Hydrazine Dietary Exposure and Risk Assessment DP Number: 0 420404

UNI T ED STATES ENVIRONMENTAL PROTECTION AGENC Y



### MEMORANDUM

DATE: June 4

, 2014 OFFICE OF CHEMICAL SAFETY

AND POLLUTION PREVENTION



### SUBJECT: Hydrazine. Scree ning Leve l Cancer Aggregate Dietary (F ood and Drinkin g Water) Ex po sure and Ri sk Assessment as Part of th e Maleic Hydrazide Registration Rev i ew.



### PC Code : None ( h ydr a zine), 05 150 1 ( maleic

h y dra z ide

, and 051503 (maleic h y dr azide, potassium sa lt)

. 

### DP Barcode: D420404



### Decision No.: 48178 1 

### Registration No

. : NA



### Petition No.: none 

### Risk Assessment Typ e : Dietary



### TXR No. : No t App lic able 

### Regulatory Act ion : Regi strat i on Review



### Case No.: 0381 (maleic hydr azide )



### CAS No

. : 302-01-2 (hydrazin e ); 123-3 3- 1 (maleic hydrazide)

, and 28382-15-2 (maleic

h ydrazide, po tassium s alt)



### MRID No.: No n e 

### 40 CFR: Not Applicable

B . C K hll". E

. IS

..

# ~~**n.dDJ-~\~ ,**  FROM: onme ropp- o 1g1an, n v uonm e nta c tentl st _L) '-"'UUf( (.)

Risk Assessme nt Branch IV ( RABI V), Health**Effec~ en**  (HE D ) ( 75 09P)



### THROUG H:

# n V. Hummel, Senior C hemis t 

# ),l.JV

RABIV, HED (7509P)

and 

## $

# ~ Thurston Morton, Senior**'st ~**  David Hrdy, Senio r Biol ogi 1 

# 7:

Dietary Expos ure Scienc e A ISory

### u~c 1 AC), HE D (7509P)



### TO: Ricar do Jon es, C h e mical Review Manage r #51

T om Moriarty, Tea m Leader RMIB1, Pe st i cide Re- Eva lu at ion Division ( 7508P)



### Executive Su mmary

Screening lev e l hydrazine cancer aggregate dietary (food and drinking water) ex po s ure and risk

a ssess ment s were co nducted u si ng the Dietary Exposure Evaluation Model software with th e



### 1 of 1 5Hydrazine Dietary Exposure and Risk Assessment DP Number: 0420404

Food Commodity Intake Database (DEEM-FCID) Version 3.16. This software uses 2003

- 2008

food consumption data from the U.S. Department of Agriculture's (USDA's) National Health

and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA). The analyses were conducted as part of the maleic hydrazide registration review to verify that the 15

ppm (0.0015%) Agency stipulated upper limit ofhydrazine in the technical grade of maleic hydrazide, which was set in ca. 1982 at the close of the maleic hydrazide Special Review (then

called Rebuttable Presumption Against Registration or RP AR)

, remains adequate. This

memorandum was reviewed by two peer reviewers ofthe DESAC per DESAC SOP 2012.1.

Male i c hydrazide and its potassium salt are currently registered for food/feed uses on onions and

potatoes. There is no registered use ofhydrazine. No hydrazine metabolism and/or magnitude

of the residue data for crops and/or livestock are available for dietary exposure and risk

assessments. Hence, screening level cancer dietary exposure and risk assessments for hydrazine

resu l ting from the registered uses of maleic hydrazide were conducted using anticipated residue

estimates for hydrazine based on avai l able maleic hydrazide data and assumed that the estimated

ratio of. maleic hydrazide to hydrazine in the technical grade of ma l eic hydrazide (100% to 0.0015%) remained unchanged in formulated end-use products and in/on crops through application/deposition/translocation and beyond. Furthermore

, it assumed that the transfer of

residues ofhydrazine in cattle tissue and milk was not significantly greater than the transfer of

total residues of maleic hydrazide (i.e.

, the tota l radioactive residues 

### (TRR) in livestock

commodities based on metabolism data). Thus, exposure for hydrazine was estimated at
0.0015% of the estimated exposure for maleic hydrazide. In the absence of chemical-specific processing data for hydrazine

, DEEM default processing factors were used for potato
flakes / granules / flour (6.5) and dried beef (1.92) and the max i mum theoretical concentration

factor for potato (5.0) was used for potato chips. In the absence of percent crop treated data,

100% crop treated was assumed. A Tier 1 estimated drinking water concentration (EDWC) for hydrazine based on fate data for hydrazine was also used.

The estimated exposure of the genera l U.S. population to hydraz i ne (food and drinking water)

from the registered uses of maleic hydrazide and assuming that the technical grade of the maleic hydrazide contains 15 ppm (0.0015%) ofhydrazine is 2.63538E-07 mg/kg/day. Applying the

Q1* of 3.0 (mg/kg / day)" 1 to the exposure value results in a cancer risk estimate of 8 x 

# w- 7

. This

estimate is consider conservative and is does not underestimate risk. The major contributors

were potatoes and potato chips.



### I. Introduction

Dietary risk assessment incorporates both exposure and toxicity of a given pesticide.

References that discuss the acute and chronic risk assessments in more detail are available on the EPNpesticides web site: " Available Information on Assessing Exposure from Pesticides

, A

User's Guide

, " 21-JUN-2000

, web link: http: // www.epa.gov / fedrg s tr/EPAPEST / 2000/July / Day-12/606l.pdf; or see SOP 99.6 (20-AUG-1999).

In 1976

, maleic hydrazide went into Special Review (then called Rebuttable Presumption Against Registration or 

### RP AR) because it met the risk criteria for oncogenic, mutagenic, and

2 of 15Hydrazine Dietary Exposure and Risk Assessment DP Number : D420404



### 3  f 15 reproductive effects. A Data Call

- In notice issued in 1980 resulted in suspension of the diethanolamine salt of maleic hydrazide (DEA

- MH) when its manufacturers did not submit the required data. All DEA

- MH reg istrations are now cancelled.

Based on other data submitted, EPA determined that the oncogenicity and reproductive effects triggers were not supported, and that only weak evidence supported the mutagenicity trigger. In concluding the RPAR in 1982, EPA al lowed continued use of maleic hydrazide and its potassium salt , but established an upper limit of 15 ppm for hydrazine (associated with tumor induction) in technical grade maleic hydrazi d e. At this level, lifetime cancer risks for both dietary and worker exposure were not deemed to be of concern. The 1988 Maleic Hydrazide Registration Standard , 1994 Maleic Hydrazide Reregistration Eligibility Decision (RED) and 2005 Maleic Hydrazide Tolerance Reassessment Eligibility Decision (TRED) continued to limit hy drazine in the technical product to 15 ppm

.

There is no record of a hydrazine dietary risk assessment conducted by HED in the current

databases. T h is hydrazine cancer dietary risk assessment is being c onducted as part of the maleic hydrazide registration review to verify that the 15 ppm (0.0015%) Agency stipulated upper limit of hydrazine in the technical grade of maleic hydrazide, which was set in ca. 1982 at the close of the maleic hydrazide Special Review (th e n called Rebuttable Presumption Against Reg istration or RPAR), remains adequate.

II. Residue Information

Maleic hydrazide and its potassium salt are currently registered for food/feed uses on onions and potatoes, as well as several terrestrial non

- food crops, including fallow land. Its major use is on tobacco. There are several currently registered technical grade products (400

- 97, 19713

- 25,

19713

- 26 and 51873

- 10) with maleic hydrazide at 95% or higher. Assuming the 15 ppm (0 .0015% ) Agency stipulated upper limit of hydrazine in the technica l grade of maleic hydrazide,

this would mean an estimated ratio of maleic hydrazide to hydrazine in the technical grade product of roughly 100% to 0.0015%.

There is no registered use of hydrazine and no tolerances for hydrazine are established. No hydrazine metabolism and/or magnitude of the residue data for crops and/ or livestock are available for dietary exposure and risk assessments. Hence, screening lev el cancer dietary exposure and risk assessments for hydrazine resulting from the registered uses of maleic hydrazide were conducted using anticipated residue estimates for hydrazine based on available maleic hydrazide data and assumed that the estimated ra tio of ma leic hydrazide to hydrazine in the technical grade of maleic hydrazide ( 100% to 0.0015%) remained unchanged in formulated

end

- use products and in/on crops through application/deposition /translocation and beyond

. Thus, exposure for hydrazine was e stimated at 0.0015% of the estimated exposure for maleic hydrazide

. Furthermore, it assumed that the transfer of residues of hydrazine in cattle tissue and milk was not significantly greater than the transfer of total residues of maleic hydrazide (i.e., t he total radioactive residues (TRR) in livestock commodities based on metabolism data).

Based on the premises and assumptions above, anticipated residues were estimated as follows.Hydrazine Dietary Exposure and Risk Assessment DP Number : D420404



### 4  f 15 Average residues of hydrazine in/on dry bulb onions and potatoes were estimated at 0.0015% of the average residues of maleic hydrazide determined in field trials conducted with maleic hydrazide at the maximum registered use rates of maleic hydrazide. Sinc e maleic hydrazide

treated potato culls and potato processing waste can be fed to cattle, residues of hydrazine in

cattle tissues and milk were estimated at 0.0015% of the maximum total residues of maleic hydrazide in cattle tissues and milk (i.e., total r adioactive residue (TRR) levels from the goat metabolism study) from feeding a reasonably balance ruminant diet. In the absence of chemical

specific processing data for hydrazine, DEEM default processing factors were used for potato flakes/granules/flour (6.5) and dried beef (1.92) and the maximum theoretical concentration factor for potato (5.0) was used for potato chips. In the absence of percent crop treated data, 100% crop treated was assumed. These anticipated residues were approved by the Anticipat ed

Residues (ARs) Focus Group of ChemSAC (4/15/14) and are summarized in the table below

.

Table 1. Anticipated Residue s (AR s ) Approved by the ARs Focus Group of ChemSAC (4/15/14) for Use in the Screening Level Hydrazine Can cer Dietary Exposure and Risk Assessment.

RAC Food

Forms Blending

Classif

ication 1 Data

Source % Crop

Treated Processing

Factors Screening Level

Chronic A Rs ( ppm) 2

Onion and Potato Commodities

Onion bulb NB AR s for hydrazine based on onion field trial data (MRID 42567805) for

maleic hydrazide and assumed 15 ppm (0.0015%) hydrazine in the maleic hydrazide technical product. See Attachment 4 for details.

100 DEEM

Default

1 40.7E

- 6

dried B DEEM

Default

9.0

Potato tuber PB or NB AR s f or hydrazine based on potato field trial data (MRID 42567804) for maleic hydrazide and assumed 15 ppm (0.0015%) hydrazine in the maleic hydrazide technical product.

See Attachment 4 for details

. DEEM

Default

1 245E

- 6

chips B Max 5.0 3
granules

/flakes B DEEM

Default

6.5 flour B

Meat and Milk Commodities

Liver AR s for hydrazine based on goat metabolism data ( MRID 4 6867202) for maleic hydrazide and assumed 15ppm (0.0015%) hydrazine in the maleic hydrazide technical product.

See Attachment 4 for details

. DEEM

Default

1 3.6E

- 6 Kidney 7.3E

- 6

Meat 0.8E

- 6 Beef, dried DEEM

default

1.92

Fat DEEM

Default

1 0.1E

- 6

Milk 1.1E

- 6

1. Classification: blended (B), partially blended (PB), not blended (NB).

2. Estimates are not in correct scientific notation but expressed in terms of E

- 6 for convenience of DEEM input.

3. In the absence of specific hydrazine data, used the maximum theoretical concentration factor for potato (5 .0 ) listed in GLN 860.1520.Hydrazine Dietary Exposure and Risk Assessment DP Number : D420404



### 5  f 15 III. Percent Crop Trea ted Information

No percent crop treated data are available for the uses of maleic hydrazide on onion and potato.

IV. Drinking Water Data

EFED generated screening level estimated drinking water concentrations (EDWCs) for hydrazine in surface and ground waters using GEN eric E stimated E

nvironmental C oncentration (GENEEC) and Pesticide Root Zone Model for Ground Water (PRZM

- GW), respectively. Modeling for hydrazine was based on fate data for hydrazine obtained from open literature, maximum use rates for maleic hydrazide and the assumption that the ratio of hydrazine to maleic hydrazide in the technical remained unchanged in formulated end

- use p roducts, through app lication/deposition and beyond. The highest modeled EDWC for hydrazine was

1.02E

- 3 ppb (Groundwater (Post Breakthrough Average)). [Email from I. Abdel

- Saheb to B. Cropp

- Kohlligian dated 5/9/14.]

The drinking water models and their de scriptions are available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/

.

V. DEEM

- FCID Program and Consumption Information

The hydrazine cancer dietary exposure assessment wa s conducted using the DEEM

- FCID, Version 3.16, which incorporates 2003

- 2008 consumption data from USDA’s NHANES/WWEIA. The data are based on the reported consumption of more than 20,000

individuals over two non

- consecutive survey days. Foods “as consumed ” (e.g., apple pie) are

linked to EPA

- defined food commodities (e.g., apples, peeled fruit

- cooked; fresh or N/S; baked;

or wheat flour

- cooked; fresh or N/S, baked) using publicly available recipe translation files developed jointly by USDA/ARS and EPA. For chronic exposure assessment, consumption data are averaged for the entire U.S. population and within population subgroups. For a chronic dietary exposure assessment, an estimate of the residue level in each food or food

- form (e.g.,

orange or orange juice) on the food commodity residue list is multiplied by the average daily consumption estimate for that food/food form to produce a residue intake estimate. The resulting

residue intake estimate for each food/food form is summed with the residue intake estimates for all other food/food forms on the commodity residue list to arrive at the total average estimated exposure. Exposure is expressed in mg/kg body weight/ day

.

VI. Toxicological Information

The US EPA National Center for Environmental Assess ment (NCEA) has classified hydrazine as a Group B2, probable human carcinogen (USEPA, 1999). The classification is based on tumors identified in mice, rats, and hamsters following oral, inhalation or intraperitoneal administration of hydrazine and hydrazi ne sulfate. Hydrazine was mutagenic in numerous assays. For the HED cancer dietary exposure and risk assessment , the oral cancer slope factor is most relevant. NCEA relied on a hydrazine sulfate (in water) gavage study in mice for the dose

- response data for the oral cancer slope factor. Liver hepatomas were observed in CBA/cb/Se male miceHydrazine Dietary Exposure and Risk Assessment DP Number : D420404



### 6  f 15 (Biancifiori, 1970). The oral cancer slope factor f or hydrazine is 3.0 (mg/kg/day)

- 1 

### using the

l inearized multistage procedure

. The carcinogenicity of hydrazine is discussed in EPA’s Integrated Risk Information System (IRIS, 2002).

VII. Results/Discussion

The estimated exposure of the general U.S. population to hydrazine (food and drinking water) from the registered uses of maleic hydrazide and assuming that the technical grade of the maleic hydrazide contains 15 ppm (0.0015%) of hydrazine is 2.63538E

- 07 mg/kg/day. Applying the Q 1 

### * of 3.0 (mg/kg/day)

- 1 

### to the exposure value results in a cancer risk estimate of 8 x 10

- 7 

### . Thi s estimate is consider conservative and is does not underestimate risk. The major contributors were potatoes and potato chips. Although there are a number of uncertainties, conservative assumptions were used in the anticipated residue estimates and dieta ry assessment including:

field trial data reflecting maximum use rates , metabolism data for cattle tissues and milk, DEEM default processing or maximum theoretical concentration factors, 100% crop treated and a Tier 1 drinking water estimate.

VIII. Ch aracterization of Inputs/Outputs

No hydrazine metabolism and/ or magnitude of the residue data for crops and/ or livestock are available for dietary exposure and risk assessments. Hence, a screening level cancer dietary exposure and risk assessment for hydrazine resulting from the registered uses of maleic hydrazide was conducted using anticipated residue (AR) estimates for hydrazine based on available maleic hydrazide data and assuming that the technical g rade of the maleic hydrazide contained 15 ppm (0.0015%) of hydrazine

. Thus, exposure for hydrazine was estimated at 0.0015% of the estimated exposure for maleic hydrazide

. Average residues of hydrazine in/on dry bulb onions and potatoes were estimated at 0.0015% of the average residues of maleic hydrazide determined in f ield trials conducted at the maximum registered use rate s of maleic hydrazide. Residues of hydrazine in cattle tissues and milk were estimated at 0.0015% of the

total radioactive residue (TRR) level s determined in the maleic hydrazide goat metabolism study adjusted for a 1x feeding level. In the absence of chemical

- specific processing data for hydrazine, DEEM default processing factors were used for potato flakes/granules/flour (6.5) and dried beef (1.92) and the maximum theoretical concentration factor for potato (5.0) was used for potato chips. In the absence of percent crop treated data for maleic hydrazide, 100% crop treated

was assumed.

Confidence in the estimates in/on dry bulb o nions and potatoes assumes that the combined effects of deposition to foliage and subsequent translocation to bulbs/tubers and environmental

forces over several weeks on residues of hydrazine and maleic hydrazide will not significantly increase the percent of hydrazine to maleic hydrazide realized in/on the maleic hydrazide

- treated

RACs

. Further, the confidence in the estimates in meat and milk assumes that residues of hydrazine will not transfer to tissues and milk to a significantly greater degree than t otal residues

of maleic hydrazide . These uncertainties are likely offset by the conservative assumptions used in the anticipated residue estimates and dietary assessment including: field trial data for dry bulb onions and potatoes reflecting maximum use rates , metabolism data for cattle tissues and milk,Hydrazine Dietary Exposure and Risk Assessment DP Number : D420404



### 7  f 15 DEEM default processing or maximum theoretical concentration factors and 100% crop treated.

IX. Conclusions

The estimated exposure of the general U.S. population to hydrazine (food and drinking water) from the registered uses of maleic hydrazide and assuming that the technical grade of the maleic hydrazide contains 15 ppm (0.0015%) of hydrazine is 2.63538E

- 07 mg/kg/day. Applying the Q 1 

### * of 3.0 (mg/kg/day)

- 1 

### to the exposure value results in a can cer risk estimate of 8 x 10

- 7



### . This

estimate is consider conservative and is does not underestimate risk.

X. List of Attachments

• Attachment 1: Cancer Residue Input F ile

• Attachment 2 : Cancer Results File

- Food and Drinking Water

• Attachment 3 : Major Contributors

- CCC R eport
Attachment 4 : Anticipated Residue (AR) Estimates Approved by the ARs Focus Group

of ChemSAC (4/15/14)Hydrazine Dietary Exposure and Risk Assessment DP Number : D420404



### 8  f 15 Attachment 1 : Cancer Residue Input file

Filename: Hydrazine Food and Water 4 21 14.R08 Chemical: Hydrazine RfD(Chronic): 0 mg/kg bw/day NOEL(Chronic): 0 mg/kg bw/day RfD(Acute): 0 mg/kg bw/day NOEL(Acute): 0 mg/kg bw/day Q*= 3
Date created/last modifie d: 04

- 21

- 2014/16:33:18 Program ver. 3.16, 03

- 08

- d

----------------------------------------------------------------------------------- EPA Crop Def Res Adj.Factors Comment Code Grp Commodity Name (ppm) * #1 #2

---------- ---- ------------------------------- ---------- ------ ------ ------- 0103296000 1C Potato, chips 245.000000 5.000 1.000 0103297000 1C Potato, dry (granules/ flakes) 24 5.000000 6.500 1.000 0103297001 1C Potato, dry (granules/ flakes)

- b 245.000000 6.500 1.000
0103298000 1C Potato, flour 245.000000 6.500 1.000 0103298001 1C Potato, flour

- babyfood 245.000000 6.500 1.000 0103299000 1C Potato, tuber, w/peel 245.000000 1.000 1.000 0103299001 1C Potato, tuber, w/peel

- babyfood 245.000000 1.000 1.000 0103300000 1C Potato, tuber, w/o peel 245.000000 1.000 1.000
0103300001 1C Potato, tuber, w/o peel

- babyfood 245.000000 1.000 1.000 0301237000 3A Onion, bulb 40.700000 1.000 1.000 0301237001 3A Onion, bulb

- babyfood 40.700000 1.000 1.000 0301238000 3A Onion, bulb, dried 40.700000 9.000 1.000 0301238001 3A Onion, bulb, dried

- babyfood 40.700000 9.000 1.000
3100044000 31 Beef, meat 0.800000 1.000 1.000 3100044001 31 Beef, meat

- babyfood 0.800000 1.000 1.000 3100045000 31 Beef, meat, dried 0.800000 1.92 0 1.000 3100046000 31 Beef, meat byproducts 7.300000 1.000 1.000 3100046001 31 Beef, meat byproducts

- babyfood 7.300000 1.000 1.000
3100047000 31 Beef, fat 0.100000 1.000 1.000 3100047001 31 Beef, fat

- babyfood 0.100000 1.000 1.000 3100048000 31 Beef, kidney 7.300000 1.000 1.000 3100049000 31 Beef, liver 3.600000 1.000 1.000 3100049001 31 Beef, liver

- babyfood 3.600000 1.000 1.000 3600222000 36 Milk, fat 1.100000 1.000 1.000
3600222001 36 Milk, fat

- baby food/infant formu 1.100000 1.000 1.0 00 3600223000 36 Milk, nonfat solids 1.100000 1.000 1.000
3600223001 36 Milk, nonfat solids

- baby food/in 1.100000 1.000 1.000
3600224000 36 Milk, water 1.100000 1.000 1.000

3600224001 36 Milk , water

- babyfood/infant form 1.100000 1.000 1.000 3600225001 36 Milk, sugar (lactose)

- baby food/ 1.100000 1.000 1.000
8601000000 86A Water, direct, all sources 1.020000 1.000 1.000 8602000000 86B Water, indirect, all sources 1.020000 1.000 1.000

* Correct Values: Residue v alues ( ppm) as entered must be multiplied by the reviewer by E

- 06

.Hydrazine Dietary Exposure and Risk Assessment DP Number : D420404



### 9  f 15 Attachment 2 : Cancer Results File

- Food and Water

US EPA Ver. 3.16, 03

- 08

- d

DEEM

- FCID Chronic analysis for HYDRAZINE NHANES 2003

- 2008 2

- day Residue file name: Hydrazine Food and Water 4 21 14.R08 Adjustment fact or #2 NOT used. Analysis Date 04

- 21

- 2014/16:40:27 Residue file dated: 04

- 21

- 2014/16:39:12
Q* = 3

=============================================================================== Total exposure by population subgroup

---------------- ---------------------------------------------------------------

Total Exposure

----------------------------------- Population mg/kg Lifetime risk * Subgroup body wt/day * (Q*= 3)

-------------------------------------- ------------- -------------- Total US Population 0.263538 7.91E

- 01

Re viewer Calculated Results* 2.63538E

- 7 * 8E

- 7 *

* Reviewer Calculated Results: Residue v alues as entered into the Residue Input File (see

A ttachment 1) must be multiplied by the reviewer by E

- 06; hence, total exposure results (i.e., mg/kg/day and Lifetime risk) have been multiplied by the reviewer by E

- 06 and expressed in

correct scientific notation

.



### Attachment 3 : Major Contributors

- CCC Report

U.S. EPA Ver. 3.16, 03

- 08

- d

DEEM

- FCID Chronic analysis for HYDRAZINE NHANES 2003

- 2008 2

- day

Residue file name: Hydrazine Food and Water 4 21 14.R08 Adjustment factor #2 NOT used. Analysis Date 04

- 21

- 2014/16:40:27 Residue file dated: 04

- 21

- 2014/16:39:12
Q* = 3

=============================================================================== Complete commodity contribution analysis for

Total US Population

-------------------------------------------------------------------------------

Crop Group = (1) Root and Tuber Vegetables Exposure analysis

------------------------- Residue Adjustment mg/kg Lifetime risk *

Food name (ppm x E

- 06)* Factors body wt/day * (Q*= 3)

---------------------------- ---------- ------------- ----------- ------------- Potato, chips (0103296000): FoodForm N/S 245.000000 5.000 1.000 0.0508302 E

- 06 * 1.52E

- 0 7 *
Potato, tuber, w /o peel (0103300000):
FoodForm N/S 245.000000 1.000 1.000 0.1149151 E

- 06 * 3.45E

- 0 7 *

----------- -------------

* Reviewer Calculated Results: Residue v alues as entered into the Residue Input File (see Attachment 1) must be multiplied by the reviewer by E

- 06; hence, total exposure results (i.e., mg/kg/day and Lifetime risk) have been multiplied by the reviewer by E

- 06 and LIfetime risk is expressed in correct s cientific notation

.Hydrazine Dietary Exposure and Risk Assessment DP Number : D420404



### 10  f 15 Attachment 4 : Anticipated Residue s (AR s ) Approved by the A R s Focus Group of ChemSAC (4/15/14)

Maleic hydrazide and its potassium salt are currently registered for food/feed uses on onions and potatoes, as well as several terrestrial non

- food crops, including fallow land. Its major use is on tobacco. There are several currently registered technica l grade products (400

- 97, 19713

- 25,

19713

- 26 and 51873

- 10) with maleic hydrazide at 95% or higher. Assuming the 15 ppm ( 0.0015%) Agency stipulated upper limit of hydrazine in the technical grade of maleic hydrazide,

this would mean an estimated ratio of m aleic hydrazide to hydrazine in the technical grade product of roughly 100% to 0.0015%. (or 1 to 1.5E

- 5 )

.

There is no registered use of hydrazine and no tolerances for hydrazine are established. No hydrazine metabolism and/or magnitude of the residue da ta for crops and/ or livestock are available for dietary exposure and risk assessments. Hence, s creening level anticipated residues for hydrazine are based on available maleic hydrazide data and assume that the estimated ratio of maleic hydrazide to hydraz ine in the technical grade of maleic hydrazide (1 to 1 .5E

- 5 based on 0.0015% Agency stipulated upper limit of hydrazine in the technical grade of maleic hydrazide) remains unchanged in formulated end

- use products and in/on crops through application/deposit ion / translocation and beyond . Furthermore, it assumes that the transfer of residues of hydrazine in cattle tissue and milk is not significantly greater than the transfer of total residues of maleic hydrazide (i.e., the total radioactive residues (TRR) in livestock commodities based on metabolism data).

Based on the premises and assumptions above, anticipate residue s were estimated as follows. Average residues of hydrazine in/on dry bulb onions and potatoes were estimated at 0.0015% of the average resid ues of maleic hydrazide determined in field trials conducted with maleic hydrazide at the maximum registered use rates for maleic hydrazide. In the absence of specific processing data for hydrazine, DEEM default processing factors were used for potato

fla kes/granules /flour (6.5) and the maximum theoretical concentration factor for potato (5.0) was used for potato chips. In the absence of percent crop treated data for maleic hydrazide, 100% crop treated was assumed. Since maleic hydrazide

- treated potato c ulls and potato processing waste can be fed to cattle, residues of hydrazine in cattle tissues and milk were estimated at 0.0015% of the maximum total residues of maleic hydrazide in cattle tissues and milk (i.e., total radioactive residue (TRR) levels fro m the goat metabolism study) from feeding a reasonably

balance ruminant diet.

Detailed Considerations

Chemical Identity

Maleic hydrazide is a solid at room temperature and is very soluble in water and methanol. Hydrazine is a colorless oily liquid , fuming in air with a penetrating odor resembling that of

ammonia. The nomenclature of maleic hydrazide and hydrazine is presented in Table 4

. 1 . The available physicochemical properties of hydrazine are presented in Table 4 .2 ; available maleic hydrazide data for the same properties are also provided for comparison.Hydrazine Dietary Exposure and Risk Assessment DP Number : D420404



### 11  f 15 Table 4 .1

. Maleic Hydrazide and Hydrazine Nomenclature

Chemical structure

Common name Maleic hydrazide

Company experimental name MH

IUPAC name 6

- hydroxy

- 2H

- pyridazin

- 3

- one

CAS name 1,2

- dihydro

- 3,6

- pyridazinedione

CAS registry number 123

- 33

- 1

Molecular Formula C4

- H4

- N2

- O2

Formula Weight 112.1

Chemical Structure H 2 N

— NH 2

Common name Hydrazine

Company experimental name NA

IUPAC name Hydrazine

CAS name Hydrazine

CAS registry number 302

- 01

- 2

Molecular Formula H 2 N

— NH 2 Formula Weight 32.0

Table 4

. 2 . Physicochemical Properties of Maleic Hydrazide (Technical Grade) and Hydrazine.

Parameter Maleic Hydrazide Hydrazine

Value Reference Value Reference

Water solubility 4507 ppm at 25  C USDA/ARS Pesticide Properties

Database Miscible EPA Air Toxics Web Site http://www.epa.gov/ttn/atw/hlthef/ hydrazin.html Vapor pressure

at 25  C 7.5 E

- 8 14.4 mm Hg

Octanol/water partition coefficient (log

K
ow ) 0.011 at pH 7 0.08Hydrazine Dietary Exposure and Risk Assessment DP Number : D420404



### 12  f 15 Maleic Hydrazide Directions for Use

Maleic hydrazide and its potassium salt are registered for use on onions and potatoes. The

maximum use rate for onion is 1 application at 2 lb ai/A with a 10

- day PHI. The maximum use

rate for potato is 1 application at 3 lb ai/A with a 4

- 6 weeks PHI.

Screening Level A R Estimate s for H ydrazine in/on Onion and Potato RACs

Onion and Potato Metabolism Data
D162009/D164425/D168996, E. Zager, 10/28/91 Maleic Hydrazide RED, T. Morton, 9/1/2005



### The qualitative nature of the residue in plants is adequately understood for the current registrations, based on studies conducted on onions and potatoes. These studies indicate that maleic hydrazide is translocated in plants, but not metabolized extensively.

Field grown onions were treated with ring

- labeled [ 14 

### C]maleic hydrazide at 2.07 lb ai/A (ca 1x the maximum registered use rate). Whole plants and bulbs were col lected at 1 hour and 2 weeks following the application. The maximum total radioactive residues (TRR) in/on bulbs were 29.1 ppm and 180 ppm dry weight maleic hydrazide equivalents at 1 hour and 2 weeks, respectively.

Field grown potatoes were treated wit h ring

- labeled [ 14 

### C]maleic hydrazide at 2.89 lb ai/A (ca 1x the maximum registered use rate). Vines and tubers were collected at 1 hour, 2 weeks and 8 weeks following the application. The maximum total radioactive residues (TRR) in/on tubers were 0.3 ppm , 176 ppm and 160 ppm dry weight maleic hydrazide equivalents at 1 hour, 2 weeks and 8 weeks, respectively.

Onion and Potato Field Trial Data
D187782, W. Smith, 7/19/93; MRID 42567805 (onion) and MRID 42567804 (potato)



### Maleic hydrazide crop field trials were conducted on potatoes and onions using application methods, timings, and rates which reflect the current use patterns of active formulation of maleic hydrazide. The AOAC hydrazine distillation method deemed a dequate for data collection was

used to d etect maleic hydrazide and the subject data were supported by adequate storage stability

data.

Onion field trials were conducted in 15 geographically representative tests each with a single broadcast application of the 2.25 lb/gal EC formulation made at 2 lbs ai/A, using ground equipment delivering 10

- 126.6 gal/A. Onion samples were harvested from each test 10

- 11 days
post

- treatment.

Potato field trials were conducted in 14 geographically representative tests each with a single broadcast application of the 2.25 lb ai/gal EC formulation made at a target rate of 3 lbs ai/A using ground equipment delivering 8.87

- 44.9 gal/A. Samples of potatoes each were harvested

from each test 20

- 21 days post

- treatment.Hydrazine Dietary Exposure and Risk Assessment DP Number : D420404



### 13  f 15 Table 4

. 3

. Summary of Residue Data from Onion and Potato Crop Field Trials.

Maleic Hydrazide Residue Levels Found (ppm) 1 Reviewer Calculated Average Hydrazine Residue Level (ppm) 3 n Min. Max. LAFT 2 HAFT 2 Median Mean Std. Dev.

Onions (Field Trials Reflect One Application at 2.0 lb ai/A; PHI 10

- 11 days)

15 <0.22 9.48 0.38 7.44 1.29 2.71 2.29 40.7E

- 6

Potato Tubers (Field Trials Reflect One Application at 3.0 lb ai/A; PHI 20

- 21 days)

14 <1.2 60.89 4 2.17 47.6 11.7 16.3 13.8 245E

- 6 1 Except for sample min/max, values reflect per trial averages; n = no. of field trials. For calculation of median, mean, and standard deviation, the LOQ (0.22 ppm for onion and 1.2 ppm for potato) was used for any results reported as <LOQ.

2 LAFT = l owest average field trial; HAFT = highest average field trial. 3 Calculated Average Hydrazine Residues = Mean Maleic Hydrazide Residues x 1.5E

- 5 (i.e. 15 ppm or 0.0015% in technical). Estimates are not in correct scientific notation but expressed in term s of E

- 6 for convenience of DEEM input. 4 The currently established tolerance for residues of maleic hydrazide in/on potato is 50 ppm. The high value of 60.89 ppm was determined to be an outlier by the Dixon Q

- test compared to the five other samples from field trials conducted in ME (D187782, W. Smith, 7/19/93).



### Conclusions. The onion and potato field trial data are appropriate for estimating anticipated residues (ARs) of hydrazine in/on onions and potatoes. These estimates are s creening level and assume that the combined effects of deposition to foliage and subsequent translocation to bulbs/tubers and environmental forces over several weeks on residues of hydrazine and maleic hydrazide will not significantly increase the percent of hydrazine t o maleic hydrazide (0.0015%

to 100%) realized in/on the maleic hydrazide

- treated RACs.

Screening Level A R Estimate s for Hydrazine in/on Potato Processed Commodities

In the absence of potato processing data for hydrazine, the maximum theoretical concentration factor for potato is 5x will be applied to potato chips and the DEEM default concentration factor 6.5x will be applied to dried potato commodities.

Screening L evel A R Estimate s for Hydrazine in Livestock Commodities

Maleic hydrazide is registered for use on potatoes. Potato culls and potato processing waste can be fed to cattle. According to Table 1 Feedstuffs (revised July 2008), these feedstuffs are among

t he most commonly fed to feedlot beef (up to 30% of the diet from all potato commodities) and high

- production dairy cattle (up to 10% of the diet from all potato commodities), and are usually mixed together. There are no registrations for maleic hydrazide on any poultry or swine feedstuff; hence, there is no expectation of finite residues in poultry or swine.

Dietary burdens for maleic hydrazide were calculated for beef and dairy cattle using the percent dry matter and percent diet specified in Table 1 Fee dstuffs (revised July 2008) . Given that this is a cancer assessment, residues of maleic hydrazide in potato culls and potato processing waste were estimated based on average field trial values for potato tubers (16.3 ppm) and the maximum

theoretical conce ntration factor for processing waste (4.0x; GLN 860.1520). Also, it wasHydrazine Dietary Exposure and Risk Assessment DP Number : D420404



### 14  f 15 assumed that on average potato culls and processing waste would be fed to cattle on a 50:50

basis.

Table 4.4. Calculation of Dietary Burdens of Maleic Hydrazide Residues to Cattl e

.

Crop Commodity Type 1 Residue 2 %DM %Diet 3 Dietary

Contribution 4

ppm input ppm
Beef Cattle (80% CC; 15% R; 5% PC) 2

Potato Culls CC 16.3 Ave 20 15 12.2

Processing Waste CC 65.2 15 15 65.2

Untreated N/A CC 0

N/A N/A 50 0

R 0 15 0

PC 0 5 0

Total

- - - - - 100 77
Dairy Cattle (45% CC; 45% R; 10% PC) 2

Potato Culls CC 16.3 Ave 20 5 4.1

Processing Waste CC 65.2 15 5 21.7

Untreated N/A CC 0

N/A N/A 35 0

R 0 45 0

PC 0 10 0

Total

- - - - - 100 26 1 R = Roughage; CC = Carbohydrate concen trate; PC = Protein concentrate.

2 Potato Culls = Average Maleic Hydrazide Residues in/on Potato = 16.3 ppm Potato Processing Waste = Ave

. Potato Residues (16.3 ppm) x Max . Theore tical Conc

. Factor (4.0x) = 65.2 ppm

3 Table 1 Feedstuffs (revised July 2008 ). Potato culls and processing waste are usually mixed together. The maximum for all potato commodities in the beef and dairy diet are 30% and 10%, respectively. For this cancer assessment, it was assumed that on ave rage potato culls and processing waste would be fed to cattle on a 50:50

basis. 4 Contribution = ([residue /% DM] X % diet) for beef and dairy cattle



### Ruminant Metabolism

D326395/D326396/D336734

, S. Hummel, 3/7/14 ; MRID 46867202 (Goat Metabolism)



### In the maleic hydrazide goat metabolism study, lactating goats were fed at 522.2 ppm with [14C]maleic hydrazide in the feed, which is about 6.8x the estimated beef cattle dietary burden (77 ppm) and about 20x the estimated dairy cattle dietary burden (26 ppm). The total radioactive residues (TRR) were 0.7006

- 1.447 ppm in milk, 1.619 ppm in liver, 3.301 ppm in kidney, 0.368 ppm in muscle, and 0.052 ppm in fat. Radioactivity in milk appeared to plateau by Day 2. Most

of the administered dose was excreted (83.23%), with the majority (~64.89%) excreted in the

urine.Hydrazine Dietary Exposure and Risk Assessment DP Number : D420404



### 15  f 15 Table 4 .5 . Total Radioactive Residues (TRR) in Milk and Tissues Following Oral Dosing with [14C]maleic hydrazide at 522.2 ppm in the Diet for 3.5 Consecutive Days

Matrix Collection

Timing % Administered

Dose TRR found

,

expressed as maleic hydrazide equivalents (ppm ) TRR at 1x

feeding level

, expressed as

maleic h ydrazide equivalents (ppm ) Reviewer

calculated hydrazine at 1x feeding level 2 (ppm)

Milk Day 1

- 4 0.14 (All days) 1.4467 (max) 0.071 1.1E

- 6

Liver At sacrifice 0.09 (All edible tissues) 1.619 0.238 3.6E

- 6 Kidney At sacrifice 3.301 0.485 7.3E

- 6

Muscle At sacrifice 0.368 0.054 0.8E

- 6

Fat At sacrifice 0.052 0.008 0.1E

- 6

1 TRR determined both at the in

- life facility and the analytical laboratory. The TRR values determined at the in

- life facility were used for all calculations. 2 Hydrazine = TRR (expressed as maleic hydrazide equivalents) at 1x feeding level X 1.5E

- 5 (i. e. 15 ppm or 0.0015% in technical). Estimates are not in correct scientific notation but expressed in terms of E

- 6 for convenience of DEEM input.



### Conclusions. TRR values from livestock metabolism data which are limited to transfer of

residues in tissues and milk are appropriate for estimating anticipated residues of hydrazine in cattle tissues and milk. These estimates are conservative and assume substantially similar transfer of hydrazine residues and maleic hydrazide residues in tissues and milk. The re is no evidence that residues of hydrazine will be incurred in tissues and milk at a substantially higher

level than the TRR.