cyromazine (Larvadex,Trigard) Proposed Pesticide Tolerance 6/93
Pesticide Tolerance for Cyromazine
AGENCY: Environmental Protection Agency
ACTION: Proposed rule.
SUMMARY: EPA proposes to establish a tolerance for residues
of the insect growth regulator cyromazine (N-cyclo-propyl-1,3,5-
triazine-2,4,6-triamine) (Armor) and its metabolite melamine
(1,3,5-triazine-2,4,6-triamine), calculated as cyromazine, in
or on mushrooms at 10.0 parts per million (ppm). This regulation
to establish maximum permissible levels for residues of the
insecticide was requested pursuant to a petition submitted by
DATES: Written comments must be received by July 21, 1993.
ADDRESSES: Comments, in triplicate, should bear the docket control
number, [PP 5F3177/P561], and be submitted to: Public Response
and Program Resources Branch, Field Operations Division (H7506C),
Office of Pesticide Programs, Environmental Protection Agency,
401 M St., SW., Washington, DC 20460. In person bring comments
to: Rm. 1128, Crystal Mall #2, 1921 Jefferson Davis Hwy., Crystal
City, VA 22202.
Information submitted in any comment concerning this document
may be claimed confidential by marking any part or all of that
information as ``Confidential Business Information'' (CBI).
Information so marked 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 to the submitter.
Written comments will be available for public inspection in
Rm. 1128 at the Virginia address given above, from 8 a.m. to
4:30 p.m., Monday through Friday, excluding legal holidays.
FOR FURTHER INFORMATION CONTACT: By mail: Phillip O. Hutton,
Product Manager (PM) 18, Registration Division (H7505C), Office
of Pesticide Programs, Environmental Protection Agency, 401
M St., SW., Washington, DC 20460. Office location and telephone
number: Rm. 202, CM #2, 1921 Jefferson Davis Hwy., Arlington,
VA 22202, (703)-557-2386.
SUPPLEMENTARY INFORMATION: In the Federal Register of January
30, 1985 (50 FR 4265), EPA issued a notice which announced that
Ciba-Geigy Corp., P.O. Box 18300, Greensboro, NC 27419, had
submitted a pesticide petition (PP 5F3177) to EPA proposing
to amend 40 CFR part 180 by establishing a tolerance, under
section 408 of the Federal Food, Drug, and Cosmetic Act, 21
U.S.C. 346a, for residues of the insecticide cyromazine (N-cyclo-
propyl-1,3,5-triazine-2,4,6-triamine) and its metabolite melamine
(1,3,5-triazine-2,4,6-triamine) in or on mushrooms at 10.0 ppm.
Further, in the Federal Register of September 25, 1985 (50 FR
38895), EPA issued a notice which announced that Ciba-Geigy
Corp. had revised the petition so that Ciba-Geigy Corp. proposed
amending 40 CFR part 180 by establishing a tolerance for the
combined residues of the insecticide cyromazine (N-cyclopropyl-
1,3,5-triazine-2,4,6-triamine) and its principal metabolite,
melamine (1,3,5-triazine-2,4,6-triamine), calculated as cyromazine
in or on the commodity mushrooms at 10.0 ppm. The proposed analytical
method for determining residues is gas chromatography.
There were no comments or requests for referral to an advisory
committee received in response to these notices of filing. Because
these notices of filing were issued 8 years ago, EPA is publishing
a proposal in regard to the petition rather than proceeding
directly to a final rule.
The scientific data submitted in the petition and other relevant
material have been evaluated. A discussion of the toxicological
data considered in support of the tolerance as well as a discussion
of the risk of cyromazine and its metabolite melamine can be
found in a rule (FAP 2H5355/P344) published in the Federal Register
of April 27, 1984 (49 FR 18120) and in the Notice of Conditional
Registration for Larvadex 0.3% Premix, published in the Federal
Register of May 15, 1985 (50 FR 20373). Subsequent to these
documents being published, the Agency has reevaluated both the
developmental toxicity of cyromazine and the carcinogenic potential
of its metabolite melamine.
Cyromazine has been classified by the Office of Pesticide
Programs' Health Effects Division's Carcinogenicity Peer Review
Committee (PRC) as Group C, i.e., possible human carcinogen.
Mammary tumors in the mouse occurred at a dose that may have
been insufficient for an adequate assessment of carcinogenic
potential. However, the incidence of mammary tumors was almost
three times the historical controls. These data were also supported
by the same tumor type in the rat, although the dosing may have
been excessive in this species. In addition, cyromazine has
some structural similarities to other mammary tumor-producing
analogs, although the relationship was not considered to be
strong. Although the evidence from the rat study alone was not
conclusive, in combination with the mouse study the weight-of-
the-evidence for the carcinogenicity of cyromazine pointed toward
a Group C classification. Because the rat study alone does not
carry much weight (there may have been excessive dosing and
because the incidence of mammary tumors was within the historical
control range), the Agency has chosen to use reference dose
calculations to estimate human dietary risk from cyromazine
Melamine, a metabolite of cyromazine, produced bladder tumors
that were accompanied by bladder stones in dosed rats. Cyromazine
did not produce bladder tumors in rats or mice, nor were any
bladder stones or any other effect in the urinary tract noted
in animals treated with cyromazine. Bladder tumors can be produced
by the introduction of inert materials like glass beads and
wax pellets into the bladder; a host of chemicals that lead
to bladder stone formation also produce bladder tumors. It appears
that irrespective of the composition of the stones, foreign
bodies in the bladder induce intense epithelial irritation,
compensatory cell proliferation, hyperplasia and, following
chronic stimulation, bladder tumors. The Agency believes that
this sequence: inflammation, hyperplasia and neoplasias would
not occur unless preceded by stone formation in the bladder.
Thus at doses far below those which induce the formation of
bladder stones, tumor formation would not be expected to occur.
The Agency thinks this to be the case for cyromazine, since
only about 10% of cyromazine appears to be metabolized to melamine,
and the maximum tolerated dose (MTD) for cyromazine in rats
is about 3,000 ppm (accordingly, it is unlikely that a dose
of cyromazine that would result in high enough melamine concentrations
to produce bladder stones and bladder tumors would be tolerated
in rats). Furthermore, human exposure to melamine from the pesticidal
use of cyromazine via residues in food is far below the dose
that was administered in the rat and it is not anticipated to
produce bladder stones, much less bladder tumors. Therefore,
the carcinogenic effects in the bladders of rats associated
with melamine were not considered to be applicable to evaluating
the carcinogenic potential of cyromazine. In sum, EPA believes
cyromazine poses a negligible cancer risk to humans.
A chronic dietary exposure/risk assessment for the proposed
use on mushrooms based on tolerance residue levels of 10 ppm
was performed. This chronic analysis compared daily exposure
estimates to a Reference Dose (RfD) of 0.0075 mg/kg body weight/day
based on a no-observable-effects-level (NOEL) of 0.75 mg/kg
body weight /day and an uncertainty factor of 100. The NOEL
is based on a 6-month dog-feeding study which demonstrated decreased
hematocrit and hemoglobin levels. Estimates (in mg/kg body weight/day
and percents of RfD occupied) for the overall (average) U.S.
population for currently published tolerances of cyromazine
are 0.001861 and 25%. With the inclusion of mushrooms, these
figures become 0.002075 and 28%. Therefore, the contribution
of the mushroom tolerance takes up an additional 3 percent of
the RfD. Since the exposure estimates are based on Theoretical
Maximum Residue Contribution, typically an overestimate of actual
exposure, and do not exceed the reference dose, the chronic
health risk of cyromazine does not appear to be significant.
Regarding developmental effects, the Agency concluded in
1985 (50 FR 20373) that cyromazine was a developmental toxicant
with a NOEL of 5 mg/kg body weight. Subsequent to this determination,
the Agency has considered the ``Weight-Of-Evidence'' document
submitted by Ciba-Geigy in support of the registrant's contention
that cyromazine is not a developmental toxicant. Based on the
document and additional information obtained by the Agency,
the Agency has concluded that the developmental effects observed
in the rabbit, namely cyclopia, diaphragmatic hernia, and hydrocephaly,
are not consistently reproducible across studies, are clearly
not cyromazine dose-related, and appear to have occurred by
The Agency has received seven studies evaluating the developmental
toxicity of cyromazine, six in the rabbit and one in the rat.
Of the six rabbit studies submitted, only one is acceptable
for regulatory purposes. This study, WIL 82001, shows developmental
effects of cyclopia, diaphragmatic hernia, and hydrocephaly
in treatment groups below the maternal lowest observable effect
level (LOEL). Buckshire New Zealand White rabbits were used
in this study. There appears to be a high background malformation
rate in Buckshire rabbits with the observations of cyclopia
and craniofacial head defects occurring in ``clusters,'' where
several studies will have no evidence of craniofacial defects
and then several studies in a row will present with these observations.
This was observed in the submitted historical control data (cyclopia
and craniofacial head defect incidence of 7.94 per 10,000 New
Zealand White Rabbit fetuses) and from evaluation of the open
literature data base for cyromazine and for craniofacial birth
defects (where it was found that the rabbit has a unique response
to certain agents in the form of cyclopia; however, these agents
have a steroidal structure which cyromazine does not possess).
It was determined that the observed frequency of the observations
could be explained by chance. The observations of diaphragmatic
hernia and hydrocephaly were not dose related and were within
the historical control range for New Zealand White Rabbits.
The Agency has determined that the NOEL for developmental toxicity
in the rabbit is 60 mg/kg/day, the highest dose tested.
The rat teratology study with cyromazine (IRDC, Study No.
382-070, 1979) using dose levels of 0, 100, 300, and 600 mg/kg/day
of technical cyromazine was reevaluated for developmental toxicity
based on observed skeletal variations and historical control
data. The maternal toxicity NOEL was determined to remain at
100 mg/kg/day with a LOEL of 300 mg/kg/day based on increased
incidence of clinical observations and decreased body weight
gain. However, reevaluation of the data determined that the
developmental toxicity NOEL was 300 mg/kg/day with a LOEL of
600 mg/kg/day due to the observations of increased incidence
of minor skeletal variations.
Dietary exposures are well below these levels. Additionally,
based on the expected levels of cyromazine exposure to unprotected
mushroom workers mixing, loading, and applying the cyromazine
end-use product Armor (anticipated daily exposure is 1.10 mg/kg/day);
the low level of cyromazine dermal absorption (less than 13%
in the rat) and the high NOEL for developmental toxicity in
the rat teratology study; the risk for developmental toxicity
to workers appears to be insignificant.
Based on the information cited above, the Agency has determined
that the establishment of the tolerance by amending 40 CFR part
180 will protect the public health. Therefore, EPA proposes
that the tolerance be established as set forth below.
Any person who has registered or submitted an application
for registration of a pesticide, under the Federal Insecticide,
Fungicide, and Rodenticide Act (FIFRA) as amended, which contains
any of the ingredients listed herein, may request within 30
days after publication of this document in the Federal Register
that this rulemaking proposal be referred to any Advisory Committee
in accordance with section 408(e) of the Federal Food, Drug,
and Cosmetic Act.
Interested persons are invited to submit written comments
on the proposed regulation. Comments must bear a notation indicating
the document control number, [PP 5F3177/P561]. 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 a.m. to 4 p.m., Monday through Friday, except
The Office of Management and Budget has exempted this rule
from the requirements of section 3 of Executive Order 12291.
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
Administrative practice and procedure, Agricultural commodities,
Pesticides and pests, Reporting and recordkeeping requirements.
Dated: June 23, 1993.
Lawrence E. Culleen,
Acting Director, Registration Division, Office of Pesticide
Therefore, it is proposed 40 CFR part 180 be amended as follows:
1. The authority citation for part 180 continues to read
Authority: 21 U.S.C. 346a and 371.
2. In . 180.414, new paragraph (e) is added, to read as follows:
. 180.414 Cyromazine; tolerances for residues.
* * * * *
(e) Tolerances are established for combined residues of the
insect growth regulator cyromazine (N-cyclo-propyl-1,3,5-triazine-
2,4,6-triamine) and its metabolite melamine (1,3,5-triazine-
2,4,6-triamine), calculated as cyromazine, in or on the following
raw agricultural commodity:
Commodity Parts per
[FR Doc. 93-15416 Filed 6-29-93; 8:45 am]