UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460      

	OFFICE OF PREVENTION, PESTICIDE

	AND TOXIC SUBSTANCES

	

  SEQ CHAPTER \h \r 1 MEMORANDUM

	Date:	9 December 2008

	SUBJECT:	Common Triazole Metabolites:  Updated Aggregate Human Health
Risk Assessment to Address Tolerance Petitions for Metconazole,
Propiconazole, Prothioconazole, and Tetraconazole.

PC Codes:  	600074 (1,2,4-Triazole), 

		600011 (Triazolylalanine), 

		600082 (Triazolylacetic Acid), 

		625618 (Triazolylpyruvic Acid)	DP Barcode:  359490

MRID No.:  None	Registration No.:  None

Petition Nos.:  7F7221, 7F7292, 08FL03, 7F7300, 7F7279, 7F7273
Regulatory Action:  Section 3, Section 18

Assessment Type:  Single Chemical, Aggregate	Registration Case No.: 
None

TXR No.:  None	CAS No.:  Multiple



	From:	Michael A. Doherty, Ph.D., Senior Chemist

		Registration Action Branch 2

		Health Effects Division (HED) 7509P

	Through:	Christina Swartz, Branch Chief

		Registration Action Branch 2, HED

	To:	Paula Deschamp, Branch Chief

		Registration Action Branch 3, HED

		Dana Vogel, Branch Chief

		Registration Action Branch 1, HED

		Barbara Madden, PM

		RIMUERB

		Registration Division (RD) 7505P

		Cynthia Giles-Parker, Branch Chief

		Fungicide Branch, RD

I.	 CONCLUSIONS

Based on conservative, health-protective assumptions, aggregate risk
estimates associated with 1,2,4-triazole (T) and the conjugated triazole
metabolites [i.e., combined residues of triazolylalanine (TA),
triazolylacetic acid (TAA), and triazolylpyruvic acid (TP)] are below
HED’s level of concern.  There are no human heath risk issues for
these metabolites that would preclude the requested uses of metconazole,
propiconazole, prothioconazole, and tetraconazole.

II.	ACTION REQUESTED

Update the aggregate human health risk assessments for T and the
conjugated triazole metabolites to account for Section 3 (new use) and
Section 18 (emergency exemption) requests for various
triazole-derivative fungicides.

III.	BACKGROUND

In 2006, HED issued aggregate human health risk assessments for T and
the conjugated triazole metabolites (M. Doherty, et al., D322215, 7 FEB
06).  Those assessments addressed a back-log of triazole use requests
that had been held by the Agency pending resolution of various
toxicological and exposure concerns for the common triazole metabolites.
 The findings of that assessment were that risk estimates for all
exposure scenarios were below HED’s level of concern.  Since that
time, a number of requests for new uses of triazole-derivative
fungicides have been submitted to the Agency.  As a result of these
requests, new dietary exposure estimates have been made for T and
combined residues of TA, TAA, and TP, and new aggregate exposure and
risk estimates are necessary.  Neither the toxicological information nor
the non-dietary exposure estimates detailed in the 2006 memorandum have
changed; thus the only alterations to the previous aggregate exposure
and risk estimates are due to changes in the dietary exposure estimates.
 For complete hazard characterization and non-dietary exposure
assessments for the common triazole metabolites, see the 2006 risk
assessment.

IV.	RESULTS/DISCUSSION

As noted above, the only revisions to the components of the previous
aggregate exposure and risk estimates are to the dietary exposure
estimates.  For the common triazole metabolites, acute and chronic
aggregate risks consist only of dietary (food + water) components and,
therefore, are equivalent to the dietary risk estimates provided in the
most recent dietary exposure assessment (Table 1, M. Doherty, D350664, 6
October 2008).  

The revised aggregate estimates are summarized below for short- and
intermediate-term scenarios for T (Tables 2 and 3, respectively).  The
conjugated triazole metabolites are formed in plants by the conjugation
of 1,2,4-T to serine.  The TA may then be further metabolized to form
TAA and/or TP.  Because of the nature of this process, HED has assumed
that it occurs within the plant itself and not on leaf surfaces. 
Therefore, the residues are not available for dermal, hand-to-mouth, or
object-to-mouth exposures and HED has not conducted a residential
exposure assessment for the triazole conjugates.  Residues of TA, TAA,
and TP may occur in soil.  1,2,4-Triazole is more toxic than TA/TAA/TP
and exposures to these via soil ingestion are unlikely to exceed those
of 1,2,4-T.  The assessment for soil ingestion of 1,2,4-T shows that
risk estimates are below HED’s level of concern; therefore, risk
estimates for soil ingestion of the conjugates will also be below
HED’s level of concern.

Table 1.  Summary of Dietary (Food and Drinking Water) Exposure and Risk
for the Common Triazole Metabolites

Population Subgroup	Acute Dietary

(95th Percentile)	Chronic Dietary	Cancer

	Dietary Exposure (mg/kg/day)	% aPAD*	Dietary Exposure

(mg/kg/day)	% cPAD*	Dietary Exposure

(mg/kg/day)	Risk

1,2,4-Triazole

General U.S. Population	0.004598	15	0.001013	20	Not Applicable	Not
Applicable

All Infants (< 1 year old)	0.010834	36	0.001937	39



Children 1-2 years old	0.009229	31	0.002684	54



Children 3-5 years old	0.007354	25	0.002163	43



Children 6-12 years old	0.004944	16	0.001370	27



Youth 13-19 years old	0.003471	12	0.000827	17



Adults 20-49 years old	0.003623	12	0.000828	17



Adults 50+ years old	0.003200	11	0.000798	16



Females 13-49 years old	0.003573	12	0.000824	17



Triazolylalanine + Triazolylacetic Acid + Triazolylpyruvic Acid

General U.S. Population	Not Applicable	Not Applicable	0.011966	13	Not
Applicable	Not Applicable

All Infants (< 1 year old)

	0.017582	20



Children 1-2 years old

	0.035536	40



Children 3-5 years old

	0.027356	30



Children 6-12 years old

	0.016523	18



Youth 13-19 years old

	0.010162	11



Adults 20-49 years old

	0.009594	11



Adults 50+ years old

	0.008931	10



Females 13-49 years old	0.034040	34	0.009535	11



* The values for the highest exposed population for each type of risk
assessment are bolded.

Table 2.  Short-term Aggregate Exposure and Risk Estimates for
1,2,4-Triazole.

Population Subgroup	Exposure Estimate, mg/kg/day1	Aggregate MOE2

	Dietary	Dermal

(M/L/A)	Dermal (Post-Applic.)	Hand-to-Mouth	Object-to-Mouth	Soil
Ingestion	Aggregate

	U.S. Population (total)	0.001013	0.00183	0.0051	N/A	N/A	N/A	0.007943
3700

All infants (< 1 year)	0.001937	N/A	0.0086	0.0041	0.0010	0.000019
0.015656	1900

Children 1-2 yrs	0.002684	N/A	0.0086	0.0041	0.0010	0.000019	0.016403
1800

Children 3-5 yrs	0.002163	N/A	0.0086	0.0041	0.0010	0.000019	0.015882
1800

Children 6-12 yrs	0.001370	N/A	0.0086	N/A	N/A	N/A	0.009970	3000

Youth 13-19 yrs	0.000827	0.00183	0.0051	N/A	N/A	N/A	0.007757	3800

Adults 20-49 yrs	0.000828	0.00183	0.0051	N/A	N/A	N/A	0.007758	3800

Adults 50+ yrs	0.000798	0.00183	0.0051	N/A	N/A	N/A	0.007728	3800

Females 13-49 yrs	0.000824	0.00183	0.0051	N/A	N/A	N/A	0.007754	3800

1 Exposure estimates for dermal, hand-to-mouth, object-to-mouth, and
soil ingestion are from J. Arthur, DP 322240, 12/9/05.

2 Aggregate MOE = NOAEL (30 mg/kg/day) ÷ Aggregate Exposure Estimate
(mg/kg/day).  Level of Concern = 1000.



Table 3.  Intermediate-term Aggregate Exposure and Risk Estimates for
1,2,4-Triazole.

Population Subgroup	Exposure Estimate, mg/kg/day	Aggregate MOE2

	Dietary	Soil Ingestion1	Aggregate

	U.S. Population (total)	0.001013	N/A	0.001013	14000

All infants (< 1 year)	0.001937	0.000019	0.001956	7600

Children 1-2 yrs	0.002684	0.000019	0.002703	5500

Children 3-5 yrs	0.002163	0.000019	0.002182	6800

Children 6-12 yrs	0.001370	N/A	0.00137	10000

Youth 13-19 yrs	0.000827	N/A	0.000827	18000

Adults 20-49 yrs	0.000828	N/A	0.000828	18000

Adults 50+ yrs	0.000798	N/A	0.000798	18000

Females 13-49 yrs	0.000824	N/A	0.000824	18000

1 Soil ingestion estimates are from J. Arthur, DP 322240, 12/9/05

2 Aggregate MOE = NOAEL (15 mg/kg/day) ÷ Aggregate Exposure Estimate
(mg/kg/day).  Level of Concern = 3000.

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