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cyromazine (Larvadex,Trigard) Proposed Pesticide Tolerance 6/93

Pesticide Tolerance for Cyromazine



AGENCY: Environmental Protection Agency 



ACTION: Proposed rule.

.

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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 

Ciba-Geigy Corp. 



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 

residues. 

   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 

chance.

   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 

legal holidays.

   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 

Programs.

   Therefore, it is proposed 40 CFR part 180 be amended as follows:



PART 180-[AMENDED]



   1. The authority citation for part 180 continues to read 

as follows:



   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:





                                                                              

                                                                              

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                           Commodity                              Parts per   

                                                                   million    

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Mushrooms......................................................         10.0  

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[FR Doc. 93-15416 Filed 6-29-93; 8:45 am]

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