not be applied to the same site in successive 
years. The maximum market penetration for Genesis will not exceed 0.2 to 1 
percent of the total wheat acreage in the United States.

Genesis has been effective across a wide range of germplasm in all market 
classes of wheat. It has a wide crop-safety margin and the seed produced from 
treated females is of high quality. Wheat is the only crop for which Genesis 
is known to be commercially efficacious. 

2. Clofencet safety. Monsanto has submitted over 40 separate mammalian and 
ecological toxicology studies in support of tolerances for clofencet. The 
following mammalian toxicity studies on clofencet (technical grade active 
ingredient (TGAI)) have been conducted: A rat acute oral toxicity study with 
an LD50 of 3,306 mg/kg/day. 

A rat dermal toxicity study with an LD50 of >500 mg/kg/day. A rat acute 
inhalation study with an LC50 of >3.8 mg/l (MON 21233 manufacturing use 
product).

A primary eye irritation study in the rabbit which showed moderate irritation.

A primary dermal irritation study in the rabbit which showed essentially no 
irritation.

A primary dermal sensitization study in guinea pigs which showed no 
sensitization.

An acute neurotoxicity study in the rat which showed no neurotoxic effects at 
any dose.

A subchronic (90-day) neurotoxicity study in the rat which showed no 
neurotoxic effects at any dose.

A 21-day dermal toxicity study in the rat which showed no toxic effects at any 
dose tested with a NOEL of 1,000 mg/kg/day. 

A 90-day feeding study in dogs with a NOEL of 50 mg/kg/day based on 
histological findings in the thymus and testes. 

A 90-day feeding study in the rat with a NOEL of 5,000 ppm in the diet based 
on decreased cumulative weight gain and slightly increased kidney weights.

A 24-month chronic feeding/oncogenicity study in the rat with a systemic NOEL 
of 1,000 ppm (47 and 58 mg/kg/day in males and females, respectively) based on 
hematology effects and histological findings in the lung and kidney. There was 
an equivocal oncogenic response in the liver and thyroid at 20,000 ppm, the 
highest dose tested. 

An 18-month oncogenicity study in the mouse with a systemic NOEL of 3,000 ppm 
(453 and 642 mg/kg/day for males and females, respectively) based on decreased 
survival in the high dose group. A slightly increased incidence of histiocytic 
sarcomas were observed in female mice at 7,000 ppm, the highest dose tested. 

A 12-month feeding study in the dog with a NOEL of 5 mg/kg/day based on 
histological changes in the testes/epididymis and thymus. 

A teratology study in the rat with a maternal and developmental NOEL of 1,000 
mg/kg/day, the highest dose level tested. 

A teratology study in the rabbit with a maternal and developmental NOEL of 150 
mg/kg/day based on excessive maternal toxicity (including mortality, abortions 
and excessive weight loss) and slight developmental effects including slight 
decreases in fetal weight and slight, non-statistically significant increased 
incidences in hydrocephaly and delayed ossification.

A two-generation reproduction study in the rat with a NOEL of 500 ppm (38 and 
52 mg/kg/day for males and females, respectively) based on a decrease in pup 
viability during the first four days of lactation. 

Several mutagenicity studies: Ames Salmonella Assay; CHO/HGPRT Point Mutation 
Assay; In Vitro Cytogenetics Assay in Human Lymphocytes; Mouse Micronucleus 
Assay; and In Vivo/In Vitro Hepatocyte DNA Repair Assay; all negative.

3. Threshold effects -- chronic effects. Based on the available chronic 
toxicity data, EPA has established the Reference Dose (RfD) for clofencet at 
0.005 milligrams (mg)/ kilogram (kg)/day. The RfD for clofencet is based on a 
1-year feeding study in dogs with a No Observable Effect Level (NOEL) of 0.5 
mg/kg/day and an uncertainty factor of 100.

Acute toxicity. Based on the available acute toxicity data, EPA has determined 
that clofencet does not pose any acute dietary risks. 

4. Non threshold effects--carcinogenicity. Using the Guidelines for 
Carcinogenic Risk Assessment published September 24, 1986 (51 FR 33992), EPA 
has classified clofencet as Group "C" for carcinogenicity (possible human 
carcinogen - limited evidence of carcinogenicity in the absence of human data) 
based on the results of carcinogenicity studies in two species.

In a 24-month feeding study in rats, statistically significant increases in 
thyroid C-cell adenomas and combined adenoma/carcinoma were observed in male 
rats at the highest dose tested (20,000 ppm). There was also a statistically 
significant positive trend for these tumors, but the incidences were within or 
only slightly above that reported for historical controls. In addition, the 
tumors were mostly benign and occurred only at an excessive dose. The highest 
dose in this study was considered to be excessive in males, and adequate in 
female rats.

In an 18-month feeding study in mice, statistically significant increases in 
histiocytic sarcomas were observed in female mice at the highest dose tested 
(7,000 ppm) with a statistically significant positive trend. The incidence of 
these tumors also exceeded historical controls. In male mice there were no 
statistically significant increases in tumors at any dose. The highest dose 
tested in both sexes was determined to have been adequate for assessing the 
carcinogenic potential of clofencet, without excessive toxicity. 

The classification of Group "C" was based on the increase in histiocytic 
sarcomas in female mice. The thyroid C-cell tumors in male rats were 
considered to have occurred only at an excessive dose. There were no apparent 
genotoxicity concerns and little additional support for carcinogenicity based 
on SAR analysis; therefore, EPA's Carcinogenicity Peer Review Committee (CPRC) 
recommended that the RfD approach be used for quantitation of human risk. 

5. Aggregate exposure. For purposes of assessing the potential dietary 
exposure under these tolerances, the EPA has estimated aggregate exposure 
based on the anticipated residue for clofencet on primary crop (PC) wheat 
grain at 96.8 ppm, rotational crop (RC) soybeans at 8.87 ppm, RC corn at 0.92 
ppm, RC sorghum at 2.05 ppm and other RC cereal grains (except rice, wild rice 
and sweet corn) at 6.7 ppm. In addition, aggregate exposure from animal 
products were estimated from tolerance values of 0.02 ppm for milk, 0.15 ppm 
for meat, 0.04 ppm for fat, 10.0 ppm for kidney, 0.5 ppm for meat by- products 
(except kidney), 0.15 ppm for poultry meat, 0.2 ppm for poultry meat by-
products, 0.04 ppm for poultry fat and 1.0 ppm for eggs. Estimated exposure is 
obtained by multiplying the anticipated residue or tolerance level residue by 
the consumption data which estimates the amount of food products consumed for 
each of the above commodities by various population subgroups. There are no 
other established (permanent) U.S. tolerances for clofencet, and there are no 
registered uses (section 3) for clofencet on food or feed crops in the United 
States.

In conducting this exposure assessment, the EPA has made very conservative 
assumptions. First, the reasonable assumption is made that 1 percent of the 
total wheat acreage will be sprayed with clofencet, but it is further assumed 
that all of this clofencet treated wheat - which is only intended for seed 
production - will enter the food chain. Monsanto estimates that a maximum of 
10 percent of this seed will enter the food chain. Second, it is assumed that 
100 percent of all labeled rotational crops will be planted on clofencet 
treated fields - even though only 1 percent of wheat fields will be treated 
with clofencet and, further, it is not possible to plant multiple crops on the 
same field. Third, full tolerance values are used for animal products rather 
than anticipated residues. These factors result in an overestimate of human 
exposure which should be taken in consideration when reviewing the calculated 
human dietary exposure values. 

Other potential sources of exposure of the general population to residues of 
pesticides are residues in drinking water and exposure from non-occupational 
sources. Based on the available studies used in EPA's assessment of 
environmental risk, the mitigation measures volunteered by Monsanto and 
requested by the EPA and the unique and restricted use characteristics of the 
chemical, Monsanto does not anticipate exposure to residues of clofencet in 
drinking water. There are no established Maximum Concentration Level (MCL) for 
residues of clofencet in drinking water. Monsanto has not estimated non-
occupational exposure for clofencet since the proposed registration for 
clofencet is limited to wheat seed production by certified hybrid seed 
technicians only. It will be a restricted use registration. Thus, the non-
occupational exposure to the general population is expected to be negligible. 

Monsanto also considered the potential for cumulative effects of clofencet and 
other substances that have a common mechanism of toxicity. Monsanto concluded 
that consideration of a common mechanism of toxicity is not appropriate at 
this time. First, clofencet is only one of two chemical hybridizing agents 
currently registered on wheat and the other one is owned by this petitioner 
and is not currently available commercially. Second, Monsanto does not have 
reliable information to indicate that toxic effects produced by clofencet 
would be cumulative with those of any other chemical compounds. Thus, Monsanto 
is considering only the potential risks of clofencet in its aggregate exposure 
assessment.

6. Determination of safety for U.S. population-- reference dose. Using the 
conservative exposure assumptions described above and based on the 
completeness and reliability of the toxicity data, EPA has concluded that 
aggregate exposure to clofencet will utilize 7.6 percent of the RfD for the 
U.S. population. EPA generally has no concern for exposures below 100 percent 
of the RfD for the U.S. population because the RfD represents the level at or 
below which daily aggregate dietary exposure over a lifetime will not pose 
appreciable risks to human health. Monsanto concludes that there is a 
reasonable certainty that no harm will result from aggregate exposure to 
clofencet residues. 

7. Safety determination for infants and children. In assessing the potential 
for additional sensitivity of infants and children to residues of clofencet, 
Monsanto considered data from developmental toxicity studies in the rat and 
rabbit and a 2-generation reproduction study in the rat. The developmental 
toxicity studies are designed to evaluate the potential for adverse effects on 
the developing organism resulting from exposure during prenatal development to 
the female parent. Reproduction studies provide information relating to 
effects from exposure to the chemical on the reproductive capability of both 
(mating) parents and on systemic toxicity. 

In a developmental toxicity study in the rat, no developmental or maternal 
toxicity were observed up to a dosage of 1,000 mg/kg/day, the highest dose 
level tested and the limit dose for this species as specified in the Pesticide 
Assessment Guidelines. The NOEL was considered to be 1,000 mg/kg/day.

In a developmental toxicity study in the rabbit, severe maternal toxicity 
(mortality, abortion, decreased body weight gain and decreased food 
consumption) and equivocal developmental toxicity (possible lower fetal body 
weights, marginal increased incidence of fetal hydroencephalus and delayed 
ossification) were observed at 500 mg/kg/ day, the highest dose level tested. 
The NOEL for both maternal and developmental toxicity was considered to be 150 
mg/kg/day. The developmental effects observed in this study were considered to 
be secondary to the severe maternal stress. 

In a 2-generation reproduction study in rats, pups from the 5,000 and 20,000 
ppm dose levels had an increased incidence of pup mortality in both matings of 
the F1 generation during lactation days 1 to 4. The NOEL was considered to be 
500 ppm (38 and 52 mg/kg/day for males and females, respectively). Although 
the increased incidence of pup mortality was significantly increased when 
compared to concurrent controls, the laboratory at which the study was 
conducted reports that their historical control incidence of pup survivability 
is less than is seen at other laboratories. A viral infection in the colony 
was suspected, but nothing was definitely proven. No effects on fertility were 
observed.

FFDCA Section 408 provides that EPA may apply an additional safety factor (up 
to 10) in the case of threshold effects for infants and children to account 
for pre- and post-natal toxicity and the completeness of the database. Based 
on current toxicological data requirements, the database relative to pre- and 
post-natal effects in children is complete. Further, in the developmental 
toxicity study in the rabbit and the 2-generation reproduction study in the 
rat, the NOEL's are already an additional 30X and an average (male/female) of 
9X, respectively, above the NOEL on which the RfD was established (5.0 
mg/kg/day from a one-year feeding study in dogs). Based on all the above 
information, Monsanto concludes that an additional uncertainty factor is not 
warranted and that the RfD of 0.05 mg/kg/day is appropriate for assessing risk 
to infants and children.

Using the conservative dietary exposure assumptions described above, EPA has 
concluded that the percent of the RfD that will be utilized by aggregate 
exposure to residues of clofencet by children aged <1 (nursing) to age 12, 
ranges from 10.5 percent for children 7 to 12 years old up to 22.7 percent for 
non-nursing infants (<1 year old). Therefore, based on the completeness and 
reliability of the toxicity data and the conservative exposure assessment, 
Monsanto concludes that there is a reasonable certainty that no harm will 
result to infants and children from aggregate exposure to clofencet residues. 

8. Estrogenic effects. No specific tests have been conducted with clofencet to 
determine whether the chemical may have an effect in humans that is similar to 
an effect produced by a naturally occuring estrogen or other endocrine 
effects. However, there were no significant findings in other relevant 
toxicity tests, i.e., teratology and multi- generation reproduction studies, 
which would suggest that clofencet produces these kinds of effects.

9. Chemical residue. The metabolism of clofencet in plants and animals is 
adequately understood for the purposes of these tolerances. There are no Codex 
maximum residues levels established for residues of clofencet on wheat or 
indicated rotational crops. There is a practical analytical method for 
detecting and measuring levels of clofencet in or on food with a limit of 
detection that allows monitoring of food with residues at or above the levels 
set in these tolerances. EPA will provide information on this method to the 
Food and Drug Administration (FDA). The method is available to anyone who is 
interested in pesticide residue enforcement from: By mail: Calvin Furlow, 
Public Response and Program Resources Branch, Field Operations Division 
(7506C), Office of Pesticide Programs, Environmental Protection Agency, 401 M 
St., SW., Washington, DC 20460. Office location and telephone number: Crystal 
Mall #2, Rm. 1128, 1921 Jefferson Davis Hwy., Arlington, VA 22202, (703) 305-
5805.

Residues of clofencet have been found to concentrate slightly (<2 x ) in wheat 
shorts and bran, and in soybean hulls and meal. The EPA examined all relevant 
data and after consideration of the restricted use of the chemical for seed 
production only, the limited opportunity for this seed to enter commerce as 
grain and the dilution factors involved in making all of the above processed 
fractions (with the exception of wheat bran) "ready to eat", the EPA 
determined that no additional tolerances were necessary to cover these 
processed fractions. All of the proposed tolerance levels are adequate to 
cover residues likely to be present from the proposed use of clofencet. 
Therefore, no special processing to reduce the residues will be necessary

10. Environmental fate. Laboratory studies indicate that clofencet has the 
potential to persist in soil and be mobile. However, the results of field 
dissipation studies indicate that downward movement of clofencet is limited. 
In addition, the limited use of clofencet for hybrid wheat seed production 
only, the current practice of never using the same seed production field in 
two consecutive years and label mitigation measures agreed upon by Monsanto 
and the EPA, will further reduce the likelihood of clofencet appearing in 
ground or surface water.

II. Administrative Matters

Interested persons are invited to submit written comments on this notice of 
filing. Comments must bear a notation indicating the document control number, 
[PF-678]. 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 4:00 p.m., Monday through Friday, except legal 
holidays. 

A record has been established for this notice of filing under docket number 
[PF-678] (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 4:00 p.m., Monday through Friday, 
excluding legal holidays. The public record is located in Room 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 as ASCII file avoiding the use of 
special characters and any form of encryption. 

The official record for this filing of notice, 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 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 4, 1996.

Stephen L. Johnson,
Director, Registration Division, Office of Pesticide Programs. 

[FR Doc. 96-31555 Filed 12-11-96; 8:45 am]