Difenoconazole - Pesticide Tolerances 8/94
40 CFR Part 180
[PP 2F4107/R2075; FRL094906092]
Difenoconazole; Pesticide Tolerances
AGENCY: Environmental Protection Agency (EPA).
ACTION: Final rule.
SUMMARY: EPA is establishing tolerances for residues of the
fungicide difenoconazole in or on certain raw agricultural commodities.
Ciba-Geigy Corp. requested this regulation to estalish the maximum
permissible levels of residues of the fungicide in or on the
EFFECTIVE DATE: This regulation becomes effective August 24,
ADDRESSES: Written objections and hearing requests, identified
by the document control number, [PP 2F4107/R2075], may be submitted
to: Hearing Clerk (1900), Environmental Protection Agency, Rm.
M3708, 401 M St., SW., Washington, DC 20460.
A copy of any objections and hearing request filed with the
Hearing Clerk should be identified by the document control number
and submitted to: Public Response and Program Resources Branch,
Field Operations Division (7506C), Office of Pesticide Programs,
Environmental Protection Agency, 401 M St., SW., Washington
DC 20450. In person, bring copy of objections and hearing request
to: Rm. 1132, CM 1B2, 1921 Jefferson Davis Hwy., Arlington,
VA 22202. Fees accompanying objections shall be labeled "Tolerance
Petition Fees" and forwarded to: EPA Headquarters Accounting
Operations Branch, OPP (Tolerance Fees), P.O. Box 360277M, Pittsburgh,
FOR FURTHER INFORMATION CONTACT: By mail: Cynthia Giles-Parker,
Product Manager (PM) 22, Registration Division, Environmental
Protection Agency, 401 M St., SW., Washington, DC 20460. Office
location and telephone number: Rm. 229, CM 1B2, 1921 Jefferson
Davis Highway, Arlington, VA 22202, (703)-305-5540.
SUPPLEMENTARY INFORMATION: EPA issued a notice published in
the Federal Register of June 10, 1992 (57 FR 24644), which announced
that Ciba-Geigy Corporation, P.O. Box 18300, Greensboro, NC
27419-8300, had submitted a pesticide tolerance petition (PP
2F4107) to EPA requesting that the Administrator, pursuant to
sections 408(d) of Federal Food, Drug and Cosmetic Act, 21 U.S.C.
346a(d), establish a tolerance for the fungicide, difenoconazole,
2-yl-methyl)-1H-1,2,4-triazole, in or on in or on wheat forage
at 0.1 part per million (ppm), wheat straw at 0.1 ppm, barley
forage at 0.1 ppm, and barley straw at 0.1 ppm. In the Federal
Register of March 30, 1994 (59 FR 14854), EPA issued in the
Federal Register a corrected filing of the notice published
in the Federal Register of January 7, 1994 (59 FR 1017), which
announced that Ciba-Geigy Corp. had submitted an amendment to
the petition, proposing to establish additional tolerances as
follows: cattle, fat, meat, and meat-by-products (mbyp) at 0.05
ppm; eggs at 0.05 ppm; milk at 0.01 ppm; goats, fat, meat, and
mbyp at 0.05 ppm; hogs, fat, meat, and mbyp at 0.05 ppm; horses,
fat, meat, and mbyp at 0.05 ppm; poultry, fat, meat, and mbyp
at 0.05 ppm; sheep, fat, meat, and mbyp at 0.05 ppm; barley
grain at 0.1 ppm; and wheat grain at 0.1 ppm. Ciba-Geigy subsequently
amended the petition to withdraw without prejudice for future
filings the tolerances for barley forage, barley straw and barley
The chemical name for difenoconazole is editorially corrected
to read: [(2S,4R)/(2R,4S)]/[2R,4R/2S,4S)] 1-(2-[4-(4chlorophenoxy)-
There were no comments or requests for referral to an advisory
committee received in response to these notices of filing.
The data submitted in the petitions and all other relevant
material have been evaluated. The toxicology data considered
in support of the tolerances include:
1. A rat acute oral study with an LD50 of 1,453 milligrams
2. A 13-week rat feeding study with a no-observed-effect-
level (NOEL) of 20 ppm (1 mg/kg/day).
3. A 13-week mouse feeding study with a NOEL of 20 ppm.
4. A 26-week dog feeding study with a NOEL of 1,000 ppm.
5. A 21-day rabbit dermal study with a NOEL of 10 mg/kg and
reduction in body weight gain and food consumption from exposure
to doses equal or greater than 100 mg/kg.
6. A carcinogenicity study in mice with a NOEL of 30 ppm
and a Lowest Effect Level (LEL) of 300 ppm due to reductions
in cumulative body weights. There was limited evidence of carcinogenicity
based on the occurrence of increased benign and/or malignant
liver tumors in males and females. The carcinogenic effects
observed are discussed below.
7. A rat chronic feeding/carcinogenicity study with a NOEL
of 20 ppm (1 mg/kg/day) for systemic effects and a LEL of 500
ppm (25 mg/kg/day) due to reductions in cumulative body weight
gains and hepatotoxicity in males. There was no evidence of
carcinogenicity under conditions of the study.
8. A 1-year dog chronic feeding study with a NOEL of 100
ppm and the LEL was 500 ppm due to reduction in food consumption
and increase in alkaline phosphatase in males at high dose.
9. A two-generation reproduction study in rats with a parental
and reproductive NOEL of 25 ppm (1.25 mg/kg/day) and an LEL
of 250 ppm (12.5 mg/kg/day) due to reduction of female body
weight gain, and significant reductions in male pup weight at
10. A developmental toxicity study in rabbits with a Maternal
NOEL of 25 mg/kg and a LEL of 75 mg/kg/day due to decreased
body weight, death of one doe and abortion, and a developmental
NOEL of 25 mg/kg and a LEL of 75 mg/kg due to increased postimplantation
loss and resorptions and significantly decreased fetal weight.
11. A developmental toxicity study in rats with a maternal
NOEL of 16 mg/kg and a LEL = 85 mg/kg due to excess salivation,
and decreased body weight gain and food consumption, and a developmental
NOEL of 85 mg/kg/day and an LEL of 171 mg/kg due to increase
bifid or unilateral ossification of thoracic vertebrate, increased
average number of ossified hyoid and decrease in average number
of sternal centers of ossification.
12. A Microbial Gene Mutation study and an Unscheduled DNA
synthesis in rat hepatocyte study were both negative. An In
vivo micronucleus assay / chromosomal analysis study showed
no increase in micronucleated polychromatic erythrocytes at
any dose tested.
13. A rat metabolism study showed that difenoconazole was
adequately absorbed and mainly eliminated via the bile. No evidence
of bioaccumulation in any tissue was noted.
The Health Effects Division Carcinogenicity Peer Review Committee
has concluded that the available data provide limited evidence
of the carcinogenicity of difenoconazole in mice and has classified
Difenoconazole as a Group C (possible human carcinogen with
limited evidence of carcinogenicity in animals) in accordance
with Agency guidelines, published in the Federal Register in
1986 (51 FR 33992, Sept. 24, 1986) and recommended that for
the determined that a quantitative risk assessment is not appropriate
for the following reasons:
1. The carcinogenic response observed with this chemical,
statistically significant increases in hepatocellular adenomas,
carcinomas and combined adenomas/carcinomas in both sexes of
CD-1 mice, occurred only at doses considered to be excessively
high for carcinogenicity testing.
2. There were no apparent tumor increases in either sex in
Sprague-Dawley rats at dietary levels up to 2,500 ppm.
3. Difenoconazole was not mutagenic in three well conducted
Based on this evidence, EPA concludes that difenoconazole
poses at most a negligible cancer risks to humans and that for
purposes of risk characterization the Margin of Expsoure (MOE)
approach should be use for quantification of human risk. In
a spring wheat processing study, no residues were detected in
grain or any processed fraction. Therefore, food/feed additive
tolerances are not needed in conjunction with this use on wheat.
Using a 100-fold safety factor and the NOEL of 1 mg/kg/day
determined by the most sensitive species from the rat chronic
feeding study, the Reference Dose (RfD) is 0.01 mg/kg/day. The
theoretical maximum residue contribution (TMRC) from the established
and proposed tolerances is 0.00041 mg/kg/day and utilizes 4
percent of the RfD for the overall U. S. population. For exposure
of the most highly exposed subgroups in the population, children
(1 to 6) and Nonnursing infants (less than 1), the TMRC is 0.000946
mg/kg/day and utilizes 9 percent of the RfD.
The dietary acute exposure MOE for developmental toxicity
effects was calculated to be 25,000 for high exposure in the
females 13+ subgroup. For substances whose acute NOEL is based
on animal studies, the Agency is not generally concerned unless
the MOE is below 100.
The metabolism of difenoconazole in plants is adequately
understood. The tolerances established for milk, eggs, meat,
fat, and meat by products will cover any dietary exposure from
secondary residues in these RACs. Due to the following chemistry
data gaps-Stability of the Technical Grade Active Ingredient
(TGAI) to Metal Ions Study [GLN 63-13], Storage Stability of
Difenoconazole in other Raw Agricultural Commodities [GLN 1714(e)],
and Additional Wheat Field Residue Trials [GLN 171-4(k)]-EPA
believes it is inappropriate to establish permanent tolerance
for the use of difenoconazole at this time. However, based on
the (1) apparent storage stability, (2) 11 acceptable field
studies (15 to 20 field trials are required), and (3) apparent
negligible residues of difenoconazole in wheat RACs, EPA believes
that the existing data support a time-limited tolerance to December
An adequate analytical method, gas chromatography with nitrogen
phosphorous detection, is available for enforcement purposes.
Because of the long lead time from establishing these tolerances
to publication of the enforcement methodology in the Pesticide
Analytical Manual, Vol. II, the analytical methodology is being
made available in the interim to anyone interested in pesticide
enforcement when requested from: Calvin Furlow, Public Information
Branch, Field Operations Division (7506C), Office of Pesticide
Programs, Environmental Protection Agency, 401 M St., SW., Washington,
DC 20460. Office location and telephone number: Rm. 242, CM
1B2, 1921 Jefferson Davis Hwy., Arlington, VA 22202, (703)-305-
The pesticide is considered useful for the purposes for which
the tolerances are sought. Based on the information and data
considered, the Agency concludes that the establishment of the
time-limited tolerances will protect the public health. Therefore,
the tolerances are established as set forth below.
Any person adversely affected by this regulation may, within
30 days after publication of this document in the Federal Register,
file written objections and/or request a hearing with the Hearing
Clerk, at the address given above (40 CFR 78.20). A copy of
the objections and/or hearing requests filed with the Hearing
Clerk should be submitted to the OPP docket for this rulemaking.
The objections submitted must specify the provisions of the
regulation deemed objectionable and the grounds for the objections
(40 CFR 178.25). Each objection must be accompanied by the fees
provided by 40 CFR 180.33(i). If a hearing is requested, the
objections must include a statement of the factual issue(s)
on which a hearing is requested, and the requestor's contentions
on each such issue, and a summary of the evidence relied upon
by the objection (40 CFR 178.27). A request for a hearing will
be granted if the Administrator determines that the material
submitted shows the following: there is a genuine and substantial
issue of fact; there is a reasonable possibility that available
evidence identified by the requestor would, if established,
resolve on or more of such issues in favor of the requestor,
taking into account uncontested claims or facts to the contrary;
and resolution of the factual issue(s) in the manner sought
by the requestor would be adequate to justify the action requested
(40 CFR 178.32).
Pursuant to the requirements of the Regulatory Flexibility
Act (Pub. L. 96-354, 94 Stat. 1164, 5 U.S.C. 601-612), the Administrator
has determined that regulations establishing new tolerances
or raising tolerance levels or establishing exemptions from
tolerance requirements do not have a significant economic impact
on a substantial number of small entities. A certification statement
to this effect was published in the Federal Register of May
4, 1981 (46 FR 24950).
List of Subjects in 40 CFR Part 180
Environmental protection, Administrative practice and procedure,
Agricultural commodities, Pesticides and pests, Recording and
Dated: August 18, 1994.
Daniel M. Barolo,
Director, Office of Pesticide Programs.
Therefore, 40 CFR part 180 is amended as follows:
1. The authority citation for part 180 continues to read
Authority: 21 U.S.C. 346a and 371
2. By adding new sec1180.475, to read as follows:
sec1180.475 Difenoconazole; tolerances for residues.
(a) Time-limited tolerances, to expire on December 31, 1998,
are established for difenoconazole, [(2S,4R)/(2R,4S)]/[2R,4R/2S,4S)]
2yl-methyl)-1H-1,2,4-triazole, in or on the following raw agricultural
Commodity Parts per
Horses, meat............................ 0.05
(b) Residues in these commodities not in excess of the established
tolerance resulting from the use described in paragraph (a)
of this section remaining after expiration of the time-limited
tolerance will not be considered to be actionable if the fungicide
is applied during the term of and in accordance with the provisions
of the above regulation.
[FR Doc. 94-20813 Filed 8-23-94; 8:45 am]