### UN ITE D STATES ENVIRONMENTAL PRO TE CTION AG EN CY

WASHINGTON, D. C. 20460

MEMORANDUM

Date: March 1 2, 2014 OFFICE OF
CHEM ICAL S AFETY AND
POLL UT I O N PREVE N T IO N



### SUBJECT: Hydrogen Cya namide: Prelimin ary Ri sk Assessment for Registration Review

PC Code: 01400 2

Decision No.: 453348

Pet ition No.: Not App li cab le (N / A)

Risk Assessment Type: Single Chemical

TXR N o

. : N / A

MRID No.: N / A DP Barcode: 393086 Registration No.: N/A Regulatory Action: Registration Re v iew

Case No.: 7005

CAS No.: 420-0 4 -2

40 CFR: N / A (non-food / non-feed use)

FROM: Jessica Kidwell, Risk Assessor

# ~**~** Abd a ll a h Khasawinah, ToxicoloBst

- , Bonni e.

# Crop**p-Kohlli~ian, Che~ist** **~nd** Dietary

# Assessor**j3~ nll\A/L-** **r-~ '\..r**  Ivan Nteves, Occupahonal/Restdenttal Ex posure Assessor

## ..:.- 

## ...........-l r**~** Risk Assessment Branch 4

H eal th Effects D ivis ion (7509P)

THROUGH: Elissa Reaves, Ph

. D.

, Branch Chief 

# c**(2___** Ri sk Assessment Branch 4

H eal th Effec t s Division (7509P)

TO: Dana Fr i e dman

, RM 52

Kevin Coste ll o, Branch Chief RMIB2, Pest icid e Re-Evaluation Division (7508P)

This document provides the Health Effects Division's ( HED 's) preliminary risk assessme n t for Hydrogen Cyanamide in support of Re g i stration Review.

### Hydro ge n Cya namide Human Health Risk Assessment DP No. D393086



### 1.0 Executive Summary

................. . ...... . ... . .. ............................. .. . .. ...................... ....... . ....... ..... 4

2.0 HED Recommendations

............ ................. .... ......... ...... ......................... ...... ...... ............... 8

2.1 Data Deficiencies ............................................................................................................ 9

2.2 Tolerance Considerations

. ............................................................................................. 9

2.3 Label Recommendations

................................................................................................ 9

2.3.2 Recommendations from Occupational Assessment..

............................................... 9

2.3.3 Recommendations f rom Residential Assessment..

.................................... .. .. .. .. .. ... 10



### 3.0 Introduction

........... .. .. .................... . .. .. .. .. .. .. . .. ................................. .. .. .. .. .. .. .. .................... 10


### 3.1 Chemical Identity

. .. ................. ........................................................................... ... .. .. .. . 10



### 3.2 Physical/Chemical Characteristics

.. ............................................................. .. .. ........ .. 11


### 3.3 Pesticide Use Pattern

........................ ...................................... . ..... ... . ... ..... .......... .. ... ..... 11



### 3.4 Anticipated Exposure Pathways

................................ .. ............................................... 13


### 3.5 Considerat ion of Environmental Justice

......................................... . .......................... 13



### 4.0 Hazard Characterization and Dose-Response Assessment..

................................ .. .. .. .. 13


### 4.1 Toxico logy S tudies Available for Ana lysis

.......... .. .......... .. .......... .. .. ......... .................. 13



### 4

. 2 Absorption, Distribution, Metabolism, & 

### Eli min at ion (ADME)

........... .. .. .. .. .. .. .. .... 14



### 4

. 2.1 Dermal Absorption

................. ........................ ... . .. ................. ............................... .. .. 15

4.3 Toxicolog ical Effec ts

.................................................................................................... 15

4.4 Safety Factor for Infants and Children (FQPA Safety Facto r)

.... . .......................... 16

4

. 5 Toxicity Endpoint and Point of Departure Se l ections

.................. .. .. ........................ 17

4.5.1 Dose-Response Assessme nt

.......................................................... .. .......................... 17

4.5.2 Recommendation for Combining Routes of Exposu res for Risk Assess ment..

... 18

4.5.3 Cancer C lassification and Risk Assessment Recommendation

............................ 18

4.5.4 Summary of Po ints of Departure and Toxicity E ndpoint s Us ed in H uman Risk

Assessment

. .. .. .. . .. .. .. . .. .. .. . .. .. .. ........ .. .. ........................................................... .. .......... ........... .. ... 19

4 .6 E ndocrine Disruption

........................................................................ . .. .. .. .. .. ...... .......... 20

5.0 Dietary Exposure and Risk Assessment..

............................................ . .......................... 21

5.1 Metabolite/Degradate Residue Profile

............................ .. .. .. ..................................... 21

5.1.1 Summary of Plant and Animal Metabolism Studies

...... .. .......... . .......................... 21

5.1.3 C omparison of Metabolic Pathways

................................ .... ........ . .......................... 22

5.1.4 Residues of Concern Summary and Rationale

........ ...... .. .. .. ...... . . . .. .. .. .. .. ...... .. ....... 23

5.2 F ood Residue Profil e

........... ...... ................................................................................... 23

5.4 D i etary Risk Assessment

............... . ... . ... ..... .. ................................. .. .. .. .. .. .. .. .. .. .. ...... .. ... 25

5.4.1 Descrip tion of Residue Data Used in Dietary Assessment

.................................... 25

5.4.2 Percent Crop Treated Used in Dietary Assessment

........................ .............. ........ 26

5.4

. 3 Acute Dietary Risk Assessment

............................................................................... 26

5.4.4 Chronic Dietary Risk Assessme nt

........................................................................... 26

5.4.5 Cancer Dietary Risk Assessment..

........................................................................... 26

5.4.6 S ummary Tab les

....................................................................................................... 27

6.0 Residential (Non -Occupational) Exposure/Risk C h aracterizat ion

............................. 27

6.1 Spray Drift

.. .. .. .......................... ................................................. ......................... . ......... 28

6.2 Residential Bystander Post-Application Inhalation Expos ur e

................................ 32

7.0 C umu lative Exposu r e/Risk Characterization

.............................................................. . 32

8.0 

### Occupational E xposure/Risk Characterization

.......... .. .. .. .. .. .. .......... .. .......................... 32

8

. 1 S hort- and Intermediate-Term Non-Cancer and Cancer Han dler Risk

................. 32

9

. 2 Occupational Post-application Expos ure/R isk Es timates

........................................ 50

Page 2 of 75

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 3 of 75 9.2.1 Occupational Post

- application Inhalation Exposure/Risk Estimates

.............. 50

9.2.2 Occupational Post

- application Dermal Exposure/Risk Estimates

................... 50

10.0 References

................................ ................................ ................................ ......................... 51 Appendix A. Toxicology Profile and Executive Summaries

................................ .................. 53

A.1 Toxicology Data Requirements

................................ ................................ ................... 53

A.2 Toxicity Profiles

................................ ................................ ................................ ............ 54

A.3 Hazard Identification and En dpoint Selection

................................ .......................... 60

A.4 Executive Summaries

................................ ................................ ................................ ... 64 Appendix B

................................ ................................ ................................ ................................ .. 73 Appendix C

................................ ................................ ................................ ................................ .. 74 Appendix D

................................ ................................ ................................ ................................ .. 75

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 4 of 75 1.0 Executive Summary

Hydrogen cyanamide is a plant growth regulator used to promote uniform bud break in a number of deciduous fruit trees and woody perennials. Currently registered uses of hydrogen cyanamide

are considered non

- food/non

- feed and are, therefore, not subject to the 1996 Food Quality Protection Act (FQPA). However, it is EPA's policy to apply risk assessment techniques developed in the implementation of the FQPA to any pesticide risk assessment, whether it falls under the FQPA or not, so long as application of the risk assessment technique is consistent with good scientific practice and is not otherwise prohibited by law.

Hydrogen cyanamide is currently registered under Section 3 for use on dormant apples, blackberries, blueberries, cherries, grapes, figs, kiwi f ruits, nectarines, and peaches

. I t is also currently registered under Section 24 (c) for use in California on dormant figs (CA040002) and in

Hawaii for use on dormant grapes (HI030003). Applications are made once per season using

airblast and ground equipment only at maximum use rates up to 17.6 lb ai/A. All end

- use products are formulated as liquid water soluble concentrates containing 50% of hydrogen cyanamide as the sole active ingredient . A pplications would be made not less than 30 days pri or to budbreak. Relevant exposure scenarios include acute and chronic dietary exposure (water only) and occupational exposures. While there are no currently registered residential uses of hydrogen cyanamide, there is potential for non

- occupational exposur es resulting from indirect spray drift of pesticide applications. Aggregate risk is not assessed since hydrogen cya na mide is registered as a non

- food use. This risk assessment was reviewed by the Risk Assessment Review Committee (RARC) on December 4 , 2013.

Hazard

Hydrogen cyanamide toxicity was evaluated in several species and studies employing a 50%

aqueous hydrogen cyanamide because of the instability and explosivity of the pure material

. Subchronic and chronic studies in rats and dogs via the oral r oute indicated that the thyroid and testes are the primary target organs of toxicity of hydrogen cyanamide. Its subchronic and chronic toxicity occurs at similar dose levels which are consistent with its rapid absorption and elimination from the body. Cli nical signs of n eurotoxicity were also seen in a chronic dog study

as tremors at the high dose. Salivation and struggling during dosing were also seen in a

subchronic dog study at the mid and high doses

. In an acute dermal toxicity study in rabbits,

clini cal signs of depression, tremors and ataxia were reported at the limit dermal dose of 1000 mg/kg. In an acute inhalation toxicity study with 50% aqueous hydrogen cyanamide aerosol, clinical signs in male and female rats included piloerection and decreased activity starting at 4.5 hours after the exposure began until day 2. Acute and subchronic neurotoxicity (ACN and SCN)

, 28

- day inhalation, subchronic dermal, and immunotoxicity studies are not available and are required.

There was no increased qualitative or quantitative fetal or offspring susceptibility in the prenatal developmental or postnatal reproduction studies in the rat . In the rabbit developmental toxicity study, maternal and developmental toxicity occurred at the highest dose tested. Maternal toxi city was limited to decreased body weight gain compared to disintegration of fetal liver structure and hemorrhagic appendix seen in the fetuses, suggesting qualitative susceptibility.

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 5 of 75 Hydrogen cyanamide was negative in a bacterial reverse gene mutation a ssay, an in vivo mouse bone marrow micronucleus assay, and in an unscheduled DNA synthesis assay. Hydrogen cyanamide was positive with and without activation in an in vitro cytogenetic study. The Health Effects Division Carcinogenicity Peer Review Committe e (CPRC) classified hydrogen cyanamide as a Group C chemical

– a possible human carcinogen. Based upon female mouse ovarian granulosa

- theca tumor rates in a 104

- week drinking water study, a Q 1 * 

### value of 6.64 x

10 - 2 

### (mg/kg/day) - 1 

### was estimated . There was no e vid ence of carcinogenicity in rats

.

Hydrogen cyanamide is classified as Toxicity Category II for acute oral

, acute dermal toxicity

, acute eye irritation

, and acute dermal irritation , and Toxicity Category IV for acute inhalation. Hydrogen cyanamide is not a dermal sensitizer.

Endpoints and Uncertainty Factors for Risk Assessment

Toxicity endpoints and points of departure (PODs) were selected for dietary , incidental oral, and occupational dermal and inhalation exposure scenarios . For the acute dietary end point, a point of departure ( POD ) of 5 mg/kg (m aternal NOAEL) for the general population was selected from a

r at developmental toxicity study. The LOAEL of 15 mg/kg/day was based on hypoactivity seen on Gestation Days 6 and 7 in 8/25 animals after 1 or 2 d ays of dosing. A n uncertainty factor ( UF ) of 10 00 X ( 1 0 X for intraspecies variation, 10 x for interspecies extrapolation and a 10 X database uncertainty factor ) was applied to the dose to obtain an acute reference dose (aRfD) of 0.005 mg/kg

. The 10X database uncertainty factor (DB UF 

### ) include s several data gaps (ACN, SCN, and immunotoxicity studies).

For the chronic dietary as well as the incidental oral and short

- and intermediate

- term dermal and

inhalation occupational endpoints , co

- critical studie s (subchronic and chronic toxicity studies in dogs) were selected since they provided the most sensitive endpoint s

. For these scenarios , a point of departure ( POD ) of 2 .0 mg/kg/day (NOAEL) was used

. The LOAEL of 5 mg/kg/day was based on multiple effects ( increased incidences of rough haircoat, desquamation of the skin, tremors, and salivation; decreased body weight gain; decreased T 4 

### in males; increased relative thyroid

- parathyroid weights in females; brown pigment in liver Kupffer cells; thymic atrophy in males; testicular inflammation; and aspermatogenesis and hypospermatogenesis ). A UF of

1000 X (10 X for intraspecies variation, 10 X for interspecies extrapolation and a 10 X database uncertainty factor for several datagaps, including ACN, SCN and immunotoxic ity studies ) was applied to the dose to obtain a chronic reference dose (cRfD) of 0.002 mg/kg/day. A Margin of Exposure ( MOE ) of 100 0 (10 X for intraspecies variation, 10 X for interspecies extrapolation and

a 10 X database uncertainty factor for five datagap s, including ACN, SCN, immunotoxicity, 28

- day inhalation and short

- term dermal toxicity studies ) is required for the incidental oral, d ermal

and inhalation exposure s

.

Dietary ( W

ater O nly) Exposure and Risk

The residue of concern in drinking water is the parent, hydrogen cyanamide. Tier 2 modeling was used to estimate drinking water concentrations of hydrogen cyanamide in ground and

surface waters

. The highest values from among all the scenarios modeled in th e drinking water assessment were from surface water. For surface water, the highest 1

- in

- 10 year peak and annual

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 6 of 75 mean values were from the MI Cherries scenario and the highest 30 year mean value was from the CA Grapes scenario. Of significance, s urface wat er values were multiplied by a percent crop

area (PCA) factor of 0.23 for Orchard/Vineyard. In addition, an aquatic buffer of 300 yard s ( 900

f ee t ), which is currently on labels to protect aquatic organisms, was used to calculate the spray

drift fraction in put for surface water modeling , reducing the percentage of drift from the default

value of 6.4% to 0.1%

.

T he 30 year distribution of daily surface water concentrations based on the MI Cherries scenario

was input into the acute dietary assessment

. The 1

- in

- 10 year annual mean based on the MI Cherries scenario and the 30 year mean based on the CA Grapes were input into the chronic and cancer dietary assessment s , respectively.

Acute and non

- cancer chronic dietary risk estimates below 100% of the acute or c hronic RfD are generally not of concern. The acute probabilistic dietary assessment for hydrogen cyanamide in drinking water results in an estimated risk of 110% of the aRfD at the 99.9 th 

### percentile of exposure, 13% of the aRfD at the 99 th 

### percentile

, and <1% of the aRfD at the 95 th 

### percentile for all population subgroups. All Infants < 1 year of age is the most highly

- exposed subgroup, utilizing 110% of the aRfD, while the General US population utilizes 33% of the aRfD , both at

the 99.9 th 

### percentile

.

Th e c hronic dietary exposure from hydrogen cyanamide in drinking water results in the
estimated risk of ≤9.1 % of the c RfD for all population subgroups. All I nfants < 1 year of a ge is the most highly

- exposed subgroup, utilizing 9.1 % of the c RfD , while the G en eral US population

utilizes 3.5 % of the c RfD

. The chronic dietary risk estimates are not of concern for the general population or other subpopulations.

The Health Effects Division Carcinogenicity Peer Review Committee (CPRC) classified hydrogen cyanamide as a Group C chemical

– a possible human carcinogen. Based upon female mouse ovarian granulosa

- theca tumor rates in a 104

- week drinking water study, a Q 1 * 

### value of

6.64 x 10 - 2 

### (mg/kg/day) - 1 

### was estimated using a cross

- species scaling factor for the administ ered dose based on equivalence of body weight to the 3⁄4 power per day (body weight 3/4 

### )

. The cancer

risk estimate from hydrogen cyanamide in drinking water is 9.3 2 x 10 - 7



### .

Residential Exposure and Risk

T here are no currently registered residential uses of hydrogen cyanamide

.

Spray Drift

The non

- occupational exposure scenario from the potential drift of pesticides applied in an agricultural setting was assessed. The spray drift assessment resulted in risk estimates of concern (MOEs <1000) at the edge of the field for all equipments (groundboom and airblast)

. Buffers ranged from 0 feet to greater than 300 feet depending on the nozzle type and application equipment.

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 7 of 75 Occupational Exposure and Risk

A chemical

- specific passive dosimetry study and three biomonitoring studies were submitted to the Agency for hydrogen cyanamide by the registrant along with a label amendment action requesting the removal of the requirement for closed cab on the label

. The exposure data from

these studies were used to estimate applicator risks as a comparison to HED’s surrogate handler exposure data. For purposes of registration review, HED updated this assessment to reflect current policies and assumptions.

Occupational Handlers

Non

- cancer risk estimates: Default HED unit exposure values with refined treated acreage resulted in combined (dermal and inhalation) non

- cancer risk estimates of concern ranging from 130 to 1200 for both mixer/loaders and applicators (LOC = 1000).

Usin g the chemical

- specific dosimetry data, all applicator scenarios resulted in risk estimates of concern via the dermal route of exposure (MOEs ranged from 31 to 960 using engineering controls). Inhalation exposure, utilizing the passive dosimetry study data , resulted in no risk estimates of concern (MOEs ≥ 1000). MOEs ranged from 990 to 5300 using engineering controls (i.e., closed cab).

Risk estimates using data from the three urine biomonitoring studies were of concern (MOEs <1000; MOEs range: 59 to 120 0) for all applicator scenarios, except for one scenario using data

from MRID 453657

- 01 [unit exposure geometric mean 0.00103 (mg/lb ai)] applying hydrogen cyanamide at the lowest rate (6.6 lb ai/A) to the most refined area treated (20 Acres; HED default

i s 40 A for airblast).

Cancer risk estimates: Default HED unit exposure values with refined treated acreage resulted in cancer risk estimates ranging from 1.4x10 - 6 

### to 1.5x10 - 3



### .

Using data from the passive dosimetry study (MRID 454074

- 03), cancer risk estimates for private applicators using closed cab airblast equipment ranged from 2.0x10 - 6 

### to 5.3x10 - 5 

### . With open cabs, the resulting cancer risk estimates were 1.4x10 - 5 

### to 7.6x10 - 5



### .

Exposure dat a for a private applicator operating airblast equipment using chemical

- resistant suits (open cab) from the three urine biomonitoring studies (MRIDs 454074

- 02, 453657

- 01, 454074

- 01), resulted in cancer risk estimates ranging from 1.4x10 - 6 

### to 2.8x10 - 5



### .

Us ing default HED unit exposure values, risk estimates for private applicators using closed cab airblast equipment ranged from 2.2x10 - 6 

### to 1.2x10 - 5 

### . HED default open cab assumption using double layer, gloves and a PF10 respirator resulted in cancer risk est imates ranging from 8.5x10 - 4



### to 4.6x10 - 3



### .

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 8 of 75 Occupational Post

-

Application

A revised preliminary quantitative post

- application inhalation exposure assessment was not performed for hydrogen c yanamide at this time

. If new policies or procedures are put in to place, the Agency may revisit the need for a quantitative occupational post

- application inhalation

exposure assessment for h ydrogen c yanamide.

A quantitative post

- application dermal assessment was not performed for this action. Hydrogen cyanamide is re gistered to be applied to deciduous crops approximately 30 days before bud break to synchronize blossoming and/or produce a more uniform bud break. The

post

- application activity associated with this chemical’s registered uses is pruning. The Agency

does no t expect significant risk from this dermal post

- application activity since at the time of application deciduous crops are in a state of dormancy where plants exhibit little or no foliage growth as indicated on the labels . Moreover, registered labels state that all pruning activities must be completed before application of pesticide

.

The Restricted Entry Interval (REI) is based on the acute dermal toxicity, eye irritation, and skin irritation effects of hydrogen cyanamide. These criteria are classified as toxicity category II based on hydrogen cyanamide’s acute toxicity profile. According to the Worker Protection Standard guidelines the minimum REI should be 24 hours, therefore the 72 hour REI on the registered labels is adequate.

Human Studies Review

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include studies from PHED 1.1; the AHETF database; the ARTF database; a chemical

- specific passive dosimetry study and three biomonitoring studies submitted to the Agency by the registrant are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included review by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency website 1



### .

2.0 HED Recommendations

HED has evaluated the toxicity and expos ure databases for the active ingredient, hydrogen cyanamide, and has conducted a human health risk assessment in support of Registration

Review. Based on this assessment, HED has determined that there are potential risk estimates of

concern for the curren tly registered uses of hydrogen cyanamide.

There are occupational handler risk estimates of concern associated with this pesticide despite refinements surrounding the input assumptions and the use of chemical

- specific data submitted

1 http://www.epa.gov/pesticides/science/handler

- exposure

- data.html and http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 9 of 75 by the registrant. Th ese refinements include: 1) the use of Personal Protective Equipment (PPE) (i.e., engineering controls), 2) reducing the number of acres treated, 3) reducing the number of days applicators treat crops per year (for cancer risk), and 4) incorporating geome tric mean unit exposure values from the chemical

- specific studies. The spray drift assessment resulted in risk estimates of concern (MOEs < 1000) at the edge of the field for all equipments (groundboom and airblast)

.

2.1 Data Deficiencies

Toxicology:

• 28

- Day Inhalation toxicity Study (870.3465)

• Subchronic Dermal toxicity Study: The registrant can conduct and submit a 7

- day (pilot) dermal toxicity study in male and female rats in order to determine the feasibility and/or potential doses for a subchronic dermal study and the effects of hydrogen cyanamide on the skin due to repeated dosing and/or b) alternative approaches (i.e., in vitro human epidermis tests such as OECD test guidelines 431 and 439) with respect to evaluating human interaction and corrosivity of hydrogen cyanamide.

• Acute and Subchronic Neurotoxicity Studies (870 .6200a and 870.6200b) •Immunotoxicity Study (870.7800)

2.2 Tolerance Considerations

Currently registered uses are considered non

- food/non

- feed uses and no tolerances have been established for residues of hydrogen cyanamide. No Codex, Canadian, or Mexican maximum residue levels (MRLs) have been established for hydrogen cyanamide.

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

None for residue chemistry. However

, an aquatic buffer of 300 yard s (900 feet), which is currently on labels to protect aquatic organisms, was used to calculate the spray drift fraction input for surface water modeling , reducing the percentage of drift from the default value of 6.4% to 0.1%. Hence, labels should specify a similar buffer zone to protect "all surface water that may be used as a source of drinking water" in accordance with the refinements used in the dietary risk

assessment.

2.3.2 Recommendations from Occupational Assessment

T he use of chemical

- resistant s uits by applicators while in an enclosed cab is inconsistent with the Agency regulation practices. In accordance with 40 CFR Section 170.240 d.5.iv, “Persons occupying an enclosed cab shall have all labeling

- specified personal protective equipment (PPE) im mediately available and stored in a chemical

- resistant container , such as a plastic bag. They shall wear PPE if it is necessary to exit the cab and contact pesticide treated

surfaces in the treated area . Once PPE is worn in treated area, it must be removed before re

entering the cab”. HED recommends taking this requirement off the label.

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 10 of 75 2.3.3 Recommendations f rom Residential Assessment

Not applicable.

3.0 In troduction

3.1 Chemical Identity

Literature Reference: Güthner, T. and Mertschenk, B. 2006. Cyanamides. Ullmann's Encyclopedia of Industrial Chemistry.



### Hydrogen cyanamide exists in two tautomeric forms, NCNH 2 

### and HNCNH. The NCNH 2 

### form predominates.

Cyanamide undergoes dimerization to form dicyandiamide. According to Merck Index, formation of dicyandiamide begins at 122o C . Dicyandiamide exists between two or more

tautomeric forms. Tautometic Form 2 shown below predominates.

As a crystalline solid, hydrogen cyanamide is combustible and deliquescent. Cyanamide nomenclature is reported below in Table 3. 1.

Table 3. 1. Hydrogen Cyanamide Nomenclature

Chemical structure

Common name Cyanamide Empirical formula CH 2 N 2 Molecular weight 42.04

PC Code 014002

IUPAC name Hydrogen cyanamide

CAS name Hydrogen cyanamide CAS registry number 420

- 04

- 2

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 11 of 75 3.2 Physical/Chemical Characteristics

Physicochemical properties of pure hydrogen cyanamide available from literature are reported

below in Appendix D

, Table 3.2

. 1.

3.3 Pesticide Use Pattern

Hydrogen cyanamide is a plant growth regulator used to promote uniform bud break in a number of deciduous fruit trees and woody perennials

. Based on the most recent information from the

OPPIN database and the LUIS Report ( current as of 9/11/2012 ) , it is presently registered under Section 3 of FIFRA for use on dormant apples, blackberries, blueberries, cherries, grapes (wine and raisin; desert; non

- desert ), kiwi fruit s (California only), peaches, and nectarines. It is registered under Section 24(c) of FIFRA on the following crops: figs in California (CA040002) and grapes in Hawaii (HI030003). It is applied with airblast and groundboom equipment approximately 30 days before bud break to produce a more uniform bud break in plants that have received less than their full chill hour requirement and, thereby, promoting more uniform flowering and, finally, more uniform maturity of fruit at harvest

.

The registered end

- use pr oducts included in this assessment are:

1. Dormex® (EPA Reg. No.54555

- 2; EPA Reg. No.CA040002; EPA Reg. No. HI030003 )

- a liquid concentrate product containing 50% ai or 4.4 lbs ai/gallon;

2. Krop

- MaxTM (EPA Reg. No. 80697

- 6)

- a liquid concentrate product conta ining 50% ai or 4.55 lbs ai/gallon; and

3. Duomax (EPA Reg. No. 84374

- 1)

- a liquid concentrate product containing 50% ai or 4.4 lbs ai/gallon.

T he currently registered uses of hydrogen cyanamide are considered non

- food /non

- feed uses based on the dormant use pattern, the end

- use product formulation which is not expected to delay decomposition of hydrogen cyanamide, the available residue data, and the general understanding of the environmental fate of hydrogen cyanamide. D rinking water and occupational exposure s

are expected. Hydrogen cyanamide is not registered for use in residential settings. Non

occupational exposure from indirect spray drift as a result of pesticide application is also being

assessed. Moreover, all three (3) registe red labels contain a RESTRICTED USE PESTICIDE clause that states that these pesticides are “f or retail sale to and use only by Certified Applicators or persons under their direct supervision and only for those uses covered by the Certified

Applicator's Cer tification. ” The products are applied once a year in the winter to promote

bud break in the spring

. Products will be applied to dormant plants, trees, and vines.

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 12 of 75 Table 3

. 3.1 . Registered Uses for Hydrogen Cyanamide

Application Timing, Type, and Equipm ent Formulation

[EPA Reg. No.] Maximum

Seasonal Application

Rate (lb ai/A) Max. No. Applic. per Season Use Directions and

Limitations

Apples, Grapes, Cherries, Kiwi Fruit, and Figs

30 days or

more before

normal

budbreak

Ground (airblast) Liquid

Concentrate (50%ai)

[54555

- 2;

80697

- 6;

84374

- 1] 17.6 Not specified on labels: Assume maximum of 1 apps/crop season at maximum rate after pruning 30 days before normal bud swell, or 35 days

before normal budbreak.

 For Grapes labels specify to make one

app lication per crop cycle.

 For desert grown grapes make the application earlier than 4 weeks prior to normal budbreak not before December 1or later than January 31.

 For Non

- Desert grown grapes make the application earlier than 4 weeks prior to normal

budbre ak but not before January 1or later than February 28.

 For Kiwi Fruit make the application earlier than four weeks prior to normal budbreak.  Aerial application is prohibited.

 Do not apply this product through any type of irrigation system.

 Duomax on Kiwi Fr uit is registered only for use in

California.

Blackberries

30 days or

more before

normal

budbreak

Ground ( ground

boom and airblast) Liquid

Concentrate (50%ai)

[54555

- 2;

84374

- 1] 13.2 Not specified on labels: Assume maximum of 1 apps/crop season at maximum rate 30 days or

more before normal budbreak and before new green growth appears.  Aerial application is prohibited.

 Do not apply this product through any type of irrigation system.

Blueberries 30 days or

more before

normal

budbreak

Ground ( groundboom

and airblast) Liquid

Concentrate (50%ai)

[54555

- 2;

80697

- 6;

84374

- 1] 6.6

- 13.2 Not specified on labels: Assume maximum of 1 apps/crop season at maximum rate 30 or more days prior to natural flower and vegetative

budbreak.  Aerial application i s prohibited.

 Do not apply this product through any type of irrigation system.

Nectarine and Peach

30 days or

more before

normal

budbreak

Ground ( groundboom

and airblast) Liquid

Concentrate (50%ai) [54555

- 2;

80697

- 6;

84374

- 1] 4.4

– 6.6 Not specified on labels: Assume maximum of 1 apps/crop season at maximum rate 30 or more days prior to normal budbreak.  Aerial application is prohibited.

 Do not apply this product through any type of irrigation system.

 Not to be used in

California

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 13 of 75 3.4 Anticipated Exposure Pathways

Humans are not expected to be exposed to hydrogen cyanamide via food as the existing uses of hydrogen cyanamide are all considered to be non

- food /non

- feed uses. Drinking water exposure is expected based on the existing use pattern and environmental fate parameters of hydrogen cyanamide. There is potential for occupational handler exposures, but there are no anticipated occupational post

- application activit ies that will result in significant exposures to workers. There are no currently registered residential uses of hydrogen cyan a mide , however

, there is potential for non

- occupational exposures resulting from indirect spray drift of pesticide application

.

3. 5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions

to Address Environmen tal Justice in Minority Populations and Low

- Income Populations," ( http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf

. As a part of every pesticide risk assessment, OPP considers a l arge variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption,

and activi ties in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessme nts for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized su bgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults ent ering or playing on treated areas post

- application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders a nd farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

T he endpoints of toxicity chosen by HED in 2001 (TXR# 0014511) have been re

- evaluated by

the hydrogen cyanamide team. Hydrogen cyanamide, a potent aldehyde dehydrogenase inhibitor, is used in alcohol aversion therapy in some countries ( e.g. Canada, Japan and Europe) to treat

chronic alcoholism. It blocks ethanol metabolism by inhibiting aldehyde d ehydrogenase which then causes an increase in blood acetaldehyde levels.

4.1 Toxicology Studies Available for Analysis

T he toxicology database for hydrogen cyanamide is not complete but is adequate for evaluating and characterizing its toxicity and selec ting endpoints for purposes of risk assessment . Studies

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 14 of 75 considered for this assessment include acute lethality (oral, dermal and inhalation routes), primary eye and dermal irritation, dermal sensitization, subchronic oral toxicity (rat

, mouse and dog ), do g chronic toxicity, rat combined chronic toxicity/carcinogenicity, mouse carcinogenicity, developmental toxicity (rat and rabbit), rat two

- generation reproductive toxicity, genotoxicity, and rat metabolism. A 28

- day inhalation study and a neurotoxicity bat tery (acute and subchronic) are not available and are required ( HASPOC TXR# 0056332 )

. An immunotoxicity study required as part of new 40 CFR Part 158 data requirements for registration of a pesticide is also not available

. A subchronic dermal toxicity study is also required (HASPOC

TXR# 0056 857 ). The dermal toxici ty study requirement was re

- evaluated by HASPOC on December 12, 2013. Additional information on the dermal exposure of hydrogen cyanamide is needed to provide data that will more accurately re flect the risk of the chemical via the dermal route. HASPOC recommends discussing potential laboratory approaches to improve characterization of dermal exposure with OPP. Suggestions include: a) the registrant conduct

and submit a 7

- day (pilot) dermal to xicity study in male and female rats in order to determine the feasibility and/or potential doses for a subchronic dermal study and the effects of hydrogen cyanamide on the skin due to repeated dosing and/or b) alternative approaches (i.e., in vitro

human epidermis tests such as OECD test guidelines 431 and 439) with respect to evaluating human interaction and corrosivity of hydrogen cyanamide. S ee Appendix A for the complete

t oxicology p rofile and e xecutive s ummaries for hydrog en cyanamide

.

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

A guideline metabolism study (MRID No. 42906401) using oral or intravenous (i.v.)

administration demonstrated that 14 

### C

- hydrogen cyanamide wa s rapidly absorbed via the oral route (> 90% of the administered dose within 24 hours)

, and rapidly distributed, metabolized, and excreted following administration to rats. Total radioactivity recoveries were high for all

oral and i.v. groups (98.7

- 105.5% of administered dose). Urine was the m ajor route of excretion (66.9

- 97.7% of administered dose). The elimination of hydrogen cyanamide was sex

- , dose

- , and route

- related. The recovery of radioactivity in the feces was higher in the i.v. group (13.2

- 15.0% of administered dose) compared to oral groups (2.76

- 4.15% of administered dose), suggesting that biliary excretion is an important r o ute following i.v. administration. Recoveries in expired CO 2 

### were higher in the males than in the females and were higher in the i.v. and single

low

- dose oral gr oups compared to the repeated oral dose and high oral dose groups. These findings suggest that there is a depletion of metabolic enzymes (or saturation) at the high

- dose group, and therefore, only a limited amount of the hydrogen cyanamide is metabolized to CO 2



### . Tissue bioaccumulation of hydrogen cyanamide was low for all groups. Most of the 14 

### C

hydrogen cyanamide was metabolized to form N

- acetylcyanamide, which is eliminated in the

urine and feces.

Published studies (summarized in TXR 0010591; MRID 421 78407) also demonstrated fast ADME processes for hydrogen cyanamide following oral, intravenous ( i.v. ), and intraperitoneal ( i. p

. ) dosing in rats, dogs, or rabbits (See Appendix B) . Following i. p

. dosing in rats, 93.4% of

the dose (radioactivity) was excreted in the urine within the first 6 hours, indicating fast

distribution and almost complete elimination within this time period . Negligible amounts were excreted as expired CO 2 

### . Following both oral and i.v. dosing in dogs, 62

- 83.1% of the dose wa s excreted in the urine within the first 24

- 27 hours. Negligible amounts of radioactivity were

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 15 of 75 excreted in the feces. The major metabolite of cyanamide excreted in the urine of rats, rabbits, dogs and hum a ns was i dentified as N

- acetylcyanamide . Following both i.v. and oral dosing in dogs, approximately 87% of the radioactivity was excreted as acetylcyanamide in the urine during the first 27 hours post exposure. Unchanged hydrogen cyanamide represented 11%

- l 2% of the dose in the dog urine ). R ats excreted a pproximately 40 %

- 45.6 % of the dose in the urine as acetylcyanamide within 48 hours post dosing. Following oral dosing

, plasma concentrations peaked after 5 minutes in rats and 30 minutes in dogs. Bioavailability was 68.7% in rats dosed with 2 mg/kg and 65 % in dogs dosed with 4 mg/kg. Following i.v. dosing, the elimination half

life in rats dosed with 2 mg/kg was 33 minutes ; the elimination half

- lives in dogs dosed with 1

- 4 mg/kg were dose dependent and ranged from 38.7 minutes to 61.3 minutes.

4.2.1 Derm al Absorption

A dermal penetration study indicated that 14 

### C

- h ydrogen c yanami d e absorbed was generally proportional to the dose and i ncreased with exposure duration

. At dermal doses of 0.1, 1, or 10 mg (8, 80, or 800 μg/cm 2 

### , respectively) the average 14 

### C

- hydrogen cyanamide equivalents absorbed within 24 hours were 1.79%, 2.84%, and 11.1%. For all dose groups at all times the majority o f the applied radioactive dose was recovered in the skin wash. The amount of radioactivity in the skin generally decrea sed with time through 24 hours, and did not appear to be related to the amount of applied dose. Since an oral NOAEL was selected for the dermal risk

assessment, a dermal absorption factor of 1 1 % should be used based on the findings in this study.

4.3 To xicological Effects

Hydrogen cyanamide toxicity was evaluated in several species and studies employing a 50%

aqueous hydrogen cyanamide because of the instability and explosivity of the pure material

. Hydrogen cyanamide subchronic and chronic toxicity in experimental animals occurs at doses of

5

- 15 mg/kg/day with NOAELs approximately one third of the LOAEL doses. Additionally, its subchronic and chronic toxicity occurs at similar dose levels which are consistent with its rapid absorption and elimination f rom the body. Subchronic and chronic studies in rats and dogs via the oral route indicated that the thyroid and testes are the primary organs of toxicity of hydrogen cyanamide. In rats, subchronic dietary feeding of hydrogen cyanamide resulted in morpholo gical activation in the thyroids consisting of an increased number of small follicles lined by cuboidal epithelium and disappearance of colloid

. T he number of inter follicular cells was increased and occasionally accompanied by a marked proliferation of f ollicular epithelial cells. Chronic oral gavage exposure of rats resulted in reduced colloid in the t hyroid and reduced T 3 

### and T 4 

### levels at

week 14

. E ffects in rats also included decreased RBC, hemoglobin , and hematocrit

. In dogs, subchronic dietary feeding resulted in decreased absolute and relative testicular weights, and thymus weights (females), aggregates of polymorphonuclear and mononuclear inflammatory cells in the parotid salivary glands, testicular atrophy, and re duced or inhibited sperm atogenesis. Effects seen in dogs following oral gavage subchronic and chronic dosing included the following: d ecreased T 4 

### in males; increased relative thyroid

- parathyroid weights in females; brown pigment in liver Kupffer cells; th ymic atrophy in males; testicular inflammation; and aspermatogenesis, and hypospermatogenesis.

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 16 of 75 There was no increased qualitative or quantitative fetal or offspring susceptibility in the prenatal developmental or postnatal reproduction studies conducted i n rats . In the rat developmental toxicity study, the maternal effects consisted of decreased body weight gain (

- 18%) and food consumption (

- 8%) at the mid dose while developmental effects occurred at the high dose and consisted of decreased fetal body wei ght, increase in diaphragmatic hernias and wavy/bent ribs. In the rabbit developmental toxicity study, maternal and developmental toxicity occurred at the highest dose tested. Maternal toxicity was limited to decreased body weight gain compared to

disinte gration of fetal liver structure and hemorrhagic appendix seen in the fetuses, suggesting qualitative susceptibility. In the 2

- generation reproduction study, parental toxicity occurred at a dose lower than the dose causing offspring toxicity. Parental tox icity consisted of significant decreases in body weight/weight gain (

- 8%/

- 18%). Offspring toxicity consisted of decreased pup viability in both generations. No reproductive toxicity occurred at the highest dose tested. Although thyroid effects were seen in rats and dogs as discussed above, a comparative thyroid study is not required at this time based on endpoints that are protective of this effect and are approximately ten times lower than the doses that cause developmental or post natal toxicity.

Clini cal signs of n eurotoxicity were seen in a chronic dog study as tremors at the high dose. Salivation and struggling during dosing were also seen in a subchronic dog study at the mid and high doses

. Acute and subchronic neurotoxicity studies are not avail able and are required. In an acute dermal toxicity study in rabbits, clinical signs of depression, tremors and ataxia were reported at a dermal dose of 1000 mg/kg. In an acute inhalation toxicity study with 50% aqueous hydrogen cyanamide aerosol, clinical signs in male and female rats included piloerection and decreased activity starting at 4.5 hours after the exposure began until day 2.

Hydrogen cyanamide is classified as Toxicity Category II for acute oral and acute

dermal toxicity, acute eye irritation and acute dermal irritation , and Toxicity Category IV

for acute inhalation. Hydrogen cyanamide is not a dermal sensitizer.

Hydrogen cyanamide was negative in a guideline bacterial reverse gene mutation assay, an in

vivo mouse bone marrow micron ucleus assay, and in an unscheduled DNA synthesis assay. It was weakly positive in Salmonella strain TA 1535 with activation but negative without activation in an NTP study. Hydrogen cyanamide was positive with and without activation in an

in vitro cytog enetic study. The Health Effects Division Carcinogenicity Peer Review Committee (CPRC) classified hydrogen cyanamide as a Group C chemical

– possible human carcinogen (TXR No. 0010592)

. This decision was based on the presence of ovarian granulosa

- theca tumo rs in female CD

- 1 mice and hemangiosarcomas in male B6C3F1 mice. There was no evid ence of carcinogenicity in rats. A Q 1 * 

### value of 6.64 x 10 - 2 

### (mg/kg/day) - 1 

### was estimated using body weight 3⁄4 

### interspecies scaling factor b ased upon female mouse ovarian granulosa

- theca tumor

rates in a 104

- week drinking water study ( TXR No. 0014510 ).

4.4 Safety F actor for Infants and Children (FQPA Safety Factor)

Since there are no currently registered food/feed uses or residential uses of hydrogen cyanamide, hydrogen cyanamide is not subject to the Food Quality Protection Act (1996). Therefore, for the purposes of the forthcoming hydrogen cyanamide risk assessment for Registration Review, an

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 17 of 75 FQPA assessment is not included. However, an additional database uncertainty factor was applied for missing studies as discussed under Section 4.5.1 Dose Response Assessment.

4.5 Toxicity Endpoint and Point of D eparture Selections

4.5.1 Dose

- Response Assessment

Toxicity endpoints and points of departure (PODs) for dietary (water) and occupational exposure scenarios are summarized below. A detailed description of the studies used as a basis for the selected endpoints are presented in Appendix A.

For the acute dietary endpoint, a point of departure ( POD ) of 5 mg/kg ( maternal NOAEL) for the general population was selected from a rat developmental toxicity study based on hypoactivity on GD 6 and 7 in 32% of the animals after 1 or 2 days of dosing at a LOAEL of 15 mg/kg/day

. A UF of 10 00 X ( 1 0x for intraspecies variation, 10 X for interspecies extrapolation and a 10 X database uncertainty factor ) was applied to the dose to obtain an acute r eference dose (a RfD ) of 0.005 mg/kg

. The 10X database uncertainty factor ( UF DB 

### ) includes several data gaps (ACN, SCN, and immunotoxicity studies).

For the chronic dietary endpoint, co

- critical studies (subchronic and chronic toxicity studies in dogs) were selected since they provided the most sensitive long

- term exposure endpoint. A

chronic POD of 2 .0 mg/kg/day (NOAEL) was selected for the general population from a subchronic oral gavage study in dogs based on effects seen in the chronic oral gavage dog study at a LOAEL of 5 mg/kg/day. These effects included the following: increased incidences of rough haircoat, desquamation of the skin, tremors, and salivation; decreased body weight gain;

decreased T 4 

### in males; increased relative thyroid

- parathyroid weights in females; brown pigment in liver Kupffer cells; thymic atrophy in males; testicular inflammation; and aspermatogenesis and hypospermatogenesis . These two studies were co

- critical since the effects from the chronic and subchronic dog studies were similar, but due to an artifact of dose selection, the subchronic dog had a higher NOAEL (2 mg/kg/day) than the chronic dog study (NOAEL = 1 mg/kg/day). The dose spread in the subchronic and chronic dog studies is also very similar. Since hydrogen cyanamide did not show progression of effects with duration of exposure, a short

- to long

- term uncertainty factor is not needed. A UF of 1000 X (10 X for intraspecies variation, 10 X for interspecies extrapolation and a 10 X database uncertainty factor as described above ) was applied

to the dose to obtain a chronic reference dose (c RfD ) of 0.002 mg/kg/day.

There are no residential uses for hydrogen cyanamide; however, indirect spray drift exposures to residential areas from pesticide application are assessed

. A short

- term i ncidental oral endpoint

w as selected specifically for this assessment. T he POD selected was the same as the POD for the chronic dietary endpoint. The residential level of concern for MOE is 100 0 . This includes 10X for interspecies extrapolation

, 10X for intraspecies variation , and 10X database uncertainty

factor

.

For both the short

- and intermediate

- term dermal and inhalation endpoints, the PODs selected were the same as POD for the chronic dietary endpoint. The occupational level of concern for

MOE of 100 0 is required for both the short

- an d intermediate

- term dermal and inhalation

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 18 of 75 scenarios. This includes 10X for interspecies extrapolation

, 10X for intraspecies variation , and 10X database uncertainty factor for five data gaps (ACN, SCN, immunotoxicity

, 28

- day inhalation, and a subchronic der ma l toxicity study), A dermal absorption factor of 11% is applied based on a dermal penetration study ( MRID No. 41504004 ). Since an oral NOAEL was selected for inhalation risk assessment, an inhalation absorption factor of 100% should be used

.

Long

- term dermal and inhalation exposure is not anticipated based on the current use pattern (one application per season) for hydrogen cyanamide. Therefore, long

- term PODs have not been

established.

4.5.2 Recommendation for Combining Routes of Exposures for Risk As sessment

Dermal and inhalation exposures to workers may be combined for hydrogen cyanamide because the toxicity endpoints for these exposure routes are the same. For spray drift exposures, d ermal

and incidental oral risk estimates for children 1 to < 2 years old were combined because the toxicity endpoint for each route of exposure is the same.

4.5.3 Cancer Classification and Risk Assessment Recommendation

The Health Effects Division Carcinogenicity Peer Review Committee (CPRC) classified hydrogen cy anamide as a Group C chemical

– possible human carcinogen (TXR No. 0010592)

. This decision was based on the presence of ovarian granulosa

- theca tumors in female CD

- 1 mice and hemangiosarcomas in male B6C3F1 mice. There was no evid ence of carcinogenicity in r ats.

A Q 1 * 

### value of 6.64 x 10 - 2 

### (mg/kg/day) - 1 

### was estimated using body weight 3⁄4 

### interspecies scaling

factor b ased upon female mouse ovarian granulosa

- theca tumor rates in a 104

- week drinking water study ( TXR No. 0014510 ).

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 19 of 75 4. 5

. 4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk

Assessment

Table 4.5.4.1 Summary of Toxicological Doses and Endpoints for Hydrogen Cyanamide for Use in Dietary and Occupational Human Health Risk Assessments

Exposure/

Scenario Point of

Departure Uncertainty

Factors RfD and

Level of

Concern for

Risk

Assessment Study and Toxicological Effects

Acute Dietary (General Population, including

Infants and Children) Maternal

N OAEL=

5 mg/kg/day UF A = 10x

UF H = 10x

UF DB = 10x Acute RfD =

0.005 mg/kg/day Developmental Toxicity Study in R ats

MRID 41288806

Maternal LOAEL = 15 mg/kg/day based on hypoactivity seen on GD6 and GD7 in 8/25 animals after 1 or 2 days of dosing.

Chronic Dietary (All Populations) NOAEL = 2 .0

mg/kg/day from

sub chronic dog UF A = 10x

UF H =10x

UF DB = 10x Chronic RfD =

0.0 02 mg/kg/day Chronic Toxicity

- Dog co

- critical with

subchronic toxicity dog study

MRID s 41288802 & 41390501 Chronic Dog: NOAEL= 1 mg/kg/day. LOAEL = 5 mg/kg/day from the chronic dog based on increased incidences of rough haircoat, desquamation of the skin, tremors, and salivation; decreased body weight gain; decreased T 4 in males; increased relative thyroid

- parathyroid weights brown pigment in liver Kupffer cells; thymic atrophy; testicular inflammation; and aspermatogenesis, and hypospermatogenesis

.

Subchronic Dog study: NOAEL = 2 mg/kg/day LOAEL = 6 mg/kg/day based

o n decreased weight gain buccal cavity redness, decreased absolute and relative testicular weights

, and thymus weights), aggregates of polymorphonuclear and mononuclear inflammatory cells in the parotid salivary glands, testicular atrophy, and reduced sperm atogenesis.

Incidental

Oral Short

Term (1

- 30 days) NOAEL = 2.0

mg/kg/day from subchronic dog UF A = 10x

UF H =10x

UF DB = 10x Residential

LOC for

MOE = 1000 Chronic Toxicity

- Dog co

- critical with

subchronic toxicity dog study

MRID s 41288802 & 41390501

Same as chronic dietary exposure endpoint.

Dermal

Short

- and

Intermediate

Term (1

- 30 days and 1

- 6 months) NOAEL = 2 .0

mg/kg/day from

sub chronic dog

DAF = 11% UF A = 10x

UF H =10x

UF DB = 10x Occupational

LOC for MOE

= 1000 Chronic Toxicity

- Dog co

- critical with

subchronic toxicity dog study

MRID 41288802 & 41390501

Same as chronic dietary exposure endpoint

.

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 20 of 75 Table 4.5.4.1 Summary of Toxicological Doses and Endpoints for Hydrogen Cyanamide for Use in Dietary and Occupational Human Health Risk Assessments

Exposure/

Scenario Point of

Departure Uncertainty

Factors RfD and

Level of

Concern for

Risk

Assessment Study and Toxicological Effects

Inhalation

Short

- and

Intermediate

Term (1

- 30 days, and 1

- 6 months) NOAEL = 2 .0

mg/kg/day from

sub chronic dog UF A = 10x

UF H =10x

UF DB = 10x Occupational

LOC for MOE

= 1000 Chronic Toxicity

- Dog co

- critical with

subchronic toxicity dog study

MRID s 41288802 & 41390501

Same as chronic dietary exposure endpoint

.

Cancer (oral, dermal, inhalation) Classification: “Group C chemical

– possible human carcinogen.”

Q 1 * , for hydrogen cyanamide is 6.64 x 10 - 2 (mg/kg/day) - 1 in human equivalents using a mg/kg body weight 3⁄4 /day interspecies scaling factor Point of Departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no ob served adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a

NOAEL. UF S = use of a short

- term study for long

- term risk assessment. UF DB = to account for the absence of key data (i.e., lack of a critical study). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.



### 4.6 Endocrine Disruption

As required by FIFRA a nd FFDCA, EPA reviews nu m erous studies to assess potential adverse

outco m es f

r om exposure to che m icals. Collecti v ely, these studies inclu d e acute, subchronic and

chronic toxicity, including ass e ss m ents of carcinogenicity, n e urotoxicity, develop m ental, reproductive, and general or syste m ic toxicity. These studies include e ndpoints which m ay be susceptible to endocrine influ e nce, including effects on endocrine target organ h istopathology, organ weights, estrus cyclicity, sexual m aturati o n, fertility, pregnancy rates, reproductive loss,

and sex rati o s in offspring. For ecol o gical h azard assess m ents, EPA evaluates ac u te tests and

chronic s t u d ies t h at a s sess growth, develop m ent al and repro d uctive effects in different

taxono m ic groups. As part of its rere g i strati o n deci s i on for hydrogen cyanamide,

EPA reviewed the s e data and s elected the m o st sen s iti v e endpoints for relevant risk assess m ent
scenarios f

rom the existing hazard database. However, as required by FFDCA section 408(p), hydrogen cyanamide is subject to the endocrine screening part of the Endocrine D i sruptor Screening Program (EDSP).

EPA has developed the EDSP to deter m ine whether certain substan ces (including pesticide active and other ingredients) m ay have an effect in hu m ans or wildli f e si m ilar to an eff

ect produced by a “naturally occurring estrogen, or o t her such e n docrine effec t s as the

Ad m i nistrator m ay designate.” The EDSP e mploys a two

- tiered approach to m aking t h e statutorily required deter m inations. Tier 1 consists of a battery of 11 screening assays to i d enti f y the pote n ti a l of a che m ical substance to i n teract with the estro g en, androgen, or thyroid (E, A, or

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 21 of 75 T) hormonal syste m s. Che m icals that go t h rough Tier 1 screening and are found to have the potential to int e ract with E, A, or T hor m onal syste m s will proceed to the next sta g e of the EDSP

where EPA will deter m ine which, if any, of t h e Tier 2 tests are neces s ary bas e d on the a vailable data. Tier 2 testing is de signed to id e nti f y any adverse endocrine

- related ef f ects caused by the

su b stance, and establish a dose

- response relationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the Agency m ust screen all pesticide che m icals. Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67

che m icals, which contains 58 pes t icide active ingredien t s and 9 inert ingredients. A second list

of ch e m icals identified for E DSP screening was published on June 14, 2013 2 

### and includes

so m e pesticides scheduled for registration review and che m icals found in water

. Neither of

these lists should be construed as a list of kno w n or likely endocrine disruptors.

For further info r m ation on the status of the EDSP, the policies and procedures, the li s ts of

c h e m icals, f

uture lists, the test g u ideli n es and the Tier 1 screening battery, please visit our

website

. 3



### 5.0 Dietary Exposure and Risk Assessment

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

With regards to the currently registered uses of hydrogen cyanamide, t he nature /magnitude of the residue is adequately understood based on a metabolism study conducted on detached grape leaves and the generally accepted environmental fate of hydrogen cyanamide based on published

information

. Available magnitude of the residue data on grapes are considered supplemental and contribute to our understanding of the rapidity of residue decline using the currently registered

formulation. The single carbon of hydrogen cyanamide is rapidly incorporated into the general carbon pool of plant s (sugars, cellulose, amino acids etc.) via the formation of urea and further decomposition to ammonium and C O 2



### . Cyanamide also undergoes dimerization to form dicyandiamide which also degrades through the same mechanisms. The potential for the level of dicyandiamide to form in crops is not known but could, under the right conditions, reach a level of significan ce relative to hydrogen cyanamide, if present . Taken together, data indicate that n o residues of concern should be present at harvest for the registered crops and dormant use pattern

.

The metabolism of the 14 

### C

- hydrogen cyanamide was followed in young d etached grape leaves from the Thompson Seedless ( Vitus vinifera ) variety. The leaves were labeled through the cut petiole with 14 

### C

- hydrogen cyanamide (2

- 3 μg 14 

### C

- hydrogen cyanamide per 0.4 g leaf, 0.7

- 0.9 μCi in 10

- 25 μl distilled water) and allowed to me tabolize in a controlled laboratory atmosphere
(25  C, Atlas xenon arc lighting) for 24 hours. During this period, volatile gases were collected

2 See h tt p :// w w w .reg u l ati on s. g o v /#! do c u m en t D etail; D =EP A

- H Q

- O PPT

- 2 0 09

- 04 7 7

- 007 4 for t h e f i n al sec o nd list

o f che m icals.

3 h tt p ://www.epa.g ov /e n d o /

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 2 2 of 75 in gas dispersion bottles containing phosphate buffer (hydrogen cyanamide trap) and potassium hydroxide (carbon dioxide trap) in series. The leaves were extracted and fractionated through exchange resins into cation (amino acid), anion (organic acid) and neutral (carbohydrate) fractions. Characterization was accomplished by thin layer, column (ion exchange and re verse phase) and paper chromatography. A range of 86 to 98% of the radiolabeled starting material was accounted for through the use of combustion analyses and liquid scintillation counting.

Consistent with published information, the registrant proposed that hydrogen cyanamide decomposes to ammonium and CO 2 

### through the formation of urea and that finally the CO 2 

### is incorporated into the general carbon pool of the grape plant. The ammonium is transformed into plant available nitrogen. See Appendix C

.

Although not discussed in the grape leaf metabolism study, c yanamide may also undergo
dimerization to form dicyandiamide . The potential for the level of dicyandiamide to form in crops resulting from the currently registered uses is not known but could, und er the right conditions, reach a level of significance relative to hydrogen cyanamide, if present

.

5.1.2 Summary of Environmental Degradation

DP# 403785, I. Abdel

- Saheb, 10/4/12



### The available environmental fate data for hydrogen cyanamide indicate that it is not persistent in soil or water. Abiotic degradation processes (hydrolysis and photolysis) are not important, as metabolism is much quicker. Cyanamide is completely miscible with water, and in batch equilibrium experiments less than 2% of the mass a dsorbed to sandy and silt loam soil. Thus, it is expected to be very mobile in soil

- water systems. The degradates of cyanamide include simple nitrogen compounds which are read ily utilized as plant nutrients. Hydrogen cyanamide also undergoes dimerization to form dicyandiamide in the environment. None of these degradates, with the exception of urea, reached a level of significance in any of the studies.

5.1.3 Comparison of Metabolic Pathways

The absorption, distribution, metabolism, and excretion of hy drogen cyanamide were studied in rats, dogs, and rabbits. Data indicate that hydrogen cyanamide is rapidly absorbed, metabolized, and excreted following oral, intravenous, or intraperitoneal dosing. The major metabolite of hydrogen cyanamide was identified as N

- acetylcyanamide, which was eliminated mainly in the urine and to a lesser degree in the feces.

In the environment, hydrogen cyanamide is expected to decompose to a number of simple nitrogen compounds which are then readily incorporated into the general carbon pool. None of these degradates, with the exception of urea, is expected to reach a level of significance as a result of the registered uses of hydrogen cyanamide. Hydrogen cyanamide also undergoes

dimerization to form dicyandiamide in the environment but not in the mammalian system. Dicyandiamide is expected to further degrade through the same mechanisms as hydrogen cyanamide. Based on aerobic soil and aerobic aquatic studies, dicyandiamide may be present in the environment, but is not expected to reach a level of significance as a result of the registered

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 23 of 75 uses of hydrogen cyanamide. Furthermore , the hydrogen cyanamide risk assessment team has determined that dicyandiamide is not likely to be more toxic than hydrogen cyanamide.

5.1.4 Residues of Concern Summary and Rationale

Hydrogen cyanamide was not reviewed by the Residues of Concern Knowl edgebase Sub

committee (ROCKS) or its predecessor. The hydrogen cyanamide risk assessment team has

determined that only the parent is a residue of concern in drinking water for risk assessment

based on the available environmental fate data which did not id entify any potentially significant degradate/metabolite of the parent.

5 .2 Food Residue Profile

Currently registered uses of h ydrogen cyanamide ha ve been determined to be non

- food/non

- feed.

No r esidues of concern are expected in food.

5.3 Water Residue Profile

DP# 403785, I. Abdel

- Saheb, 10/4/12



### As determined by the hydrogen cyanamide risk assessment team, t he residue of concern in drinking water for risk assessment is the parent compound, hydrogen cyanamide. No ground or surface water monitoring data were available for hydrogen cyanamide and the estimated drinking water concentrations ( EDWCs ) were generated with Tier 2 modeling. For Tier 2 ground water assessments, the Pesticide Root Zone Model

- Ground Water ( PRZM

- GW ) Model was used.

PRZM

- GW User Inte rface is a Visual Basic tool that generates input files for PRZM, runs PRZM, and performs some post processing. A daily time series file, peak and average concentrations are the main output products. For Tier 2 surface water assessments, two models

were used in tandem

, Pesticide Root Zone Model (PRZM3.12 ) and E xposure Analysis Modeling Systems ( EXAMS 2.98 )

.

The highest values from among all the scenarios modeled in the drinking water assessment were from surface water. For surface water, the highest 1

- i n

- 10 year peak and annual mean values

were from the MI Cherries scenario and the highest 30 year mean value was from the CA Grapes

scenario. Surface water values were multiplied by a percent crop area (PCA) factor of 0.23 for Orchard/Vineyard. In addition, an aquatic buffer of 300 yard ( 900 f ee t ), which is currently on labels to protect aquatic organisms, was used to calculate the spray drift fraction input for surface water modeling , reducing the percentage of drift from the default value of 6 .4% to 0.1%

. Although a non

- standard approach, a volatility routine was also employed due to the reported volatility of hydrogen cyanamide; however, this refinement did not make a significant difference in the resulting EDWC most likely due to low Hen r y’s law constant. Furthermore, due to a lack of data, several model inputs were based on open literature data and estimates using EPA’s EpiSuite model.

T he 30 year distribution of daily surface water concentrations based on the MI Cherries scenario

was in put into the acute dietary assessment

. The 1

- in

- 10 year annual mean based on the MI Cherries scenario and the 30 year mean based on the CA Grapes were input into the chronic and cancer dietary assessment, respectively.

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 24 of 75 Table 5.3. 1 shows the surface water and groundwater scenarios which provide the highest

EDWCs recommended for the human health risk assessment. All registered crops were modeled to explore the highest exposure possible from the registered use of hydrogen cyanamide

.

Exposure in surface wate r EECs is higher than groundwater because runoff (major rout of transportation in surface water) is more effective in getting the pesticide to water than leaching (in gourd

- water movement). Physiochemical properties of the pesticide (e.g. high solubility a nd low soil adsorption) play a major role in chemical availability in surface water vs. groundwater. Hydrogen cyanamide is highly soluble (7.8 X 10 +5 

### ppb) with low Soil Partition Coefficient K OC 

### , of 7.3 mL/g.

Regardless of scenario, these modeled EDWC are screening level values designed to represent an upper bound estimate of exposure. These upper bound estimates are by their nature influenced by a number of assumptions and inputs. Specifically for Hydrogen Cyanamide the model inputs are influenced by th e available fate data and the fact that no valid guideline data were available for adsorption/desorption and hydrolysis. Therefore, adsorption/desorption was estimated using quantitative structural activity (QSAR) and a hydrolysis value was selected from a n open literature study. While the values chosen add uncertainty and would tend to yield higher exposure (e.g. low Koc yields greater runoff and leaching) it is unknown how these estimates would differ from guideline data.

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 25 of 75 Table 5.3. 1. Estimated Drinking Water Concentrations (EDWC) of hydrogen cyanamide residues in surface water and ground water recommended for use in dietary risk

assessment.

S cenario

Model (application rate lb a.i./A, frequency) Surface Water

1

- in

- 10 year Hydrogen cyanamide Concentration

(μg/L)*

Peak Annual Mean 30

- Year Mean

MIcherries.std PRZM (V. 3.12)/EXAMS (V.2.98) (17.6 lb/acre, 1x) 50.4 3.36 0.67**

PRZM

- GW (V. 1.0) (17.6 lb/acre, 1x) Highest daily value Simulation Avg. value 0.841 μg/L

0.060 μg/L

* Surface water EDWC Values were multiplied by PCA of 0.23. ** Based on the highest 30

- year mean (CA grapes) among all scenarios modeled in this

assessment.

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

Acute probabilist ic, c hronic , and cancer d ietary exposure and risk assessments for drinking water only were conducted using the Dietary Exposure Evaluation Model DEEM

- FCID, Version 3.16 which uses food consumption data from the U.S. Department of Agriculture’s National Hea lth and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA). This dietary survey was conducted from 2003 to 2008. Only registered uses of hydrogen cyanamide

, as of the date of this memorandum, are included in these assessments.

The hy drogen cyanamide estimated drinking water concentrations (EDWCs) used in these dietary risk assessments w ere provided by EFED ( D P# 403785, I. Abdel

- Saheb, 10/4/12 ), and incorporated directly into the dietary assessments. Water residues were incorporated in DEEM

FCID via entry into the food categories “water, direct, all sources” and “water, indirect, all

sources.” No ground or surface water monitoring data were ava ilable for hydrogen cyanamide and the EDWCs were generated with Tier 2 modeling.

The highest EDWCs from among all the scenarios modeled in the drinking water assessment

were from surface water. EDWCs in s urface water in corporated two significant adjustments: (1)

values were multiplied by a percent crop area (PCA) factor of 0.23 for Orchard/Vineyard and (2) an aquatic buffer of 300 yard ( 900 f ee t ), which is currently on labels to protect aquatic organisms, was used to calculate th e spray drift fraction input for surface water modeling

, reducing the percentage of drift from the default value of 6.4% to 0.1%

.

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 26 of 75 T he 30 year distribution of daily surface water concentrations was input into the acute dietary

assessment

. The 1

- in

- 10 ye ar annual mean and the 30 year mean were input into the chronic and cancer dietary assessment, respectively.

5.4.2 Percent Crop Treated Used in Dietary Assessment

Because hydrogen cyanamide is considered a non

- food /non

- feed use, percent crop treated data were not used in the dietary assessments

5.4.3 Acute Dietary Risk Assessment

T he acute probabilisti c dietary assessment for hydrogen cyanamide in drinking water results in

an estimated risk of ≤1 10 % of the acute reference dose (aRfD) at the 9 9.9 th 

### percentile of

exposure , 13% of the aRfD at the 99 th 

### percentile, and <1% of the aRfD at the 95 th 

### percentile for all population subgroups. All infants < 1 year of age is the most highly

- exposed subgroup, utilizing 1 10 % of the aRfD, while the general US population utilizes 33% of the aRfD , both at

the 99.9 th 

### percentile

. See Table 5.4.6

. 1 in Section 5.4.6.

5.4.4 Chronic Dietary Risk Assessment

The c hronic dietary exposure from hydrogen cyanamide in drinking water results in the

es timated risk of ≤ 9.1 % of the chronic reference dose (cRfD ) for all population subgroups. All

Infants < 1 year of age is the most highly

- exposed subgroup, utilizing 9.1 % of the c RfD , while the general US population utilizes 3.5 % of the c Rf D. See Table 5 .4.6.2 in Section 5.4.6.

5.4.5 Cancer Dietary Risk Assessment

The Health Effects Division Carcinogenicity Peer Review Committee (CPRC) classified hydrogen cyanamide as a Group C chemical

– a possible human carcinogen. Based upon female mouse ovarian gr anulosa

- theca tumor rates in a 104

- week drinking water study, a Q 1 * 

### value of

6.64 x 10 - 2 

### (mg/kg/day) - 1 

### was estimated using body weight 3⁄4 

### interspecies scaling factor (Lori L. Brunsman memorandum; March 22, 2001, TXR 0014510). The cancer risk from hydrogen

c yanamide in drinking water is 9.3 2 x 10 - 7



### . See Table 5.4. 6 .3 in Section 5.4.6

.

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 27 of 75 5.4.6 Summary Table s

TABLE 5. 4 .6.1 . Summary of Acute Probabilistic Dietary Exposure and Risk Estimates for Hydrogen Cyanamide. Population Subgroup*

[Years of Age] DEEM Acute Probabilistic Dietary Analysis (Drinking Water Only)

aRfD (mg/kg/ day) 95 th Percentile 99 th Percentile 99.9 th Percentile

Exposure (mg/kg/day) %

aRfD Exposure (mg/kg/day) %

aRfD Exposure (mg/kg/day) %

aRfD

General US Population

0.005 0.000018

<1 0.000273 5.5 0.001642 33

All Infants [<1] 0.000028 0.000620 13 0.005299 1 10

Children [1

- 2] 0.000024 0.000387 7.8 0.002477 50
Children [3

- 5] 0.000021 0.000332 6.7 0.002045 41
Children [6

- 12] 0.000014 0.000234 4.7 0.001496 30
Youth [13

- 19] 0.000011 0.000193 3.9 0.001289 26
Adults [20

- 49] 0.000018 0.000275 5.6 0.001646 33
Adults [50

- 99] 0.000019 0.000282 5.7 0.001534 31
Females [13

- 49] 0.000017 0.000272 5.5 0.001666 34

* Values for the population subgroup with the highest risk are in bold type

.

TABLE 5.4.6.2. Summary of Chronic Dietary Exposure and Risk Estimates for Hydrogen Cyanamide. Population Subgroup* [Years of Age] DEEM Chronic Dietary Analysis (Drinking Water Only) cRfD (mg/kg/day) Exposure Estimate (mg/kg/day) % cRfD

General US Population

0.002 0.000070 3.5

All Infants [<1] 0.000181 9.1

Children [1

- 2] 0.000101 5.1

Children [3

- 5] 0.000086 4.3

Children [6

- 12] 0.000062 3.1

Youth [13

- 19] 0.000051 2.6

Adults [20

- 49] 0.000070 3.5

Adults [50

- 99] 0.000069 3.5

Females [13

- 49] 0.000070 3.5



### * Values for the population subgroup with the highest risk are in bold type

.

TABLE 5.4.6.3 Summary of Cancer Dietary Exposure and Risk Estimates for Hydrogen Cyanamide. Population Subgroup DEEM Cancer Dietary Analysis (Drinking Water Only)
Q 1 * Exposure Estimate

(mg/kg/day) Estimated cancer Risk

General US Population 0.0664 0.000014 9.32 x 10 - 7



### 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

There are no registered residential uses for hydrogen cyanamide.

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 28 of 75 6.1 Spray Drift

Off

- target movement of pesticides can occur via many types of pathways and it is governed by a variety of factors. Sprays that are released and do not deposit in the application area end up off

target and can lead to exposures to those it may directly contact. They can also deposit on

surfaces where contact with residues can eventuall y lead to indirect exposures ( e.g. , children playing on lawns where residues have deposited next to treated fields). The potential risk estimates from these residues can be calculated using drift modeling coupled with methods employed for residential risk assessments for turf products.

The approach to be used for quantitatively incorporating spray drift into risk assessment include assessing exposures for children (1 to < 2 years old) and adults who have contact with turf where

residues are assumed to have deposited via spray drift thus resulting in an indirect exposure scenario. Aside from the predicted residues available for transfer, the routes of exposure and assessment methodology is analogous to how exposures to turf products are considered in risk

a ssessment.

In order to evaluate the drift potential and associated risks, an approach based on drift modeling coupled with techniques used to evaluate residential turf uses of pesticides was utilized. Essentially, a residential turf assessment based on exposure to deposited residues has been completed to address drift from the agricultural applications of hydrogen cyanamide

. In the spray drift scenario, the deposited residue value was determined based on the amount of spray drift that may occur at varyi ng distances from the edge of the treated field using the AgDrift (v2.1.1) model. Once the deposited residue values were determined, the remainder of the spray drift assessment was based on the algorithms and input values specified in the recently revised (2012) Standard Operating Procedures For Residential Risk Assessment (SOPs)

.

A screening approach was developed for situations where specific label guidance for application parameters is not available. 4

, 5 

### AgDrift is appropriate for use only when applications are made by aircraft, airblast sprayers, and groundboom sprayers. When AgDrift was developed, a series of screening values (i.e., the Tier 1 option) were incorporated into the model and represent each equipment type and use under varied conditions. The screening options specifically recommended in this methodology were selected because they are plausible and represent a reasonable upper bound level of drift for common application methods in agriculture . In all cases, each scenario is to be evaluated unless it is not plausible based on the anticipated use pattern (e.g., herbicides are not typically applied to tree canopies) or specific label prohibitions (e.g., aerial applications are not allowed).

C ombined Risk Estimates From Lawn Deposition Adjacent to Applications The spray drift risk estimates are based on an estimated deposited residue concentration as a result of the screening level agricultural application scenarios. Hydrogen cyanamide is used on various deciduous crops and can be applied via airblast and groundboom equipment. The recommended drift scenario screening level options are listed below:

4 http://www.agdrift.com/

5 Note that for many cases the scenarios outlined in the screening approach represent actual use practice so risk assessors sho uld be aware and characterize these appropriately.

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 29 of 75  Groundboom applications are based on the AgDrift option for high boom height and
using very fin e to fine spray type using the 90th percentile results.

 Orchard airblast applications are based on the AgDrift option for Sparse
(Young/Dormant) tree canopies.

In addition to the screening level spray drift scenarios described above, additional results ar e provided which represent viable drift reduction technologies (DRTs) that represent potential risk management options. In particular, different spray qualities have been considered as well as the impact of other application conditions (e.g., boom height , crop canopy conditions).

Dermal and incidental oral risk estimates were combined because the toxicity endpoint for each route of exposure is the same. The total applicable level of concern is 1000 so MOEs <1000

would be of concern. Adult and c hildren’ s (1 to <2 year s old) dermal and children incidental oral risk estimates from indirect exposure to hydrogen cyanamide related to spray drift result in

buffers of 150 to 300 feet.

Exposures were considered for 50 feet wide lawns where the nearest side of the property was directly adjoining the treated field (at field edge) and at varied distances up to 300 feet

downwind of a treated field. Results are presented in Table 6 .1.1 and 6.1.2 and indicate that there are risks of concern from airblast and groundb oom applications even 300 feet downwind of

the treated field.

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 30 of 75 Table 6.1.1. Adult Dermal Buffer Summary

Equipment Canopy Density AR (lb ai/A) TTR (ug/cm2) At Edge 10 Feet 25 Feet 50 Feet 75 Feet 100 Feet 125 Feet 150 Feet 200 Feet 250 Feet 300 Feet

Dermal MOE

Apples, Grapes, Cherries, Kiwi Fruit, and Figs

Groundboom (Grapes and Kiwi Fruit ) High Boom Very

fine to Fine

17.6 1.96 15 30 49 79 110 140 160 200 250 340 390

Low Boom Very

fine to Fine 32 86 140 210 280 340 390 460 550 690 920

High Boom Fine

to
Medium/Coarse 56 140 210 310 390 460 550 550 690 920 920

Low Boom Fine

to
Medium/Coarse 83 230 340 460 550 690 920 920 1,400 1,400 1,400

Airblast Sparse 19 33 62 140 250 400 610 860 1,500 2,500 3,400

Normal 920 1,400 2,100 3,100 4,600 5,500 6,900 9,200 9,200 14,000 14,000

Dense 65 99 160 280 410 560 710 860 1,200 1,500 1,800

Vineyard 340 670 1,300 2,300 3,400 4,600 5,500 6,900 9,200 14,000 14,000

Blackberries and Blueberries

Groundboom High Boom Very

fine to Fine

13.2 1.47 20 39 66 100 150 180 220 260 330 460 520

Low Boom Very

fine to Fine 43 110 180 280 370 460 520 610 730 920 1,200

High Boom Fine

to
Medium/Coarse 75 190 280 410 520 610 730 730 920 1,200 1,200

Low Boom Fine

to
Medium/Coarse 110 310 460 610 730 920 1,200 1,200 1,800 1,800 1,800

Airblast Sparse 26 44 83 180 330 540 820 1,100 2,000 3,300 4,600

Normal 1,200 1,800 2,800 4,100 6,100 7,300 9,200 12,000 12,000 18,000 18,000

Dense 87 130 210 370 550 750 940 1,100 1,600 2,000 2,400

Vineyard 460 900 1,700 3,100 4,600 6,100 7,300 9,200 12,000 18,000 18,000

Nectarine and Peach

Airblast Sparse

6.6 0.73 51 88 170 370 670 1,100 1,600 2,300 4,100 6,700 9,200

Normal 2,400 3,700 5,600 8,200 12,000 15,000 18,000 24,000 24,000 37,000 37,000

Dense 170 260 420 730 1,100 1,500 1,900 2,300 3,200 4,100 4,900

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 31 of 75 Table 6 .1. 2 . Children Incidental Oral ( HtM ) and dermal Combined Summary

Equipment Canopy Density AR (lb ai/A) TTR (ug/cm2) At Edge 10 Feet 25 Feet 50 Feet 75 Feet 100 Feet 125 Feet 150 Feet 200 Feet 250 Feet 300 Feet

Combined MOE
Apples, Grapes, Cherries, Kiwi Fruit, and Figs

Groundboom (Grapes and Kiwi Fruit ) High Boom Very

fine to Fine

17.6 1.95 6 13 21 33 47 59 69 84 110 150 170

Low Boom Very

fine to Fine 14 37 59 90 120 150 170 200 230 290 390

High Boom Fine to

Medium/Coarse 24 62 90 130 170 200 230 230 290 390 390

Low Boom Fine to

Medium/Coarse 36 98 150 200 230 290 390 390 590 590 590

Airblast Sparse 8 14 26 59 110 170 260 370 650 1,100 1,500

Normal 390 590 900 1,300 2,000 2,300 2,900 3,900 3,900 5,900 5,900

Dense 28 42 67 120 170 240 300 370 510 650 780

Vineyard 150 290 530 980 1,500 2,000 2,300 2,900 3,900 5,900 5,900

Blackberries and Blueberries

Groundboom High Boom Very

fine to Fine

13.2 1.47 8 17 28 45 63 78 92 110 140 200 220

Low Boom Very

fine to Fine 18 49 78 120 160 200 220 260 310 390 520

High Boom Fine to

Medium/Coarse 32 82 120 170 220 260 310 310 390 520 520

Low Boom Fine to

Medium/Coarse 47 130 200 260 310 390 520 520 780 780 780

Airblast Sparse 11 19 35 78 140 230 350 490 870 1,400 2,000

Normal 520 780 1,200 1,700 2,600 3,100 3,900 5,200 5,200 7,800 7,800

Dense 37 56 89 160 230 320 400 490 680 870 1,000

Vineyard 200 380 710 1,300 2,000 2,600 3,100 3,900 5,200 7,800 7,800

Nectarine and Peach

Airblast Sparse

6.6 0.73 22 37 71 160 280 460 690 980 1,700 2,800 3,900

Normal 1,000 1,600 2,400 3,500 5,200 6,300 7,800 10,000 10,000 16,000 16,000

Dense 74 110 180 310 470 640 800 980 1,400 1,700 2,100

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 32 of 75 6.2 Residential Bystander Post

- Application Inhalation Exposure

Volatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in D ecember 2009, and received the SAP’s final report on
March 2, 2010 6 

### . The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post

- application inhalation exposure into the Agency's risk assessments. If new policies or procedures are developed, the Agency may revisit the need for a quantitative post

application inhalation exposure assessment for hydrogen cyanamide.

7.0 Cumulative Exposu re/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as

to hydrogen cyanamide and any other substances and hydrogen cyanamide does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that hydrogen cyanamide has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning

common mechan ism determinations and procedures for cumulating effects from substances

found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/

.

8.0 Occupational Exposure/Risk Cha racterization

8 .1 Short

- and Intermediate

- Term Non

- Cancer and Cancer Handler Risk

HED uses the term handlers to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct job functions or tasks related to applications and exposures can vary depending on the specifics of each ta sk. Job requirements (amount of chemical used in each application), the kinds of equipment used, the target being treated, and the level of protection used by a handler can cause exposure levels to differ in a manner specific to each application event.

Based on the anticipated use patterns and current labeling, types of equipment and techniques that can potentially be used, occupational handler exposure is expected from the registered uses. The quantitative exposure/risk assessment developed for occupat ional handlers is based on the following scenarios:

Mixer/Loaders:

 Mixing/loading liquids for airblast applications; and

6 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 33 of 75  Mixing/loading for groundboom applications.

Applicators:

 Applying sprays with airblast equipment; and

 Applying sprays with groundboo m equipment.

Occupational Handler Exposure Data and Assumptions A series of assumptions and exposure factors served as the basis for completing the occupational handler risk assessments. Each assumption and factor is detailed below on an individual basis.

Application Rate : Maximum application rates, as outlined in Table 4.1 and below, were used in the occupational

handler calculations.

 Apples, Grapes, Cherries, Kiwi Fruit, and Figs

– 17.6 lb ai/A

 Blackberries and Blueberries

– 13.2 lb ai/A

 Nectari ne and Peach

– 6.6 lb ai/A

Unit Exposures: It is the policy of HED to use the best available data to assess handler exposure. Sources of generic handler data, used as surrogate data in the absence of chemical

- specific data, include PHED 1.1, the AHETF database, the Outdoor Residential Exposure Task Force (ORETF) database, or other registrant

- submitted occupational exposure studies. Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA.

The standa rd values recommended for use in predicting handler exposure that are used in this assessment, known as “unit exposures”, are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table 7 

### ”, which, along with additional informatio n on HED policy on use of surrogate data, including descriptions of the various sources, can be found at the Agency website 8



### .

Area Treated or Amount Handled: HED normally would use a default of 40 acres per day for airblast and 80 for groundboom for trea tment of orchards and vineyards in accordance with the Science Advisory Council for Exposure Policy 9.1. However, per a previous assessment back in 2007 (D333780; M. Collantes; 2/9/07), in order to refine information regarding the number of

acres treated per day the registrant, Degussa AG, had submitted a telephone survey of 24 vineyard and orchard growers (table grapes, cherries, blueberries and figs) from California and Florida who used hydrogen cyanamide. The survey results indicated that of the 24 part icipants 25% treated less then 20 acres a day, 60% treated less then 40 acres a day and 17% treated 40 to 50 acres a day. HED then refined hydrogen cyanamide’s assessment to present worker exposure potential risks when treating 20, 30, and 40 acres in a d ay. For the current registration review, a

re

- assessment was conducted utilizing 20, 30, and 40 acres per day to update and reflect HED’s most current assumptions and default values.

Body Weight : The standard body weight for the general population (80 k g) was used for all exposure scenarios covered in this risk assessment since the endpoints selected were not

7 Available: http://www.epa.gov/opp00001/science/handler

- exposure

- table.pdf

8 Available: http://www.epa.gov/pesticides/science/handler

- exposure

- data.html

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 34 of 75 developmental and/or fetal effects.

Absorption factors: A dermal absorption factor of 11% was used for the exposure assessment.

Since no inhala tion absorption data are available, toxicity by the inhalation route is considered to be equivalent to the estimated toxicity by the oral route of exposure.

Exposure Duration: HED classifies exposures from 1 to 30 days as short

- term and exposures 30 days to six months as intermediate

- term. Exposure duration is determined by many things, including the exposed population, the use site, the pest pressure triggering the use of the pesticide, and the cultural practices surrounding that use site. For most agr icultural uses, it is reasonable to believe that occupational handlers will not apply the same chemical every day for

more than a one

- month time frame; however, there may be a large agribusiness and/or commercial applicators who may apply a product over a period of weeks (e.g., completing multiple applications for multiple clients within a region).

For hydrogen cyanamide, short

- and intermediate

- term endpoints are the same; therefore,

estimates of short

- term exposure/risk are protective of any potential longer

- term exposures.

Mitigation/Personal Protective Equipment: Estimates of dermal and inhalation exposure were calculated for various levels of personal protective equipment (PPE). Results are presented for “baseline,” defined as a single layer of cl othing consisting of a long sleeved shirt, long pants, shoes plus socks, no protective gloves, and no respirator, as well as baseline with various levels

of PPE as necessary (e.g., gloves, respirator, etc). All hydrogen cyanamide product labels direct mixers, loaders, applicators and other handlers to wear a chemical resistant protective suit,

chemical

- resistant gloves, chemical

- resistant footwear plus socks , protective eyewear, chemical

resistant headgear for overhead exposure, and a chemical

- resistant apron (except Dormex®). Only Duomax includes the use of a half

- or full

- face cartridge or canister style respirator or powered air

- purifying respirator (PF10 )

. All labels include an engineering control statement indicating that the products “must be mixed, loaded, and transferred only in a closed system.”

Days per year of exposure: To assess cancer risk, it is assumed that private growers would be exposed 10 days per year and commercial applicators would be exposed 30 days per year. The term “private grower” means that the grower or one of the workers would apply the pesticides to land owned or operated by the grower. Commercial applicators means the applic ators are completing multiple applications for multiple clients. The Agency considered the cancer risk assessment to include only private applicators at 10 use events per year since the registrant have indicated that hydrogen cyanamide is applied seasonal ly during a narrow window of 21 days per year and given the number of growers using the pesticide; the area over which these crops are spread; and the number of applicators available to make the applications, it is unlikely that a given applicator applies hydrogen cyanamide more than five days per season. Moreover, agronomic/product use survey indicated a range of one to ten days (D333780; M. Collantes; 2/9/07).

Years per Lifetime of Exposure: It is assumed that handlers would be exposed for 35 years out of a 78 year lifespan.

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 35 of 75 Lifetime Expectancy: Life expectancy values are from the Exposure Factors Handbook 2011

Edition Table 18

- 1 (U.S. EPA, 2011). The table shows that the overall life expectancy is 78 years based on life expectancy data from 2007. In 2007, the average life expectancy for males was 75 years and 80 years for females. Based on the available data, the recommended value for use in cancer risk assessments is 78 years.

Occupational Handler Non

- Cancer Exposure and Risk Estimate Equations

Po tential daily exposures for occupational handlers were calculated using the following

formulas:

Daily Exposure (mg ai /day) = UE (μg ai / lb ai) * AR (lb ai /A) * AT (A /day) * 1E

- 3 mg/μg

where: Daily Exposure = Amount (mg ai/day) that is available fo r dermal or inhalation absorption,

UE = Unit Exposure (μg ai / lb ai),

AR = maximum application rate according to proposed label (lb ai /A), and

AT = daily acres treated (A /day).



### The daily doses were calculated using the following formula:

Ave rage Daily Dose (mg ai/kg/day) = [Daily Exposure (mg ai/day) * Absorption (%)] Body Weight (kg)

where: Average Daily Dose = Absorbed dose received from exposure to a pesticide in a given scenario (mg pesticide active ingredient/kg body weight/day), Daily Exposure = Amount (mg ai/day) that is available for dermal or inhalation absorption, Absorption Factor = A measure of the amount of chemical that crosses a biological boundary such as the skin and lungs (%), and Body Weight = Body weight determine d to represent the population of interest in a risk assessment (kg).



### Margin of Exposure: Non

- cancer risk estimates for each application handler scenario are calculated using a Margin of Exposure (MOE), which is a ratio of the toxicological endpoint to the daily dose of concern. The daily dermal and inhalation dose received by occupational handlers were compared to the appropriate POD (i.e. NOAEL) to assess the risk to occupational handlers for each exposure route. All MOE values were calculated using t he following formula:

MOE = POD (typically a NOAEL in mg/kg/day) ADD (mg/kg/day)



### where:

MOE = Margin of Exposure: value used by HED to represent risk or risk estimates (unitless),

POD = Point of Departure,

NOAEL = No Observed Adverse Effect Level (mg/kg/day): Dose level in a toxicity study, where no observed adverse effects occurred in the study, and

ADD = Average Daily Dose (mg/kg/day): the absorbed dose received from exposure to a pesticide in a given scenario.

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 36 of 75 Combining Exposures/Risk Estimates: Dermal and inhalation risk estimates were combined in this assessment, since the toxicological effects for these exposure routes were similar. Dermal and inhalation risk estimates were combined using the following formula:

Total MOE = Point o

f Departure (mg/kg/day) / Combined dermal + inhalation dose (mg/kg/day)



### Summary of Occupational Handler Non

- Cancer Exposure and Risk Estimates The occupational handler exposure and risk estimates are summarized below in Table 9.1.1. All scenarios present ed risk estimates of concern (MOEs < 1000) except the mixing/loading scenario for airblast on 20 acres (lowest number of acres treated per day refinement) at the lowest application rate (6.6 lbs ai/A), and the application scenario at 13.2 lbs ai/A with gro undboom equipment. The range of values presented here represent the use of engineering controls for both exposure routes, dermal and inhalation, from the lowest application rate of 6.6 lb s ai/A to the highest application rate registered of 17.6 lb s ai/A. N on

- Cancer risk estimate results were updated in light of the area refinement data submitted by the registrant, discussed previously and thoroughly explained in D333780 ; M. Collantes; 2/9/07.

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 37 of 75 Table 9 .1.1. Occupational Exposure and Risk Estimates for Hydrogen Cyanamide Handler Scenario

Crop or Target Maximum

Application

Rate 1

(lb ai/A) Dermal

Unit Exposure 2
(ug/lb ai) Dermal Dose 4

(mg/kg/day) Dermal MOE 5

(LOC:1000) Inhalation

Unit Exposure 2
(ug/lb ai) Inhalation Dose 6

(mg/kg/day) Inhalation MOE 7

(LOC:1000) Total Engineering

Controls

Combined MOE 8

LOC:1000

Area Treated 3 (A) Area Treated 3

(A) Area Treated 3 (A) Area Treated 3 (A) Area Treated 3 (A)

20 30 40 20 30 40 20 30 40 20 30 40 20 30 40

Mixer/Loader (Airblast and Groundboom)

Nectarine

and Peach (Only Airblast) 6.6 SL/No G : 220 0.040 0.060 0.080 50 33 25 No

- R : 0.219 0.00036 0.00054 0.00072 5500 3700 2800

1200 780 590 SL/G : 37.6 0.0068 0.010 0.014 290 200 150 PF5 R : 0.0438 0.000072 0.00011 0.00015 28000 19000 14000

DL/G : 29.1 0.0053 0.0079 0.011 380 250 190 PF10 R : 0.0219 0.000036 0.000054 0.000072 55000 37000 28000

EC : 8.6 0.0016 0.0023 0.0031 1300 850 640 EC : 0.083 0.00014 0.00021 0.00027 14000 9800 7300

Blackberries

and

Blueberries 13.2 SL/No G : 220 0.080 0.12 0.16 25 17 13 No

- R : 0.219 0.00072 0.0011 0.0015 2800 1900 1400

590 400 290 SL/G : 37.6 0.014 0.021 0.027 150 98 73 PF5 R : 0.0438 0.00015 0.00022 0.00029 14000 9300 6900

DL/G : 29.1 0.011 0.016 0.021 190 130 94 PF10 R : 0.0219 0.000072 0.00011 0.00015 28000 19000 14000

EC : 8.6 0.0031 0.0047 0.0062 640 430 320 EC : 0.083 0.00027 0.00041 0.00055 7300 4900 3600

Apples, Grapes, Cherries, Kiwi Fruit, and Figs 17.6 SL/No G : 220 0.11 0.16 0.21 19 13 9.4 No

- R : 0.219 0.00096 0.0015 0.0019 2100 1400 1000

440 290 220 SL/G : 37.6 0.018 0.027 0.036 110 73 55 PF5 R : 0.0438 0.00019 0.00029 0.00039 10000 6900 5200

DL/G : 29.1 0.014 0.021 0.028 140 94 71 PF10 R : 0.0219 0.00010 0.00015 0.00019 21000 14000 10000

EC : 8.6 0.0042 0.0062 0.0083 480 320 240 EC : 0.083 0.00037 0.00055 0.00073 5500 3600 2700

Airblast Applicator

Nectarine

and Peach 6.6 SL/No G : 220 0.32 0.48 0.64 6.2 4.2 3.1 No

- R : 0.219 0.0078 0.0117 0.0155 260 170 130

720 480 360 SL/G : 37.6 0.29 0.43 0.58 6.9 4.6 3.5 PF5 R : 0.0438 0.0016 0.0023 0.0031 1300 850 640

DL/G : 29.1 0.27 0.40 0.54 7.5 5 3.7 PF10 R : 0.0219 0.00078 0.0012 0.0016 2600 1700 1300

EC : 8.6 0.00 27 0.0040 0.0053 750 500 380 EC : 0.083 0.00011 0.0002 0.0002 18000 12000 8900

Blackberries

and

Blueberries 13.2 SL/No G : 220 0.64 0.96 1.3 3.1 2.1 1.6 No

- R : 0.219 0.016 0.023 0.0311 130 85 64

360 240 180 SL/G : 37.6 0.58 0.87 1.2 3.5 2.3 1.7 PF5 R : 0.0438 0.0031 0.0047 0.0062 640 430 320

DL/G : 29.1 0.54 0.81 1.1 3.7 2.5 1.9 PF10 R : 0.0219 0.0016 0.0023 0.0031 1300 850 640

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 38 of 75 Table 9 .1.1. Occupational Exposure and Risk Estimates for Hydrogen Cyanamide Handler Scenario

Crop or Target Maximum

Application

Rate 1

(lb ai/A) Dermal

Unit Exposure 2
(ug/lb ai) Dermal Dose 4

(mg/kg/day) Dermal MOE 5

(LOC:1000) Inhalation

Unit Exposure 2
(ug/lb ai) Inhalation Dose 6

(mg/kg/day) Inhalation MOE 7

(LOC:1000) Total Engineering

Controls

Combined MOE 8

LOC:1000

Area Treated 3 (A) Area Treated 3

(A) Area Treated 3 (A) Area Treated 3 (A) Area Treated 3 (A)

20 30 40 20 30 40 20 30 40 20 30 40 20 30 40

EC : 8.6 0.0053 0.0080 0.011 380 250 190 EC : 0.083 0.00023 0.00034 0.00045 8900 6000 4500

Apples, Grapes,

C herries, Kiwi Fruit, and Figs 17.6 SL/No G : 220 0.86 1.3 1.7 2.3 1.6 1.2 No

- R : 0.219 0.0208 0.031 0.042 96 64 48

270 180 130 SL/G : 37.6 0.77 1.2 1.5 2.6 1.7 1.3 PF5 R : 0.0438 0.0042 0.0062 0.0083 480 320 240

DL/G : 29.1 0.72 1.1 1.4 2.8 1.9 1.4 PF10 R : 0.0219 0.0021 0.0031 0.0042 960 640 480

EC : 8.6 0.0071 0.011 0.014 280 190 140 EC : 0.083 0.0003 0.00045 0.00060 6700 4500 3300

Groundboom (Over

- the

- Row) Applicator

Blackberries

and

Blueberries 13.2 SL/No G : 78.6 0.029 0.043 0.057 70 47 35 No

- R : 0.34 0.0011 0.0017 0.0023 1800 1200 890

1000 670 500 SL/G : 16.1 0.0058 0.0088 0.012 340 230 170 PF5 R : 0.068 0.00023 0.00034 0.00045 8900 6000 4500

DL/G : 12.6 0.0046 0.0069 0.0091 440 290 220 PF10 R : 0.034 0.00011 0.00017 0.00023 18000 12000 8900

EC : 5.1 0.0019 0.0028 0.0037 1100 720 540 EC : 0.043 0.00014 0.00021 0.00028 14000 9400 7000

Grapes and

Kiwi Fruit 17.6 SL/No G : 78.6 0.038 0.057 0.076 52 35 26 No

- R : 0.34 0.0015 0.0023 0.0030 1300 890 670

750 500 370 SL/G : 16.1 0.0078 0.012 0.016 260 170 130 PF5 R : 0.068 0.0003 0.00045 0.00060 6700 4500 3300

DL/G : 12.6 0.0061 0.0091 0.012 330 220 160 PF10 R : 0.034 0.00015 0.00023 0.00030 13000 8900 6700

EC : 5.1 0.0025 0.0037 0.0049 810 540 400 EC : 0.043 0.00019 0.00028 0.00038 11000 7000 5300

1. Based on registered labels: (Dormex® (EPA Reg. No.54555

- 2; EPA Reg. No.CA040002; EPA Reg. No. HI030003); Krop

- MaxTM (EPA Reg. No. 80697

- 6); Duomax (EPA Reg. No. 84374

- 1);

2. Based o n the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2012); Level of mitigation: Baseline, P PE, Eng. Controls;

3. Exposure Science Advisory Council Policy #9.1 and survey data provided by the registrant;

4. Dermal Dose = Dermal U nit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/acre) x Area Treated (A/day) x DAF (%) / BW (kg);

5. Dermal MOE = Dermal NOAEL (mg/kg/day)/Dermal Dose (mg/kg/day);

6. Inhalation Dose = Inhalation Unit Exposure (ug/lb ai) x C onversion Factor (0.001 mg/ug) x Application Rate (lb ai/acre) x Area Treated (A/day) / BW (kg);

7. Inhalation MOE = Inhalation NOAEL (mg/kg/day)/ Inhalation Dose (mg/kg/day);

8. Total MOE = NOAEL (mg/kg/day)/Dermal Dose + Inhalation Dose OR Total MOE = 1/(1/De rmal MOE + 1/Inhalation MOE). Engineering controls combined MOEs presented the lowest exposure risks.

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 39 of 75 Occupational Handler Cancer Exposure and Risk Equations Cancer risk estimates were calculated using a linear low

- dose extrapolation approach in which a Lifetime Average Daily Dose (LADD) is first cal culated and then compared with a Q 1 

### * that has been calculated for hydrogen cyanamide based on dose response data in the appropriate toxicology study (Q 1 

### * = 6.64 x 10 - 2 

### (mg/kg/ day) - 1 

### ). Absorbed average daily dose (ADD) levels were used as the basis for calculating the LADD values. Dermal and inhalation ADD values were first added together to obtain combined ADD values. LADD values were then calculated and compared to the Q 1 

### * to obtain cancer risk estimates.

Lifetime Average Daily Dose: After the development of the ADD values, the next step required to calculate the carcinogenic risk estimate is to amortize these values over the working lifetime of occupational handlers based on use patterns, which results in the LADD for that use. Finally,

a 35 year career and a 78 year lifespan were used to complete the calculations. LADD values

were calcul ated using the following equation:

LADD = ADD x Days per year of exposure x Years per Lifetime of exposure

365 days/year Lifetime Expectancy

where:

LADD = Lifetime Average Daily Dose

- the amount as absorbed dose received from exposure to a pesticide in a given scenario over a lifetime (mg pesticide active ingredient/kg body weight/day),

ADD = Average Daily Dose

- the amount as absorbed dose received from exposure to a pesticide in a given scenario on a daily basis (mg pesticide active ingredient/kg body weight/day), Days per year of exposure = the an nual frequency of an application by an individual (days/year), Years per Lifetime of exposure = the amount of a lifetime that an individual spends engaged in a career involving pesticide exposure (35 years), and Lifetime Expectancy = the average life ex pectancy of an individual (78 years).



### Cancer Risk Estimates: Finally, cancer risk estimate calculations were completed by comparing the LADD values calculated above to the Q 1 

### * for hydrogen cyanamide (Q 1 

### * = 6.64 x 10 - 2


### (mg/kg/day) - 1 

### ). The Agency consider ed more typical users in these calculations (i.e., private applicators at 10 events per year). Cancer risk estimates were calculated using the following equation:

Total Cance r Risk Estimate = (Dermal LADD + Inhalation LADD) x Q 1 *

where:

Cancer Risk Estimate = Probability of incidence of cancer cases over a lifetime (unitless),

Dermal LADD = Dermal Lifetime Average Daily

- Dose the amount as absorbed dose received from dermal exposure to a pesticide in a given scenario over a lifetime (mg pesticide active ingredient/kg body weight/day),

Inhalation LADD = Inhalation Lifetime Average Daily Dose

- the amount as absorbed dose received from inhalation exposure to a pesticide in a given scenario over a lifetime (mg pesticide active ingredient/kg body we ight/day), and Q 1 * = Quantitative dose response factor used for linear, low

- dose response cancer risk calculations (mg/kg/day) - 1

.



### Summary of Occupational Handler Cancer Exposure and Risk Estimates

T he occupational private handler cancer estim ated risks for airblast and groundboom equipment mixing/loading exposure ranged from 1.4x10 - 6 

### to 1.7x10 - 4 

### . Airblast equipment applicator cancer estimated risks ranged from 2.3x10 - 6 

### to 1.5x10 - 3 

### . The groundboom equipment applicator cancer

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 40 of 75 risk estimates ra nged from 1.7x10 - 6 

### to 6.4x10 - 5 

### . The range of values represent the use of engineering controls for both exposure routes, dermal and inhalation, from the lowest application rate of 6.6 lb ai/A to the highest application rate registered of 17.6 lb ai/A. Can cer risk results were also updated in light of the area refinement data submitted by the registrant, discussed previously and thoroughly explained in D333780; M. Collantes; 2/9/07. Cancer risk estimates

are summarized below in Table 9.1.2 below.

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 41 of 75 Table 9.1.2. Cancer Risk Estimates for Hydrogen Cyanamide for Applications.

Crop or Target Dermal &

Inhalation

PPE Dermal Absorbed

Daily Dose 1
(mg/kg/day) Inhalation

Absorbed Daily Dose 1
(mg/kg/day) Dermal LADD 2
(mg/kg/day) Inhalation LADD 3
(mg/kg/day) Total LADD Cancer Risk

Estimates

Area Treated (Acres) Area Treated (Acres) Area Treated (Acres) Area Treated (Acres) Area Treated (Acres) Area Treated (Acres)

20 40 20 40 20 40 20 40 20 40 20 40 Mixer/Loader (Airblast and Groundboom)

Nectarine

and Peach (Only Airblast) SL/No G

No

- R 0.04 0.08 0.00036 0.00072 0.00049 0.00098 0.0000044 0.0000089 0.00049 0.00099 3.30E

05 6.60E

05

SL/G

PF5 R 0.007 0.014 7.2E

- 05 0.00015 0.00008 0.00017 0.00000089 0.0000018 8.5E

- 05 0.00017 5.60E

06 1.10E

05

DL/G

PF10 R 0.005 0.011 3.6E

- 05 7.2E

- 05 0.00006 0.00013 0.00000044 0.00000089 6.5E

- 05 0.00013 4.30E

06 8.60E

06

EC 0.002 0.003 0.00014 0.00027 0.00002 0.000038 0.0000017 0.0000034 2.1E

- 05 4.2E

- 05 1.40E

06 2.80E

06

Blackberries

and

Blueberries SL/No G

No

- R 0.08 0.16 0.00072 0.00145 0.00098 0.002 0.0000089 0.000018 0.00099 0.002 6.60E

05 1.30E

04

SL/G

PF5 R 0.014 0.027 0.00015 0.00029 0.00017 0.00034 0.0000018 0.0000036 0.00017 0.00034 1.10E

05 2.30E

05

DL/G

PF10 R 0.011 0.021 7.2E

- 05 0.00015 0.00013 0.00026 0.00000089 0.0000018 0.00013 0.00026 8.60E

06 1.70E

05

EC 0.003 0.006 0.00027 0.00055 0.000038 0.000077 0.0000034 0.0000067 4.2E

- 05 8.3E

- 05 2.80E

06 5.50E

06

Apples, Grapes, Cherries, Kiwi Fruit, and Figs SL/No G

No

- R 0.11 0.21 0.00096 0.0019 0.0013 0.0026 0.000012 0.000024 0.0013 0.0026 8.60E

05 1.70E

04

SL/G

PF5 R 0.018 0.036 0.00019 0.00039 0.00022 0.00045 0.0000024 0.0000047 0.00023 0.00045 1.50E

05 3.00E

05

DL/G

PF10 R 0.014 0.028 0.0001 0.00019 0.00017 0.00035 0.0000012 0.0000024 0.00017 0.00035 1.10E

05 2.30E

05

EC 0.004 0.008 0.00037 0.00073 0.000051 0.0001 0.0000045 0.000009 5.6E

- 05 0.00011 3.70E

06 7.30E

06 Airblast Applicator

Nectarine

and Peach SL/No G

No

- R 0.32 0.64 0.0078 0.016 0.004 0.0079 0.000096 0.000191 0.0041 0.0081 2.70E

04 5.40E

04

SL/G

PF5 R 0.29 0.58 0.0016 0.0031 0.0036 0.0071 0.000019 0.000038 0.0036 0.0071 2.40E

04 4.70E

04

DL/G

PF10 R 0.27 0.54 0.00078 0.0016 0.0033 0.0066 0.00001 0.000019 0.0033 0.0066 2.20E

04 4.40E

04

EC 0 0.01 0.00011 0.00023 0.000033 0.0001 0.0000014 0.0000028 3.4E

- 05 6.8E

- 05 2.30E

06 4.50E

06

Blackberries

and

Blueberries SL/No G

No

- R 0.64 1.29 0.016 0.031 0.0079 0.016 0.00019 0.00038 0.0081 0.016 5.40E

04 1.10E

03

SL/G

PF5 R 0.58 1.16 0.0031 0.0062 0.0071 0.014 0.000038 0.000076 0.0071 0.014 4.70E

04 9.30E

04

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 42 of 75 Table 9.1.2. Cancer Risk Estimates for Hydrogen Cyanamide for Applications.

Crop or Target Dermal &

Inhalation

PPE Dermal Absorbed

Daily Dose 1
(mg/kg/day) Inhalation

Absorbed Daily Dose 1
(mg/kg/day) Dermal LADD 2
(mg/kg/day) Inhalation LADD 3
(mg/kg/day) Total LADD Cancer Risk

Estimates

Area Treated (Acres) Area Treated (Acres) Area Treated (Acres) Area Treated (Acres) Area Treated (Acres) Area Treated (Acres)

20 40 20 40 20 40 20 40 20 40 20 40

DL/G

PF10 R 0.54 1.07 0.0016 0.0031 0.0066 0.013 0.000019 0.000038 0.0066 0.013 4.40E

04 8.60E

04

EC 0.01 0.01 0.00023 0.00045 0.000065 0.00013 0.000003 0.0000055 6.8E

- 05 0.00014 4.50E

06 9.30E

06

Apples, Grapes, Cherries, Kiwi Fruit, and Figs SL/No G

No

- R 0.86 1.72 0.021 0.042 0.011 0.021 0.00026 0.00051 0.011 0.022 7.30E

04 1.50E

03

SL/G

PF5 R 0.77 1.54 0.0042 0.0083 0.0095 0.019 0.000051 0.0001 0.0095 0.019 6.30E

04 1.30E

03

DL/G

PF10 R 0.72 1.43 0.0021 0.0042 0.0088 0.018 0.000026 0.000051 0.0088 0.018 5.80E

04 1.20E

03

EC 0.01 0.01 0.0003 0.0006 0.000087 0.00017 0.0000037 0.0000074 9.1E

- 05 0.00018 6.00E

06 1.20E

05

Groundboom (Over

- the

- Row) Applicator

Blackberries

and

Blueberries SL/No G 0.029 0.057 0.0011 0.0023 0.00036 0.0007 0.000014 0.000028 0.00037 0.00073 2.50E

05 4.80E

05

SL/G 0.006 0.012 0.00023 0.00045 0.000071 0.00014 0.0000028 0.0000055 7.4E

- 05 0.00015 4.90E

06 1.00E

05

DL/G 0.005 0.009 0.00011 0.00023 0.000057 0.00011 0.0000014 0.0000028 5.8E

- 05 0.00012 3.90E

06 8.00E

06

EC 0.002 0.004 0.00014 0.00028 0.000023 0.000045 0.0000017 0.0000035 2.5E

- 05 4.9E

- 05 1.70E

06 3.30E

06

Grapes and

Kiwi Fruit SL/No G 0.038 0.076 0.0015 0.003 0.00047 0.00093 0.000018 0.000037 0.00049 0.00097 3.30E

05 6.40E

05

SL/G 0.008 0.016 0.0003 0.0006 0.000096 0.00019 0.0000037 0.0000074 0.0001 0.0002 6.60E

06 1.30E

05

DL/G 0.006 0.012 0.00015 0.0003 0.000075 0.00015 0.0000018 0.0000037 7.7E

- 05 0.00015 5.10E

06 1.00E

05

EC 0.003 0.005 0.00019 0.00038 0.000031 0.000061 0.0000023 0.0000047 3.3E

- 05 6.5E

- 05 2.20E

06 4.30E

06

1. Dermal and Inhalation Daily Dose data from table 9 .1.1;

2. Dermal LADD = Dermal dose * Days per year of exposure x 10 Years per lifetime of exposure / (365 days/year x Lifetime expectancy );

3. Inhalation LADD = Inhalation Dose * Days per year of exposure x Years per lifetime of exposure / (365 days/year x Lifetime e xpectancy );

4. Total LADD = total absorbed d ose [Dermal dose + Inhalation Dose] * Days per year of exposure x Years per lifetime of exposure / (365 days/year x Lifetime expectancy )

5. Cancer risk estimates = LADD * Q 1 * , where Q 1 * = 6.64 x 10

- 2 (mg/kg/day)

- 1

.

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 43 of 75 Chemical

- Specific Data

In 2006, the registrant, Degussa AG, requested an amendment to the Dormex  label (Reg. No.

54555

- 2). The latter label required the use of both, a chemical resistant suit and an enclosed cab for applicators. T he registrant’s label amendment consiste d in removing the requirement of the enclosed cab on the label and for this purpose submitted passive dosimetry and biomonitoring data with the intention of providing evidence that a chemical resistant suit is equiva lent in protection to an enclosed cab. C onsequently, HED completed an assessment comparing the data submitted by the registrant against the Agency’s default assumptions found in the Pesticide Handler Exposure Database (PHED) to determine whether the registrant’s request to remove

enclosed cab re quirement cab was justified. The result of this comparison showed that the overall exposures to handlers were still of concern for most scenarios. Therefore, HED recommended

that the enclosed

- cab requirement remain on the label. A thorough discussion of th is data and

assessment can be found in D306179 ( M. Collantes; 03/10/2006 ) . For purposes of registration review, a re

- assessment utilizing the submitted data (Passive Dosimetry Study and Biomonitoring Studies) was completed in order to reflect the most curr ent updates in HED’s assumptions and default values as appropriate

.

Registration Review Data Comparison
The exposure data for occupational applicators from these studies were used to calculate risk estimates, and then compared to the risk estimates calcul ated using HED default assumptions. HED only assessed the applicator exposure since it was noted in the passive dosimetry study that

t here was insufficient information to confidently calculate an exposure value of mg/lb ai handled

for the mixer/loaders. Although blueberries, blackberries, kiwi fruit and grapes can be treated by either groundboom and/or airblast equipment only airblast risk estimates using the Occupational Pesticide Handler Unit Exposure Surrogate Reference Table are presented below as the y represent the worst exposure scenarios.

Table 9.1.3 summarizes the five applicator scenarios identified from the studies that were included in the comparison

.
Table 9 .1.3. Applicator Scenarios Included in the Risk Estimate Comparison.

Source of Data Scenario Unit Exposure (mg/lb ai)

Dermal Inhalation

Occupational Pesticide Handler Unit Exposure Surrogate Reference Table Open

Cab Airblast using double layer and gloves and

PF10 Respirator 1.48 4.71x10 - 4

Closed Cab 0.0146 6.8x10 - 5

Passive Dosimetry Study (MRID 454074

- 03) Open

Cab Cover

- all and Double Row Boom Sprayer on Grapes 0.07993 0.0018

Closed Cab Test 1: 0.01146 0.00023
Test 2: 0.06745

Biomonitoring Study (MRID 454074

- 02) Closed

Cab Airblast on Grapes, Tyvek Suits 0.0032

Biomonitoring Study (MRID 453657

- 01) Closed

Cab Over

- the Row Sprayers on Grapes, and

Chemical Resistant Rainsuits 0.00103

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 44 of 75 Table 9 .1.3. Applicator Scenarios Included in the Risk Estimate Comparison.

Source of Data Scenario Unit Exposure (mg/lb ai)

Dermal Inhalation Biomonitoring Study (MRID 45407

- 01) Open

Cab Airblast on Fruit Trees, and Chemical

Resistant Suits 0.00392



### Calculations using the exposure data from the passive dosimetry study and the biomonitoring studies were performed in the same manner as those using HED default inputs and assumptions. One exception is that for the biomonitoring studies, a dermal absorption factor is not neede d. By definition, a biomonitoring study measures the total internal dose the human volunteer received through all exposure routes.

Non

- Cancer Risk Estimate Comparison (Passive Dosimetry Study) Applicator using engineering controls (i.e., closed cab):

Both set of data (HED default and chemical

- specific dosimetry data) resulted in risk estimates of concern (MOEs < 1000) via the dermal route of exposure. HED default unit exposures dermal MOEs ranged from 140 to 750. Passive dosimetry dermal MOEs ranged from 31 to 960. Via the inhalation route of exposure, no risk estimates of concern were identified using HED default data (MOEs > 1000). Inhalation MOEs ranged from 3300 to 18000. Passive dosimetry data resulted in no risk estimates of concern, except for on e scenario (i.e., applicator using 17.6 lb ai/A over 40 acres of crop). Inhalation MOEs ranged from 990 to 5300. A summary of these results are provided below in Table 9.1.4.

Applicator without engineering controls (i.e., open cab):

HED default data ass umed with double layer and gloves and a PF10 Respirator and chemical

specific dosimetry data done with coveralls resulted in risk estimates of concern for both the inhalation and dermal routes of exposure (MOEs < 1000) via the dermal route of exposure. HE D default unit exposures dermal MOEs ranged from 1.4 to 7. Passive dosimetry dermal MOEs ranged from 26 to 140. From the inhalation route of exposure, risk estimates of concern were identified for all scenarios using the passive dosimetry data (MOEs rang ed from 130 to 670). HED default data also resulted in risk estimates of concern except for applicators using 6.6 lb ai/A or 13.2 lb ai/A over 20 acres. MOEs ranged from 480 to 2600).

Non

- Cancer Risk Estimate Comparison (Biomonitoring Studies)

Risk estim ates using data from the three urine biomonitoring studies where chemical resistant suits were used, were of concern (combined MOEs <1000; MOEs range: 59 to 1200) for all applicator scenarios, except for one scenario using data from MRID 453657

- 01 [unit ex posure geometric mean 0.00103 (mg/lb ai)] 9 

### applying hydrogen cyanamide at the lowest rate (6.6 lb ai/A) to the most refined area treated (20 Acres). Results are summarized below in Table 9.1.5

9 A unit exposure geometric mean was used because the registrant indicated that the calculated margins of exposure and cancer risk in the ORE assessment for hydrogen cyanamide were based on various central tendency methods, generally favoring the arithmetic mean; that in assessing data which is log

- normally distributed exposure monitoring data will result in an arithmetic

mean that is 2

- 3 fold greater than the corresponding geometric mean values. Therefore, HED revised its calculations using geometric means since the majority of the data pas sed tests for log

- normality (D333780; M. Collantes; 2/9/07).

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 45 of 75 Cancer Risk Estimate Comparison (Passive Dosimetry Study)

Us ing the passive dosimetry study (MRID 454074

- 03) data, cancer risk estimates for private applicators using closed cab airblast equipment ranged from 2x10 - 6 

### to 5x10 - 6 

### . HED default risk estimates for the aforementioned scenario ranged from 2.2x10 - 6 

### to 1.2x1 0 - 5 

### . Passive dosimetry study open cab applicator with coveralls resulted in cancer risk estimates that ranged from

1.4x10 - 5 

### to 7.6x10 - 5 

### . HED default open cab assumption using double layer, gloves and a PF10 respirator resulted in cancer risk estimates r anging from 4.6x10 - 3 

### to 8.5x10 - 4 

### . A summary of these results are provided below in Table 9.1.6.

Cancer Risk Estimate Comparison (Biomonitoring Studies) Exposure data from the three urine biomonitoring studies (MRIDs 454074

- 02, 453657

- 01, and

454074

- 01) us ing chemical

- resistant suits, resulted in cancer risk estimates ranging from

1.4x10 - 6 

### to 2.8x10 - 5 

### . A summary of these results are provided Table 9.1. 7.

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 46 of 75 Table 9 .1.4. Non

- Cancer Exposure and Risk Estimate Comparisons: Passive Dosimetry Study (MRID 454074

- 03) and Handler Unit Exposure Surrogate Reference Table.

Crop Application

Rate 1

(lb ai/A) Test Acres

Treated 2

(A) Dermal Daily Dose 3

(mg/kg/day) Dermal MOE 4 Inhalation Daily Dose 5
(mg/kg/day) Inhalation MOE 6

Dosimeters 7 HED

Data 8 Dosimeters HED

Data Dosimeters 9 HED

Data 10 Dosimeters HED

Data
Closed Cab Applicator

Nectarine

and Peach 6.6 Test 1 20 0.0021 0.0026 960 750 0.00038 0.00011 5300 18000

30 0.003 0.0040 640 500 0.00057 0.00017 3500 12000

40 0.004 0.0053 480 380 0.00076 0.00022 2600 8900

Test 2 20 0.012 0.0026 160 750

No Data N/A

30 0.018 0.0040 110 500

40 0.024 0.0053 82 380

Blackberries

and

Blueberries 13.2 Test 1 20 0.004 0.0053 480 380 0.00076 0.00022 2600 8900

30 0.006 0.0079 320 250 0.0011 0.00034 1800 5900

40 0.008 0.011 240 190 0.0015 0.00045 1300 4500

Test 2 20 0.024 0.0053 82 380

No Data N/A

30 0.037 0.0079 54 250

40 0.049 0.011 41 190

Apples, Grapes, Cherries, Kiwi Fruit, and Figs 17.6 Test 1 20 0.006 0.0071 360 280 0.0010 0.00030 2000 6700

30 0.008 0.011 240 190 0.0015 0.00045 1300 4500

40 0.011 0.014 180 140 0.0020 0.00060 990 3300

Test 2 20 0.033 0.0071 61 280

No Data N/A

30 0.049 0.011 41 190

40 0.065 0.014 31 140

Open Cab Applicator

Nectarine

and Peach 6.6

N/A 20 0.015 0.269 140 7 0.00297 0.001 670 2600

30 0.022 0.403 92 5 0.00446 0.001 450 1700

40 0.029 0.537 69 3.7 0.00594 0.002 340 1300

Blackberries

and

Blueberries 13.2 20 0.029 0.537 69 3.7 0.00594 0.002 340 1300

30 0.044 0.806 46 2.5 0.00891 0.002 220 860

40 0.058 1.074 34 1.9 0.01188 0.003 170 640

Apples, Grapes, Cherries, Kiwi Fruit, and Figs 17.6 20 0.039 0.716 52 2.8 0.00792 0.002 250 970

30 0.058 1.074 34 1.9 0.01188 0.003 170 640

40 0.077 1.433 26 1.4 0.01584 0.004 130 480

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 47 of 75 1. Based on registered labels: (Dormex® (EPA Reg. No.54555

- 2; EPA Reg. No.CA040002; EPA Reg. No. HI030003); Krop

- MaxTM (EPA Reg. No. 80697

- 6); Duomax (EPA Reg. No. 84374

- 1).

2. Exposure Science Advisory Council Policy #9.1 and survey data provided by the registrant.

3. Dermal Dose = Dermal Unit Exposure (mg/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/acre) x Area Treate d (A/day) x DAF (%) / BW (kg).

4. Dermal MOE = Dermal NOAEL (mg/kg/day)/Dermal Dose (mg/kg/day).

5. Inhalation Dose = Inhalation Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/acre) x Area Treated (A/day) / BW (kg).

6. Inhalation MOE = Inhalation NOAEL (mg/kg/day)/ Inhalation Dose (mg/kg/day).

7. Passive Dosimetry Study Dermal Unit Exposure s: Engineering Controls (Closed Cab) Test 1 = 0.01146 mg/lb ai; Test 2 = 0.06745 mg/lb ai. Open cab groundboom, coveralls = 0 .07993 mg ai/A.

8. HED Default Data Airblast Dermal Unit Exposure: Engineering Controls (Closed Cab) = 0.0146 mg/lb ai. Open Cab, doub le layer and gloves and a PF10 Respirator = 1.48 mg ai/A.

9. Passive Dosimetry Inhalation Unit Exposure: Engineering Controls (Closed Cab) = 0.00023 mg/lb ai. Open Cab groundboom, covera lls = 0.0018 mg ai/A.

10. HED Default Data Airblast Inhalation Unit Exposure : Engineering Controls (Closed Cab) = 6.8x10

- 5 mg/lb ai. Open Cab, double layer and gloves and a PF10 Respirator = 4.7x10

- 4 mg ai/A.

Table 9 .1.5. Non

- Cancer Exposure and Risk Estimate Comparison: Biomonitoring Studies.

Scenario Crop Unit Exposure (Geometric Mean) from Biomonitoring Studies 1
(mg/lb ai) Application

Rate 2

(lb ai/A) Acres

Treated 3

(A) Absorbed Daily Dose 4
(mg/kg/day) MOE 5

LOC=1000

MRID

454074

- 02 MRID

453657

- 01 MRID

454074

- 01 MRID

454074

- 02 MRID

453657

- 01 MRID

454074

- 01 MRID

454074

- 02 MRID

453657

- 01 MRID

454074

- 01

Airblast Nectarine and

Peach 0.0032 0.00103 0.00392 6.6 20 0.0053 0.0017 0.0065 380 1200 310

30 0.0079 0.0025 0.0097 250 800 210

40 0.011 0.0034 0.013 180 590 150

Blackberries

and Blueberries 0.0032 0.00103 0.00392 13.2 20 0.011 0.0034 0.013 180 590 150

30 0.016 0.0051 0.019 130 390 110

40 0.021 0.0068 0.026 95 290 77

Apples, Grapes, Cherries, Kiwi Fruit, and Figs 0.0032 0.00103 0.00392 17.6 20 0.014 0.0045 0.017 140 440 120

30 0.021 0.0068 0.026 95 290 77

40 0.028 0.0091 0.034 71 220 59

1. MRID 454074

- 02

- The Determination of N

- acetylcyanamide in Urine of Workers Exposed to Dormex as a Measure of Exposure;

MRID 453657

- 01

- The Evaluation of Worker Exposure During Loading and Spray Application of Dormex to Dormant Grapevines;

MRID 454074

- 01

- The Evaluation of Spray Applicator Exposure During Airblast Spray Application of Dormex to Dormant Fruit Trees.

2. Based on registered labels: (Dormex® (EPA Reg. No.54555

- 2; EPA Reg. No.CA040002; EPA Reg. No. HI030003 ); Krop

- MaxTM (EPA Reg. No. 80697

- 6); Duomax (EPA Reg. No. 84374

- 1).

3. Exposure Science Advisory Council Policy #9.1 and survey data provided by the registrant.

4. Absorbed Daily Dose = Study Unit Exposure (mg/lb ai) x Conversion Factor (0.001 mg/ug) x Applicati on Rate (lb ai/acre) x Area Treated (A/day) / BW (kg).

5. MOE = NOAEL (2 mg/kg/day)/Dose (mg/kg/day).

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 48 of 75 Table 9 .1.6. Cancer Exposure and Risk Estimate Comparison: Passive Dosimetry Study (MRID 454074

- 03) Surrogate Reference Table.

Crop Test Total Dose (mg/kg/day) LADD (Private Applicator) Cancer Risk (Private Applicator)

Dosimeters PHED Dosimeters PHED Dosimeters PHED

Applicator Closed Cab

Nectarine and Peach Test 1 0.0025 0.0028 0.000030 0.000034 2.0E

- 06 2.3E

- 06

0.0037 0.0041 0.000045 0.000051 3.0E

- 06 3.4E

- 06

0.0049 0.0055 0.000060 0.000068 4.0E

- 06 4.5E

- 06

Test 2 0.012 0.0026 0.00015 0.000033 1.0E

- 05 2.2E

- 06

0.018 0.0040 0.00023 0.000049 1.5E

- 05 3.2E

- 06

0.024 0.0053 0.00030 0.000065 2.0E

- 05 4.3E

- 06

Blackberries and Blueberries Test 1 0.0049 0.0055 0.000060 0.000068 4.0E

- 06 4.5E

- 06

0.0074 0.0083 0.000091 0.00010 6.0E

- 06 6.8E

- 06

0.0098 0.011 0.00012 0.00014 8.0E

- 06 9.0E

- 06

Test 2 0.024 0.0053 0.00030 0.000065 2.0E

- 05 4.3E

- 06

0.037 0.0079 0.00045 0.000098 3.0E

- 05 6.5E

- 06

0.049 0.011 0.00060 0.00013 4.0E

- 05 8.7E

- 06

Apples, Grapes, Cherries, Kiwi Fruit, and Figs Test 1 0.0066 0.0074 0.00008 0.000091 5.4E

- 06 6.0E

- 06

0.010 0.011 0.00012 0.00014 8.0E

- 06 9.0E

- 06

0.013 0.015 0.00016 0.00018 1.1E

- 05 1.2E

- 05

Test 2 0.033 0.0071 0.00040 0.000087 2.7E

- 05 5.8E

- 06

0.049 0.011 0.00060 0.00013 4.0E

- 05 8.7E

- 06

0.065 0.014 0.00080 0.00017 5.3E

- 05 1.2E

- 05

Applicator Open Cab

Nectarine and Peach

N/A 0.017 1.0 0.00021 0.013 1.4E

- 05 8.5E

- 04

0.026 1.6 0.00032 0.019 2.1E

- 05 1.3E

- 03

0.035 2.1 0.00043 0.026 2.9E

- 05 1.7E

- 03

Blackberries and Blueberries 0.035 2.1 0.00043 0.026 2.9E

- 05 1.7E

- 03

0.052 3.1 0.00064 0.039 4.3E

- 05 2.6E

- 03

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 49 of 75 Table 9 .1.6. Cancer Exposure and Risk Estimate Comparison: Passive Dosimetry Study (MRID 454074

- 03) Surrogate Reference Table.

Crop Test Total Dose (mg/kg/day) LADD (Private Applicator) Cancer Risk (Private Applicator)

Dosimeters PHED Dosimeters PHED Dosimeters PHED

0.070 4.2 0.00086 0.051 5.7E

- 05 3.4E

- 03

Apples, Grapes, Cherries, Kiwi Fruit, and Figs 0.047 2.8 0.00057 0.034 3.8E

- 05 2.3E

- 03

0.070 4.2 0.00086 0.051 5.7E

- 05 3.4E

- 03

0.093 5.6 0.0011 0.069 7.6E

- 05 4.6E

- 03

1. Dermal and Inhalation Daily Dose data from table 9 .1.4;

2. Total Absorbed Daily Dose (mg/kg/day) = Absorbed Dermal Daily Dose + Absorbed Inhalation Daily Dose;

3. Lifetime Average Daily Dose (LADD) = Total Absorbed Dose (mg/kg/day) x 10 or 30 exposure days/365 days x 35 work years/78 y rs life expectancy; it is assumed that private growers would be exposed 10 days per year and commer cial applicators 30 days;

4. Cancer Risk = Q1*(6.64E

- 2 mg/kg/day)

- 1 x Lifetime Average Daily Dose (mg/kg/day).

Table 9 .1.7: Cancer Exposure and Risk Using Biomonitoring Studies.

Scenario Crop Absorbed Daily Dose 1 (mg/kg/day) LADD 2 (Private Applicator) Canc er Risk 3 (Private Applicator)

Studies MRID

454074

- 02 MRID

453657

- 01 MRID

454074

- 1 MRID

454074

- 02 MRID

453657

- 01 MRID

454074

- 1 MRID

454074

- 02 MRID

453657

- 01 MRID

454074

- 1

Airblast Nectarine and Peach 0.0053 0.0017 0.0065 0.000065 0.000021 0.000080 4.3E

- 06 1.4E

- 06 5.3E

- 06

0.0079 0.0025 0.0097 0.000097 0.000031 0.00012 6.4E

- 06 2.1E

- 06 8.0E

- 06

0.011 0.0034 0.013 0.00014 0.000042 0.00016 9.3E

- 06 2.8E

- 06 1.1E

- 05

Blackberries and Blueberries 0.011 0.0034 0.013 0.00014 0.000042 0.00016 9.3E

- 06 2.8E

- 06 1.1E

- 05

0.016 0.0051 0.019 0.0002 0.000063 0.00023 1.3E

- 05 4.2E

- 06 1.5E

- 05

0.021 0.0068 0.026 0.00026 0.000084 0.00032 1.7E

- 05 5.6E

- 06 2.1E

- 05

Apples, Grapes, Cherries, Kiwi Fruit, and Figs 0.014 0.0045 0.017 0.00017 0.000055 0.00021 1.1E

- 05 3.7E

- 06 1.4E

- 05

0.021 0.0068 0.026 0.00026 0.000084 0.00032 1.7E

- 05 5.6E

- 06 2.1E

- 05

0.028 0.0091 0.034 0.00034 0.00011 0.00042 2.3E

- 05 7.3E

- 06 2.8E

- 05

1. Dermal and Inhalation Daily Dose data from table 9 .1.5;

2. Lifetime Average Daily Dose (LADD) = Total Absorbed Dose (mg/kg/day) x 10 exposure days/365 days x 35 work years/78 yrs life expectancy; it is assumed that pr ivate growers would be exposed 10 days per

year;

3. Cancer Risk = Q1*(6.64E

- 2 mg/kg/day)

- 1 x Lifetime Average Daily Dos e (mg/kg/day).

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 50 of 75 9 .2 Occupational Post

- application Exposure/Risk Estimates

HED uses the term post

- application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re

entry exposure). Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting. Post

- application exposure levels vary over t ime and depend on such things as the type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical’s degradation properties. In addition, the timing of pesticide applications,

relative to harvest activities, can greatly reduce the potential for post

- application exposure.

9 .2.1 Occupational Post

- application Inhalation Exposure/Risk Estimates

Based on the Agency's current practices, a quantitative post

- application inhalation exposure

assessment wa s not performed for hydrogen c yanamide at this time. However, there are multiple potential sources of post

- application inhalation exposure to individuals performing post

application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act S cientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 10 

### . The Agency is in the process of evaluating the SAP report as well as available post

- application inhalation exposure data generated by the ARTF and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational post

- application inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post

- application inhalation exposure

assessment for h ydrogen c yanamide.

Although a quantitative occupational post

- application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resulting f rom application of pesticides outdoors is likely to result in higher exposure than post

- application exposure.

9

. 2 .2 Occupational Post

- application Dermal Exposure/Risk Estimates

A quantitative post

- application dermal assessment was not performed for this action. Hydrogen cyanamide is registered to be applied to deciduous crops approximately 30 days before bud break to synchronize blossoming and/or produce a more uniform bud break. The

post

- application activity with the potential of occurring during the time of application is pruning. The Agency does not expect significant risk from this dermal post

- application activity since at the time of application deci duous crops are in a state of dormancy where plants exhibit little or no foliage growth as indicated on the labels. Moreover, registered labels state that all pruning activities must be completed before application of pesticide.

10 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 51 of 75 The Restricted Entry Interval (REI) relies on the acute dermal toxicity, eye irritation, and skin irritation effects of hydrogen cyanamide. These criteria are classified as toxicity category II based on hydrogen cyanamide’s acute toxicity profile. According to the Worker Prote ction Standard guidelines the minimum REI should be 24 hours, therefore

, the 72 hour REI on the registered labels is adequate.

10 .0 References

Abdel

- Saheb

. I. 10/4/12 . D403785. 

## Revised Recommendations for Tier II Estimated Surface Drinking Water Concentr ations and Estimated Ground Water Concentrations (EDWCs) for Hydrogen Cyanamide for Use in Human Health Risk Assessment.

Brunsman, L. 3/22/01. TXR No. 0014510. Revised Hydrogen Cyanamide Quantitative Risk Assessment (Q 1 * 

### ) Based on Mouse Drinking Water Study with mg/kg Body Weight 3/4 

### /Day Interspecies Scaling Factor.

Collantes, M. 3/10/06. D306179. Occupational and Residential Exposure Risk Assessment for Hydrogen Cyanamide for Use on Grapes and Fruit Tree Orchards: Req uest to Amend Personal Protective Equipment Use on Registered Label.

Cropp

- Kohlligian, B. 11/8/12, D406396

. Hydrogen Cyanamide

. Residue Chemistry Considerations for Registration Review.

Cropp

- Kohlligian, B. 11/7/12, D405734, Hydrogen Cyanamide

. Acute

, C hronic , and Cancer Dietary ( Drinking Water Only) Exposure and Risk Assessments for Registration Review.

Email. 9/20/12. Email correspondence from Shanna Recore, HED to Jessica Kidwell, HED.

Greear, W. and Rinde, E. 9/15/93. TXR No. 0010592. Carcinogenic ity Peer Review of Hydrogen Cyanamide.

Güthner, T. and Mertschenk, B. 2006. Cyanamides. Ullmann's Encyclopedia of Industrial Chemistry.

Hawkins, M. 10/3/07. Review of Cyanamide Incident Reports. D339290.

Nieves, I. 3/12/14

. D405735. Hydrogen Cyanamide. Occupational and Residential Exposure

Assessment for Registration Review.

Rury, K. 6/13/12. TXR No. 0056332. Hydrogen Cyanamide: Summary of Hazard and Science Policy Council (HASPOC) Meeting of May 10, 2012: Recommendations on the need for a 28

- day inhalation study, a subchronic dermal study, and a neurotoxicity battery.

Rury, K. 9/17/12. TXR No. 0056437. Hydr ogen Cyanamide: Summary of Hazard and Science Policy Council (HASPOC) Meeting of August 9, 2012: Reconsideration of the 28

- day dermal toxicity study.

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 52 of 75 Rury, K. 1/23/14

. TXR No. 0056857. Hydrogen Cyanamide: Summary of Hazard and Science Policy Council (HA SPOC) Meeting of December 12, 2013: Reconsideration of the Requirement

for a 28

- day dermal toxicity study.

Whalen, J. 3/26/01. TXR No. 0014511. Hydrogen Cyanamide: Report of the Hazard

Identification Assessment Review Committee.

Whalen, J. 6/12/01. D27 1362. Hydrogen Cyanamide: Risk Assessment for Occupational Uses on Grapes, Apples, Blueberries, Cherries, Peaches, Nectarines, and Plums.

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 53 of 75 A ppendix A

. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CF R 158.340) for the non

- food use for Hydrogen Cyanamide are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols

were used.

Test Technical

Required Satisfied

870.1100 Acute Oral Toxicity

................................ ....................... 870.1200 Acute Dermal Toxicity

................................ .................. 870.1300 Acute Inhalation Toxicity

................................ .............. 870.2400 Primary Eye Irritation

................................ .................... 870.2500 Primary Dermal Irritation

................................ .............. 870.2600 Dermal Sensitization

................................ ...................... Yes

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)

................................ ............... 870.3150 Oral Subchronic (nonrodent)

................................ ......... 870.3200 21

- Day Dermal

................................ .............................. 870.3250 90

- Day Dermal

................................ .............................. 870.3465 21

- /90

- Day Inhalation

................................ .................... yes

yes

yes

no

yes yes

yes

no

-

no

870.3700a Developmental Toxicity (rodent)

................................ ... 870.3700b Developmental Toxicity (nonrodent)

............................. 870.3800 Reproduction

................................ ................................ . yes

yes

yes yes

yes

yes

870.4100a Chronic Toxicity (rodent)

................................ .............. 870.4100b Chronic Toxicity (nonrodent)

................................ ........ 870.4200a Oncogenicity (rat)

................................ .......................... 870.4200b Oncogenicity (mouse)

................................ .................... 870.4300 Chronic/Oncogenicity

................................ .................... yes

yes

yes

yes

yes yes

yes

yes

yes

yes

870.5100 Mutagenicity

— Gene Mutation

- bacterial

..................... 870.5300 Mutagenicity

— Gene Mutation

- mammalian

................ 870.5375 Mutagenicity

— Structural Chromosomal Aberrations

... 870.5900 Mutagenicity

— Other Genotoxic Effects

....................... yes

yes

yes

yes yes

yes

yes

yes

870.6100a Acute Delayed Neurotox. (hen)

................................ ..... 870.6100b 90

- Day Neurotoxicity (hen)

................................ ........... 870.6200a Acute Neurotox. Screening Battery (rat)

....................... 870.6200b 90

- Day Neuro. Screening Battery (rat)

.......................... 870.6300 Develop. Neuro

................................ .............................. no

no

yes

yes

no -

-

no

no

-

870.7485 General Metabolism

................................ ...................... 870.7600 Dermal Penetration

................................ ........................ 870.7800 Immunotoxicity

................................ ............................. yes

yes
Yes yes

yes

no

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 54 of 75 A.2 Toxicity Profile s

Table A.2. 1 Acute Toxicity Profile

- Hydrogen Cyanamide 50% aqueous* [PC 014002]

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 870.1100 Acute oral toxicity (TXR

5009273 ) 47469101 (2005) Oral LD 50 Females

= 313 mg/kg II

870.1200 870.1200 Acute dermal toxicity :

rabbits (TXR 5009273 ) 47469102 (2005) LD 50 = 1707 mg/kg

♂

LD 50 = > 5050 mg/kg ♀ II

870.1300 870.1300 Acute inhalation toxicity

(TXR 5009273 ) 47469103 (2005) LC 50 >2.32 mg/L IV

870.2400 870.2400 Acute eye irritation (TXR

5009273 ) 47469104 (2005) Moderate II

870.2500 870.2500 Acute dermal irritation (TXR

5009273 ) 47469105 (2005) Moderate in

females, but no

irritation in males II

870.2600 870.2600 Skin sensitization (TXR

5009273 ) 47469106 (2006) Negative NA

* Hydrogen cyanamide toxicity was evaluated in acute, subchronic and chronic studies employing a 50% aqueous hydrogen

cyanamide because of the instability and explosivity of the pure material



### .

Table A.2. 3 Subchronic, Chronic and Other Toxicity Profile

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

8703150 28

- Day Oral

gavage

- Rat

TXR 0010591 42202902 (1988) Range finding 0, 5, 10, 20 or 40 mg a.i./kg/day 50% aqueous LOAEL = 5 mg a.i./kg/day based on

histological changes (decreased colloidal content and small closely packed follicular cells) in male thyroid

NOAEL <5 mg a.i./kg/day

870.3150 28

- Day Dietary

-

Rat

TXR 0005681 (p.18) 00148027 (1974) Range finding 0, 100, 300, 1000, or 3000

ppm Cyanamid L 500: slightly turbid, bluish liquid. (estimated mg/kg/day 0, 10, 28, 75. 150) LOAEL = 100 ppm ( est. 10 mg/kg/day) based

on hepatocellular degeneration

NOAEL <100 ppm ( The study report is very short 6 pages, does not provide much information.)

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 55 of 75 Table A.2. 3 Subchronic, Chronic and Other Toxicity Profile

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.3150 Subchronic

Dietary

- Rat

[ TXR 0005681 (p.20) ] 00148028 (1975)

0, 20, 60, or 180 ppm Cyanamid L 500 slightly turbid, bluish liquid. (estimated 0, 1.5, 4.5, 13.5 mg a.i. /kg/day) Unacceptable (due to a

lack of individual animal

data) NOAEL = 1.5 mg a.i./kg/day (20 ppm)

LOAEL = 4.5 mg a.i./kg/day (60 ppm) based on morphological activation in the thyroids of

males consistin g of an increased number of small follicles lined by cuboidal epithelium and disappearance of colloid, and the number of

interfollicular cells was increased and occasionally accompanied by a marked proliferation of follicular epithelial cells ). (The study report is very short, 12 pages, does not provide much information).

870.3150 Subchronic

Dietary/Oral

gavage

- Dog

[ HED Document 0008150 (p. 15),

0014571 ] 41390501

Week 1: 0, 30, 100, or 300 ppm

Weeks 2

- 13: 0. 0.6, 2, or 6 mg a.i./kg/day 50% aqueous Acceptable/Guideline NOAEL = 2 mg a.i./kg/day

LOAEL = 6 mg a.i./kg/day (decreased weight gain (females), buccal cavity redness,

decreased absolute and relative testicular weights (males), and thymus weights (females), aggregates of polymorphonuclear and

mo nonuclear inflammatory cells in the parotid salivary glands, testicular atrophy, and reduced or inhibited spermatogenesis.)

870.3200 21

- Day Dermal

– A study has not been performed. This study is required ( TXR 0056857 )

.
870.3465 90

- Day Inhalation

- Rat – A study has not been performed. This study is required TXR 0056332 )

.

870.3700a Gavage

Developmental Toxicity

- Rat

[ HED Document 0008150 (p.78) ] 41288806 (1989) 0, 5, 15, or 45 mg a.i./kg/day 50% aqueous Acceptable/Guideline Maternal NOAEL = 5 mg a.i./kg/day

Maternal LOAEL = 15 mg a.i./kg/day (decreased body weight gain ( ↓ 18%) and decreased food consumption ( ↓ 8%)

, hypoactivity seen on GD6 and GD7 in 8/25 animals after 1 or 2 days of dosing ) Developmental NOAEL = 15 mg a.i./kg/day Developmental LOAEL = 45 mg a.i./kg/day (decreased fetal body weight, increase in diaphragmatic hernias, and wavy/bent ribs.)

870.3700b Gavage

Developmental Toxicity

- Rabbit

[ HED Documents 0008150 (p.71),

0010591 ] 41288805 (1989)

42178406 (stability) 0, 4, 12, or 36 mg/kg/day (0, 2, 6, or 18 mg a.i./kg/day) 50% aqueous Acceptable/Guideline Maternal NOAEL = 6 mg a.i./kg/day

Maternal LOAEL = 18 mg a.i./kg/day (decreased body weight gain during gestation ( ↓ 109%)) Developmental NOAEL = 6 mg a.i./kg/day

D evelopmental LOAEL = 18 mg a.i./kg/day (disintegration of liver structure)

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 56 of 75 Table A.2. 3 Subchronic, Chronic and Other Toxicity Profile

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.3800 G avage

Reproductive Toxicity

[ HED Document 0010591,

0014571 ] 41566504 (1990)

0, 2.5, 7.5, or 30 mg a.i./kg/day (F 0 during premating) or 0, 1.25, 3.75, or 15 mg a.i./kg/day (during F 1 premating, F 0 and F 1 female gestation and lactation) 50% aqueous Acceptable/Guideline Parental NOAEL = 2.5 mg a.i./kg/day

Parental LOAEL = 7.5 mg a.i./kg/day (based on statistically signi ficant decreases in body weight/weight gain ( ↓ 8%/ ↓ 18%) in the F 0 ) Reproductive NOAEL = 15 mg a.i./kg/day (HDT) Reproductive LOAEL > 15 mg a.i./kg/day Offspring NOAEL = 3.75 mg a.i./kg/day Offspring LOAEL = 15 mg a.i./kg/day (decreased pup viability in both generations and decreased pup weight in first generation)

870.4100a Gavage Chronic

Toxicity (20

- Month)

- Rat

[ HED Document

0010591 ] 42178404 (1991)

0, 2.5, 7.5, or 30 mg a.i./kg/day for 16 weeks, then 0, 1, 2.5, or 7.5 mg a.i./kg/day weeks 17

- 91 (due to excessive toxicity) 50% aqueous Acceptable/Guideline NOAEL = 2.5 mg a.i./kg/day

LOAEL = 7.5 mg a.i./kg/day (significant decreases in body weight gain, reduced colloid in the thyroid, and reduced T 3 and T 4 levels; at week 14, adverse effects included decreased RBC, Hb, and Hct. There is no evidence of carcinogenicity

. [NOTE: This study met the requirements for a chronic toxicity study in rats, but does not meet guideline requirements for a carcinogenicity

s tudy.]

870.4100b Gavage Chronic

Toxicity

- Dog

[ HED Document 0008150, 0010591,

0014571 ] 41288802 (1989)

0, 0.2, 1.0, or 5.0 mg a.i./kg/day 50% aqueous Acceptable/Guideline NOAEL = 1.0 mg a.i./kg/day

LOAEL = 5.0 mg a.i./kg/day (increased incidences of rough haircoat, desquamation of the skin, tremors, and salivation; decreased body weight gain; decreased T 4 in males; increased relative thyroid

- parathyroid weights in females; brown pigment in liver Kupffer cells; thymic atrophy in males; testicular inflammation; and aspermatogenesis, and hypospermatogenesis) There is no evidence of carcinogenicity

.
870.4300 Drinking Water

Carcinogenicity (100 weeks in males, 104 weeks in females)

- Mouse

[ HED Documents 0008422,

0010591 ] 41566502 (1990)

42178405 (Addendum 1991) 0, 70, 200, or 600 ppm Males: 0, 5.0, 13.6, or 36.8 mg a.i./kg/day Females: 0, 6.9, 16.9, or 49.0 mg a.i./kg/day 50% aqueous Acceptable/Guideline NOAEL = 6.9 mg a.i./kg/day

LOAEL = 16.9 mg a.i./kg/day (increased incidence of urinary bladder and kidney lesions in females, and decreased Kaplan

- Meier survival rate in females.) At 600 ppm, there is decreased body weight gain in males, and decreased survival, ovarian stromal/luteal hyperplasia in females; a nd urinary bladder and kidney lesions in both

sexes. There is an increased incidence of ovarian granulosa

- theca tumors and related tumors (thecoma, luteoma) at 200 and 600 ppm (16.9 and 49.0 mg a.i./kg/day, respectively).

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 57 of 75 Table A.2. 3 Subchronic, Chronic and Other Toxicity Profile

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.4200 Bioassay of

Calcium Cyanamide

- Rats.

National Cancer Institute Study No. (NIH) 79

- 1719; 1979

[ HED Document 0005681,

0008162 ] 00148030 (1979) 0, 100, or 200 ppm (approximately 0, 2.5, or 5.0 mg a.i./kg/day) in the

feed Acceptable/

Non

- Guideline There is no evidence of carc inogenicity

.

The NOAEL and LOAEL are not established.

The CPRC determined that oral carcinogenicity/toxicity studies of calcium cyanamide and hydrogen cyanamide can be used interchangeably. The CPRC determined that dosing is adequate for assessing the ca rcinogenic potential of calcium cyanamide based upon the results of a

range

- finding study, and supported by the findings of a chronic dietary study with hydrogen cyanamide.

870.4200 Bioassay of

Calcium Cyanamide

- Mice

National Cancer Institute Study No. (NIH) 79

- 1719; 1979

[ HED Document 0005681,
0008162,

0010591 ] 00148030 (1979)

0, 500, or 2 0 00 ppm (approximately 0, 38, or 188 mg a.i./kg/day) in the

feed Acceptable/

Non

- Guideline NOAEL = 500 ppm (~38 mg a.i./kg/day)

LOAEL = 2500 ppm (~188 mg a.i./kg/day) based on increased mortality in males.

There is an increased incidence of hemangiosarcomas in male B6C3F1 mice.

The CPRC determined that oral carcinogenicity/

- toxicity studies of calcium cyanamide and hydrogen cyanamide can be used interchangeably. The CPRC determined that dosing is adequate for assessing the carcinogenic potential of calcium cyanamide based upon the results of the range

- finding study.

870.4300 Chronic Toxicity/

-

Carcinogenicity

Rat Although a 20

- month chronic study of hydrogen cyanamide was performed (MRID 42178404), there is no carcinogenicity component to it. This is not a data gap because the Cancer Peer Review Committee (CPRC) was able to assess the carcinogenic potential of hydrogen cyanamide with the available data.

870.5100 Bacterial Reverse

Gene Mutation Test (Ames Assay) with Hydrogen Cyanamide

[ HED Document

0006628 ] 40389608 (1987) 53% aqueous Acceptable/Guideline Negative at doses ranging from 0.1 to 15 μL/plate ± metabolic reactivation (HCN)

870.5100 Bacterial Reverse

Gene Mutation Test (Ames Assay) with

Calcium Cyanamide Haworth et al. 1983.

Environ. Mutagen. Vol 5. (Suppl 1) 1983 3

- 142 Weak positive (+ activation) in Salmonella

strain TA 1535 at 333 μ g/plate with rat or hamster S9; negative without activation. Results consistent from two laboratories testing

for NT P (CaCN)

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 58 of 75 Table A.2. 3 Subchronic, Chronic and Other Toxicity Profile

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.5300 In Vitro

Cytogenetic Assay Measuring

Chromosomal

Aberration Frequencies in

Chinese Hamster Ovary (CHO)

Cells
[ HED Document

0006628 ] 40389609 (1987) 53% aqueous Acceptable/Guideline The test material induced dose

- related

chromosomal aberrations in Chinese hamster

o vary cells into the cytotoxic toxic range (≥ 141 μg/ml (

- S9); ≥ 875 μg/ml (+S9)).

870.5395 In Vivo

Micronucleus Assay

- Mouse

[ HED Document

0006628 ] 40389610 (1987) 53% aqueous Acceptable/Guideline Negative : The test material failed to induce significant increases in micronuclei in bone marrow polychromatic erythrocytes over a dose range from 31.44 to 330.5 mg/kg, the HDT inducing clinical toxicity (death and ruffled coats).

870.5550 Unscheduled

DNA Synthesis in Rat Hepatocytes

[ HED Document

0006628 ] 40389607 (1987) 53% aqueous Acceptable/Guideline Negative; The test material did not induce significant changes in nuclear labeling of primary hepatocytes over a dose range of 5.95 to 143 ug/mL when compared to the solvent control.

870.6200 a Acute

Neurotoxicity

- Rats – This is a data gap . HASPOC required this study (TXR 0056332 )

.

870.6200b Subchronic

Neurotoxicity

- Rats – This is a data gap . HASPOC required this study TXR 0056332 )

.

870

- 7800 Immunotoxicity This is a data gap

.

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 59 of 75 Table A.2. 3 Subchronic, Chronic and Other Toxicity Profile

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.7485 Metabolism

- Rat

Literature Review

[ HED Document

0010591 ] 42178407 (1991) Acceptable/Non

Guideline Hydrogen cyanamide is rapidly absorbed,

metabolized, and excreted in the urine following oral, intravenous (I.V.), and intraperitoneal (I.P.) dosing in rats, dogs, or rabbits. Following I.P. dosing in rats, 93.4% of

the dose is excreted in the urine within the first 6 hours, indicating that hydrogen cyanamide is rapidly metabolized and almost completely eliminated from the body. Negligi ble amounts are excreted as expired CO 2 . Following both oral and I.V. dosing in dogs, 62

- 83.1% of the

dose is excreted in the urine within the first 24

- 27 hours. Negligible amounts of radioactivity are excreted in the feces. The major metabolite of cy anamide excreted in the urine of rats, rabbits, dogs, and humans was identified as N

acetylcyanamide. The conversion of cyanamide to N

- acetylcyanamide in vitro is catalyzed by an acetyl

- S

- CoA

- dependent N

acetyltransferase present in rabbit and dog

liver.

870.7485 Metabolism

- Rat

[ HED Document

0010895 ] 42906401 (1993)

Acceptable/Guideline Rats were administered a single gavage dose of 1 or 20 mg/kg 14 C

- hydrogen cyanamide or administered daily doses of 1 mg/kg unlabeled hydrogen cyanamide for 14 days followed by a single dose of 1 mg/kg 14 C

- hydrogen cyanamide on day 15. An additional group received a single I.V. dose of 1 mg/kg 14 C

hydrogen cyanamide. The study demonstrated

that 14 C

- hydrogen cyanamide is rapidly absorbed, distributed, metabolized, and excreted following oral and I.V. administration in rats. Total recoveries of the radioactivity are high for all oral and I.V. groups (98.7

- 105.5%

of adm inistered dose). Urine is the major route of excretion (66.9

- 97.7% of administered dose). Hydrogen cyanamide elimination is sex

- , dose

- , and route

- related. Limited amount is

metabolized to CO2. Tissue bioaccumulation of was low for all groups. Most of th e 14 C

hydrogen cyanamide is N

- acetylated to form N

acetylcyanamide, which is eliminated in the

urine and feces.

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 60 of 75 Table A.2. 3 Subchronic, Chronic and Other Toxicity Profile

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.7600 Dermal

Penetration

- Rat

HED Document

0010591 41504004 (1989)

Radio purity by TLC 77.5% (decomposition on TLC plates)

Non

Acceptable/Guideline A single dermal dose of 0.1, 1, or 10 mg (8, 80, or 800 μg/cm 2 , respectively) 14 C

- hydrogen cyanamide, administered to three groups of male rats (24/group), is rapidly absorbed, distributed and eliminated. In general, as the

dose l evel and the duration of exposure increased, the percentage of the dose absorbed also increased. Using the direct procedure to calculate skin absorption, the average 14 C

hydrogen cyanamide equivalents absorbed within 24 hours are 1.79%, 2.84%, and 11.1%

o f the applied dose for the low

- , mid

- , and high

- dose groups, respectively. The data can be utilized for risk assessment purposes as a

worst case scenario. Although purity was not reported, HED is not concerned about this deficiency.



### A.3 Hazard Identification and Endpoint Selection

A.3.1 Acute Reference Dose (aRfD)

- Females age 13

- 49

An endpoint for acute dietary exposure for females age 13

- 49 was not selected since there was no single dose endpoint available in the database that was appropria te for this scenario.

A.3.2 Acute Reference Dose (aRfD)

- General Population

Study Selected : Developmental T oxicity S tudy in the Ra t.

MRID No. : 41288806

Executive Summary : See Appendix A, Guideline 870.3700a

Dose and Endpoint for Risk Assessment : Maternal NOAEL= 5 mg/kg based on hypoactivity in

3 2 % of the animals during the first two days of dosing (GD 6 and 7) at a maternal LOAEL of 15 mg/kg.

Uncertainty Factor(s) : 1000. This includes 10X for intraspecies variation, 10 X for interspecies extrapolation and a 10X database uncertainty factor (lack of ACN, SCN, 28

- day inhalation,

subchronic dermal, and immunotoxicity studies)

.

Comments about Study/Endpoint/Uncertainty Factor : The developmental rat study is appropriate

for the duration and population of concern since the effects occurred following a single dose. The effect is consistent with effects seen in the database. The acute oral study was also a candidate since it showed clinical signs of decreased activity in one of two animals after one dose at 27.5

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 61 of 75 mg/kg, lowest dose tested, with a 3x for lack of NOAEL. The developmental rat study was selected since the endpoint was more robust and had a clear NOAEL. Since there are no tolerances established for this chemical, an a cute RfD (aRfD) is derived to address the risk from drinking water exposure only.

A.3.3 Chronic Reference Dose (cRfD )

Stud ies Selected : Co

- Critical Studies: Subchronic gavage toxicity study in dogs and Chronic gavage toxicity study in dogs.

MRID Nos : 41390501 (subchronic dog); 41288802 (chronic dog)

Executive Summary : See Appendix A, Guideline s 870.3150 and 870.4100b

Dose and Endpoint for Risk Assessment : NOAEL = 2.0 mg a.i./kg/day from the subchronic dog study. The LOAEL of 5 mg/kg/day from the chronic dog study was based on increased incidences of rough haircoat, desquamation of the skin, tremors, and salivation; decreased body weight gain; decreased T 4 

### in males; increased relative thyroid

- parathyroid weights in females; brown pigment in liver Kupffer cells; thymic atrophy in males; testicular inflammation; and aspermatogenesis, and hypospermatogenesis

.

Uncertainty Factor(s) : 1000 This includes 10X for intraspecies variation, 10 X for interspecies extrapolation and a 10X database uncertainty factor (lack of ACN, SCN, 28

- day inhalation,

subchronic dermal, and immunotoxicity studies)

.

Comments about Study/Endpoint/Uncertainty Factor : The subchronic and one year dog studies are appropriate for both the duration and route and provided the most sensitive long

- term exposure endpoint. These studies are considered co

- critical since they had similar effects but

due to an artifact of dose selection the subchronic dog had a higher NOAEL (2 mg/kg/day) than the chronic dog study (NOAEL = 1 mg/kg/day). The dog is also the most sensitive to the toxic effects of hydrogen cyanamide where the targets of organ toxicity (the thymus, thyroid and testes) are mostly affected. A short

- to long

- term uncertainty factor is not needed in this case since hydrogen cyanamide does not show progression of effects with duration of exposure

. Since there are no tolerances established for this chemical, a chron ic RfD (cRfD) is derived to address the risk from drinking water exposure only.

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 62 of 75 A.3.4 Incidental Oral Exposure (Short

- and Intermediate

- Term)

Studies Selected : Co

- Critical Studies: Subchronic gavage toxicity study in dogs and Chronic gavage toxicity study in dogs.

MRID Nos : 41390501 (subchronic dog); 41288802 (chronic dog)

Executive Summary : See Appendix A, Guideline s 870.3150 and 870.4100b

Dose and Endpoint for Risk Assessment : NOAEL = 2.0 mg a.i./kg/day from the subchronic dog study. The LOAEL of 5 mg/kg/day from the chronic dog study was based on increased incidences of rough haircoat, desquamation of the skin, tremors, and salivation; decreased body weight gain; decreased T 4 

### in males; increased relative thyroid

- parathyroid weights in females; brown pigment in liver Kupffer cells; thymic atrophy in males; testicular inflammation; and aspermatogenesis, and hypospermatogenesis

.

Uncertainty Factor( s) : Occupational Level of Concern (LOC) for MOE = 1000 The 1000 includes 10X for intraspecies variation, 10 X for interspecies extrapolation and a 10X database uncertainty factor (lack of ACN, SCN, 28

- day inhalation, subchronic dermal, and immunotoxicity s tudies) . Dermal Absorption Factor ( DAF ) = 11%.

Comments about Study/Endpoint/Uncertainty Factor : The subchronic and one year dog studies are appropriate for both the duration and route and provided the most sensitive exposure endpoint. These studies a re considered co

- critical since they had similar effects but due to an artifact of dose selection the subchronic dog had a higher NOAEL (2 mg/kg/day) than the chronic dog study (NOAEL = 1 mg/kg/day). The dog is also the most sensitive to the toxic

effects of hydrogen cyanamide where the targets of organ toxicity (the thymus, thyroid and testes) are mostly affected. A short

- to long

- term uncertainty factor is not needed in this case since hydrogen cyanamide does not show progression of effects with duration of exposure

.

A.3.5 Dermal Exposure (Short

- and Intermediate

- Term )

Studies Selected : Co

- Critical Studies: Subchronic gavage toxicity study in dogs and Chronic gavage toxicity study in dogs.

MRID Nos : 41390501 (subchronic dog); 41288802 (chronic dog)

Executive Summary : See Appendix A, Guideline s 870.3150 and 870.4100b

Dose and Endpoint for Risk Assessment : NOAEL = 2.0 mg a.i./kg/day from the subchronic dog study. The LOAEL of 5 mg/kg/day from the chronic dog study was based on increased

incidences of rough haircoat, desquamation of the skin, tremors, and salivation; decreased body weight gain; decreased T 4 

### in males; increased relative thyroid

- parathyroid weights in females; brown pigment in liver Kupffer cells; thymic atrophy in males; testicular i nflammation; and aspermatogenesis, and hypospermatogenesis

.

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 63 of 75 Uncertainty Factor(s) : Occupational Level of Concern (LOC) for MOE = 1000 The 1000 includes 10X for intraspecies variation, 10 X for interspecies extrapolation and a 10X database uncertainty factor (lack of ACN, SCN, 28

- day inhalation, subchronic dermal, and immunotoxicity studies) . Dermal Absorption Factor ( DAF ) = 11%.

Comments about Study/Endpoint/Uncertainty Factor : The sub chronic and one year dog studies are appropriate for both the duration and route and provided the most sensitive exposure endpoint. These studies are considered co

- critical since they had similar effects but due to an

artifact of dose selection the subchr onic dog had a higher NOAEL (2 mg/kg/day) than the chronic dog study (NOAEL = 1 mg/kg/day). The dog is also the most sensitive to the toxic effects of hydrogen cyanamide where the targets of organ toxicity (the thymus, thyroid and testes) are mostly affect ed. A short

- to long

- term uncertainty factor is not needed in this case since hydrogen cyanamide does not show progression of effects with duration of exposure

.

A.3.6 Inhalation Exposure (Short

- and Intermediate

- Term)

Studies Selected : Co

- Critical Studies: Subchronic gavage toxicity study in dogs and Chronic gavage toxicity study in dogs.

MRID Nos : 41390501 (subchronic dog); 41288802 (chronic dog)

Executive Summary : See Appendix A, Guideline s 870.3150 and 870.4100b

Dose and Endpoi nt for Risk Assessment : NOAEL = 2.0 mg a.i./kg/day from the subchronic dog study. The LOAEL of 5 mg/kg/day from the chronic dog study was based on increased incidences of rough haircoat, desquamation of the skin, tremors, and salivation; decreased body

we ight gain; decreased T 4 

### in males; increased relative thyroid

- parathyroid weights in females; brown pigment in liver Kupffer cells; thymic atrophy in males; testicular inflammation; and aspermatogenesis, and hypospermatogenesis

.

Uncertainty Factor(s) : Occ upational Level of Concern for MOE = 1000 This includes 10X for intraspecies variation, 10 X for interspecies extrapolation and a 10X database uncertainty factor (lack of ACN, SCN, 28

- day inhalation, subchronic dermal, and immunotoxicity studies)

.

Comments about Study/Endpoint/Uncertainty Factor : The subchronic and one year dog studies are appropriate for both the duration and route and provided the most sensitive exposure endpoint. These studies are considered co

- critical since they had similar effects but due to an artifact of dose selection the subchronic dog had a higher NOAEL (2 mg/kg/day) than the chronic dog study (NOAEL = 1 mg/kg/day). The dog is also the most sensitive to the toxic effects of hydrogen cyanamide where the targets of organ toxicity (the thymus, thyroid and testes) are mostly affected. A short

- to long

- term uncertainty factor is not needed in this case

sin ce hydrogen cyanamide does not show progression of effects with duration of exposure

. Since an oral NOAEL was selected for inhalation risk assessment, an inhalation absorption factor

of 100% should be used

.

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 64 of 75 A.4 Executive Summaries

A.4.1 Subchronic Toxi city

870.3100 90

- Day Oral Toxicity

- Rat

- MRID 00148028

In a subchronic study (MRID 00148028) Wistar

- derived weanling rats (10/sex/dose) were administered hydrogen cyanamide (50% aqueous) in the diet at 0, 20, 60 or 180 ppm (estimated 0, 1.5, 4.5, or 1 3.5 mg a.i./kg/day) for 90 days. No deaths occurred and animals did n ot display any abnormal behavior. There were no differences in bodyweight gain, food consumption, or

food efficiency among treated and control groups. There were no differences in hemato logical

parameters, se ru m enzyme activities, serum protein or serum albumin values among treated and control groups. There were no differences in the urina lysis parameters among treated and control

groups. The relative weight of the liver was slightly increased in males in the 180 ppm group and the relative weight of the thymus was decreased in females in the 180 ppm group. At necropsy, there were no pathological findings that could be attributed to administration of the

test materia l. On microscopic examination of the tissues, the thyroids of 3 males and 2 females in the 180 ppm group and 1 male in the 60 ppm group had treatment

- related changes consisting of morphological activation of the thyroid, seen as an increased number of smal l follicles lined by cuboidal epithelium and disappearance of colloid. In addition, the number of interfollicular cells was increased which was occasionally accompanied by a marked proliferation of follicular epithelial cells. M ales in the l80ppm group exhibited an increase in the number of small foci of necrotic liver cells with a slight de gre e of single liver cell necrosis. Based on histological changes in the thyroids of males, the LOAEL was 60 ppm (4.5 mg/kg/day) and the NOAEL is 1.5 mg/kg/day. The study was classified as Unacceptable/non

- guideline due to limited reporting (lack of individual animal data).

870.3100 90

- Day Oral Toxicity

- Mouse

. Not available

870.3150 90

- Day Oral Toxicity

- Dog

- MRID No. 41300501

A stabilized 50% aqueous solution of hydrogen cyanamide was orally administered to groups of 4 male and 4 female beagle dogs for 13 consecutive weeks (MRID No. 41300501). During study week 1, the test substance was administered in the diet at levels of 0, 30, 100, or 300 ppm. Because dogs in the high

- dose group did not readily eat their food, the test article was administered daily by gavage during study weeks 2

- 13 at dose levels of 0, 0.6, 2, or 6 mg a.i./kg/day. There were no compound

- related effects o n survival, eye health, clinical pathology, or gross pathology. Oral dosing was traumatic to the mid

- and high

- dose dogs. They salivated heavily prior to dosing, struggled during dosing, and had redness of the buccal mucosa. The high

- dose females weighe d 12% less than the controls at 91 days. Absolute (and relative) testicular weights were decreased 39% (36%) in the high

- dose males. Absolute (and relative) thymic weights were reduced 43% (33%) in the high

- dose females. In response to buccal

irritation , some dogs had aggregates of polymorphonuclear and mononuclear inflammatory cells in the parotid salivary glands, though the incidences were not dose

- related. A dose

- related effect on spermatogenesis was seen in all dosed groups with 3/4 high

- dose males having no evidence of spermatogenesis in the testes or epididymides. Testicular atrophy was also seen in the high

- dose

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 65 of 75 males. NOAEL = 2 mg a.i./kg/day. LOAEL = 6 mg a.i./kg/day (decreased weight gain (females), buccal cavity redness, decreased absolute and relative testicular weights (males), and thymus weights (females), aggregates of polymorphonuclear and mononuclear inflammatory cells in the parotid salivary glands, testicular atrophy, and reduced or inhibited spermatogenesis). The study is acceptab le/guideline.

870.3200 21/28

- Day Dermal Toxicity

– Rat

Data Gap.

870.3465 90

- Day Inhalation

– Rat

This study is not available and it is required. A 28

- day inhalation study will satisfy this requirement.

A.4.2 Prenatal Developmental Toxicity

870.3 700a Prenatal Developmental Toxicity Study

- Rat

- MRID 41288806

In a rat developmental toxicity study (MRID 41288806), hydrogen cyanamide (50% aqueous)

was administered to 25 mated female Crl:CD BR rats/dose in by gavage at dose levels of 0, 10, 30, 90 mg/kg bw/day ( 0, 5, 15 or 45 mg a.i./kg/day) from days 6 through 16 of gestation.

Females were sacrificed on GD 20.

Maternal toxicity was manifested in lower body weight gain (59%

- 82% of the control) and decreased food consumption (81%

- 92% of the contro ls) at the mid and high doses. The maternal LOAEL is 15 mg a.i./kg bw/day, based on decreased body weight gain (

- 18%) and decreased food consumption (

- 8%) during gestation

. H ypoactivity was seen on GD6 and GD7 in 8/25 animals after 1 or 2 days of dosing

. The maternal NOAEL is 5 mg a.i./kg bw/day.

Developmental toxicity was manifested as slight significant decrease in mean fetal weight (87% of the control) and increase in diaphragmatic hernias and wavy/bent ribs at the high dose. The

root DER noted a n on

- significant increase in early resorptions at the high dose. Examination of the raw data in the study report revealed that one female accounted for 14 resorptions out of a total 26 resorptions. The developmental LOAEL is 45 mg a.i./kg bw/day, based o n increase in diaphragmatic hernias and wavy/bent ribs . The developmental NOAEL is 15 mg a.i./kg bw/day.

The developmental toxicity study in the rat is classified Acceptable/Guideline. This study was conducted prior to the new OPPTS guidelines; however, it satisfies the guideline requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414) in the rat.

870.3700b Prenatal Developmental Toxicity Study

- Rabbit

- MRID# 41288805 & MRID # 42178406 (supplement)

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 66 of 75 In a developmental toxicity study (MRID# 41288805 & MRID # 42178406 (supplement) ), hydrogen cyanamide ( 49 % aqueous solution ) was administered by gavage to New Zealand white rabbits (24

- 25/dose) at dose levels of 0, 2, 6 or 18 mg a.i. /kg/day from gestational days 6

– 19,

inclusive. Maternal toxicity, observed at the high dose was manifested as decreased body weight gain (

- 109 %) during the gestation period

. The maternal LOAEL is 18 mg a.i. /kg/day , based on decreased body weight gain . Th e maternal NOEL is 6 mg/kg/day. There was an increase in the number of small fetuses in the high dose group, however litter rates were comparable. Fetal body weight and crown rump lengths were slightly decreased (no statistical significance) in the high dose group. There was an increase in the incidence of focal disintegration of the liver structure and hemorrhagic appendix in the fetuses in the high dose group. There was also an increase in the incidence of retinal folds in the mid and high dose groups . The focal disintegration of the liver is considered an adverse effect and treatment related. However the

increase in the incidence of retinal folds was considered to be unremarkable as was the increase in the hemorrhagic appendix on litter basis. No o ther visceral/skeletal anomalies or abnormalities were reported that were due to treatment. Reproductive parameters were not affected by the treatment. The developmental LOAEL is 18 mg a.i. /kg/day , based on disintegration of the fetal liver structure. Th e NOAEL is 6 mg a.i. /kg/day

. This study is

classified as Acceptable/Guideline and satisfies the guideline requirement for a developmental toxicity study (83

- 3b) in rabbits.

A.4.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects

- Rat

- MRID 41566504

In a two generation reproduction study (MRID 41566504), hydrogen cyanamide (50% aqueous) was administered to 26 Crl:CD BR rats/sex/dose by gavage at dose levels of 0, 2.5, 7.5, or 30 mg a.i. mg/kg BW/day (F 0 

### during premating through week 12). Because of severe weight loss in

the F 0 

### animals from the high dose group, the dose levels were amended to 0, 1.25, 3.75, or 15 mg a.i. mg/kg BW/day from then on for two consecutive generations.

Clinical signs of toxici ty (rough hair coat, thin appearance) were observed during the first 8 weeks of dosing at 30 mg a.i. mg/kg BW/day, but were not observed after reducing the dose to 15 mg a.i. mg/kg BW/day. Parental toxicity was seen as significant decreased body weight an d body gain in both sexes in the F 0 

### generation at the mid dose (7.5 mg a.i. mg/kg BW/day) and high

- dose (30 mg a.i. mg/kg BW/day). However, in the F 1 

### parents, when the doses were reduced, these effects were seen only at the high dose of 15 mg a.i. mg/kg B W/day. Food consumption was reduced in both generations at the high dose too. Based on the decreased body weight/gain (

- 8%/

- 18%) in the F 0 

### generation , the Parental systemic LOAEL is 7. 5 mg a.i. mg/kg BW/day. The parental systemic NOAEL is 2. 5 mg a.i. mg/ kg BW/day.

Reproductive toxicity was observed in both generations as reduced fertility and decreased gestation (both non

- statistical significance) at the high dose. The reproductive LOAEL is therefore 15 mg a.i./kg bw/day and the NOAEL is 3.75 mg a.i./kg bw/day.

Offspring toxicity was seen as reduced pup viability in both generations at the high dose only. In the earlier DER, reduced pup viability was considered to be treatment

- related at all dose levels.

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 67 of 75 However, when litters that totally died between days 0 and 4 were excluded, this effect was seen only at the high dose. Decreased pup body weight was seen sporadically in the F 1 

### generation only on Days 7 and 21, but not Day 4. Although, the observed pup body weights were statistically significant, the standard deviations were large at all treatments. Because, it was not

seen in the F 2 

### generation and the decrease was not dose dependent, the pup body weight changes

in the F 1 

### are considered incidental. The Offspring toxicity LOAEL of hydrogen cyanamide in this study is 15 mg a.i./kg bw/day based on pup reduced viability and the NOAEL is 3.75 mg a.i./kg bw/day.

This reproduction toxicity study in the rat is classified Acceptable/Guideline. This study was conducted prior to the new OPPTS guidelines; however , it satisfies the guideline requirement for

a two

- generation reproduction study (OPPTS 870.3800; OECD 416) in the rat

A.4.4 Chronic Toxicity

870.4100a (870.4300) Chronic Toxicity

– Rat

- MRID 42178404

In a chronic study (MRID 42178404) a queous hydrogen cyanamide was administered via oral gavage to male and female C rl:CDBR rats at dose levels of 0, 2.5, 7.5, or 30 mg/kg/day active ingredient for 16 weeks; dose levels were lowered to 0, 1, 2.5 or 7.5 mg/kg/day at week 17

because of excessi ve toxicity. Dosing continued through week 91. The results of this study indicate the thyroid as a possible target organ for hydrogen cyanamide toxicity. An increase in

the incidence of reduced colloid was noted in the mid

- and high

- dose animals. In addit ion, the analysis of thyroid hormone levels revealed possible treatment

- related effects on thyroid function as indicated by decreases in both thy rox ine and triiodothyronine levels in males receiving 7.5 mg/kg/day. Although a previous mouse oncogenicity st udy (cited in the study report as Hazleton Project No. 55613) identified the ovary as a potential target organ, there were no treatment

related ovarian lesions noted in this rat study.

Significant reductions in body

- weight gain were observed in both mid

- and high

- dose males and females, especially during the first 16 weeks of th e study. A slight but statistically non

significant decrease in food consumption was noted in the high

- dose males and females during the first 16 weeks of the study.

Numerous diffe rences from control rats were noted in clinical pathology parameters, particularly

at week 14. Results of the 14

- week hematological analyses suggested anemia (decreased red blood cell count, hemoglobin and hematocrit levels) only in the high

- dose males; th ese effects were not significant following week 14, possibly reflecting the lowering of dose levels at week 17. Increases in lymphocyte count were seen in mid

- and high

- dose males and females at week

14. Platelet counts were decreased in mid

- and high

- dose males and females at weeks 14 and 27, but were still within the normal range. Among the clinical chemistry parameters observed in both

mid

- and/or high

- dose animals at week 14, there were significant decreases in glucose and globulin levels, and increases in GGT activity.

Based on significant decreases in body weight gains and an increased incidence of reduced colloid in the thyroid, the LO A EL is 7.5 mg/kg/day active ingredient hydrogen cyanamide in

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 68 of 75 males and females. The NO A EL is 2.5 mg/kg/day active ing redient hydrogen cyanamide for

both sexes.

870.4100b Chronic Toxicity

- Dog

- MRID Nos. 41288802 and 41566501

In a chronic toxicity study in dogs (MRID Nos. 41288802 and 41566501) aqueous hydrogen cyanamide (50% w/w, 53% w/w a.i.) was administered by ga vage to groups of 4 male and 4 female dogs. For the first 2 weeks the dogs were dosed with 0, 0.2, 1.0 or 5.0 mg/kg/day of the 50% technical (equivalent to 0, 0.1, 0.5, or 2.5 mg a.i./kg/day), then the doses were doubled to 0, 0.4, 2.0 or 10.0 mg/kg/day f or the rest of the study (equivalent to 0, 0.2, 1.0 or 5.0 mg a.i./kg/day).

There were no deaths during this study, and no compound

- related effect on food consumption, eye health, hematologic or urinalysis parameters, or gross pathology. At the high

- dos e, tremors were observed in 3/4 males and 2/4 females, ptyalism was observed in 4/4 males and 4/4 females, and desquamation was observed in 1/4 males and 2/4 females. One mid

- dose female also had ptyalism. Rough haircoat was observed in 1/4 mid

- dose and 1/4 high

- dose males and in 2/4 high

- dose females. Body weights at the high

- dose were reduced 14% in males and 17% in females by the end of the study. The only clinical chemistry anomaly was a 44% decrease in T 4 

### in high

- dose males.

Relative thyroid/par athyroid weights were increased 56% in high

- dose females. Compound

related histopathologic found at the high

- dose including brown pigment in Kupffer cells of the liver in 3/4 males and 4/4 females; testicular lesions including aspermatogenesis in 1/4 male s, hypospermatogenesis in 2/4 males, and chronic inflammation in 2/4 males; and thymic atrophy in 4/4 males. No neoplastic lesions were observed.

NOAEL = 1.0 mg a.i./kg/day LOAEL = 5.0 mg a.i./kg/day (increased incidences of rough haircoat, desquamatio n of the skin, tremors, and salivation; decreased body weight gain; decreased T 4 

### in males; increased relative thyroid

- parathyroid weights in females; brown pigment in liver Kupffer cells; thymic atrophy in males; testicular inflammation; and aspermatogenes is, and hypospermatogenesis) The study is classified Acceptable/guideline and it satisfies the requirement for a Guideline Series 870.4100 Chronic Toxicity in Dogs.

A.4.5 Carcinogenicity

870.4200a Carcinogenicity Study

- rat

Although a 20

- month chronic study of hydrogen cyanamide was performed (MRID 42178404), there is no carcinogenicity component to it. This is not a data gap because the Cancer Peer Review Committee (CPRC) was able to assess the carcinogenic potential of hydrogen cyanamide

with the available data.

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 69 of 75 870.4200b Carcinogenicity ( drinking water )

- Mouse

- MRID 41566502 & 42178405

In a carcinogenicity study (MRID 41566502 and 42178405) hydrogen cyanamide was administered in the drinking water to groups of 60 CD

- 1 mice/sex for 100 weeks to males and for 104 weeks to females at levels of 0, 70, 200, or 600 ppm (for males: 0, 5.0, 13.6, and 36.8 mg a.i./kg/day; for females: 0, 6.9, 16.9, and 49.0 mg a.i./kg/day). The LOAEL derived from this study was 200 ppm (16.9 mg a.i./kg/day) base d on: females

- increased incidence of urinary bladder and kidney lesions (non significant); decreased survival rate (Kaplan

- Meier) in females. In addition at 600 ppm in males (36.8 mg a.i./kg/day) there was decreased body weight gain (significant); in fe males (49.0 mg a.i./kg/day) the decreased survival was significant and there was ovarian stromal/luteal hyperplasia. In both sexes there were urinary bladder and kidney

lesions. The NO AEL is 70 ppm (6.9 mg a.i./kg/day).

There was an increased incidence ( female) of ovarian granulosa

- theca tumors and related tumors (thecoma, luteoma) at 200 and 600 ppm. There were no significant compound

- related tumors observed in male mice. For total ovarian granulosa

- theca tumors there was a statistically significant inc rease (p <0.01) by pair

- wise comparison with controls at the HDT (600 ppm). There was also a statistically significant positive trend (p <0.01). Dosing was considered adequate for assessing the carcinogenic potential of hydrogen cyanamide. Adequacy of dos ing was based on a significant increase in mortality in 600 ppm females (77%) compared to control (60%) and an increased incidence of kidney and urinary bladder lesions in male and female mice at 600 ppm the highest dose tested.

870.4200b Carcinogenicity (feeding)

- Mouse

- MRID 00148030

In a National Cancer Institute study (MRID 00148030), g roups of 50 male and 50 female B6C3F1 mice were dosed with calcium cyanamide (estimated 48

- 66% a.i.) in their feed at concentrations of 500 or 2000 ppm (approximatel y 37 or 150 mg a.i./kg/day) for a period of 100 weeks. An additional 20 males and 20 females served as negative controls. A n increase in malignant hemangiosarcoma was seen at 2000 ppm (HDT). The incidence of hemangiosarcoma

was twice that observed in his torical control mice; however, the increase was not statistically significant by pairwise comparison with control mice although there was a statistically significant positive trend (p<0.01).The increase in malignant lymphoma/leukemia in female

B6C3F1 mice administered Calcium Cyanamide up to 2000 ppm in the diet for 100 weeks was not considered biologically significant by the CPRC. Dosing was considered to be adequate in both sexes for assessing the carcinogenic potential of Calcium Cyanamide. The LOAEL w as 2000 ppm (188 mg/kg/day) based on increased mortality (males)

. There was a slight decrease in body weight at both doses but it could not be adequately evaluated because it was presented graphically. The NOAEL was 500 ppm (38 mg/kg/day). The study was classified Acceptable/non

- guideline.

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 70 of 75 A.4.6 Mutagenicity

Gene Mutation

870. 5100 Bacterial reverse gene mutation

MRID 40389608 Acceptable/Guideline Negative at doses ranging from 0.1 to 15 μl/plate with or

without S9 in S. typhimurium strains TA98, TA100, TA1535,

TA1537

870.5100

Bacterial Reverse Gene Mutation Test (Ames Assay) with Calcium Cyanamide

Haworth et al. 1983. Environ. Mutagen. Vol 5. (Suppl 1)

1983 3

- 142 Weak positive (+ activation) in Salmonella strain TA 1535 at 333μg/plate with rat or hamster S9; negative without activation. Results consistent from two laboratories testing for NTP (CaCN)

Cytogenetics

OPPTS 870.5300

In vitro cytogenic chromosomal aberration assay in Chinese hamster ovary cells (CHO)

. MRID 40389609 Acceptable/Guideline The test material induced dose

- related chromosomal aberrations in Chinese hamster ovary cells into the cytotoxic toxic range (≥ 141 μg/ml (

- S9); ≥ 875 μg/ml (+S9)).

Other Genotoxicity

870.5395

In Vivo Micronucleus Assay

- Mouse

MRID 40389610 Acceptable/Guideline Negative: The test material failed to induce significant

increases in micronuclei in bone marrow polychromatic erythrocytes over a dose range from 31.44 to 330.5 mg/kg, the HDT inducing clinical toxicity (death and ruffle d coats).

870.5550, Unscheduled DNA synthesis in primary rat hepatocytes MRID 40389607 Acceptable/guideline Negative; The test material did not induce significant changes

in nuclear labeling of primary hepatocytes over a dose range of 5.95 to 143 ug/mL when compared to the solvent control.

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 71 of 75 A.4.7 Neurotoxicity

870.6100 Delayed Neurotoxicity Study

- Hen

This study is not available and is not required.

870.6200 Acute Neurotoxicity Screening Battery

This study is not available and is required.

870.6200 Subchronic Neurotoxicity Screening Battery

This study is not available and is required.

870.6300 Developmental Neurotoxicity Study

This study is not available and is not required.

A.4.8 Metabolism

870.7485 Metabolism

- Rat

- MRI D 42906401

The absorption, distribution, metabolism, and excretion of hydrogen cyanamide were studied in groups of rats administered a single oral gavage dose of 1 or 20 mg/kg 14 

### C

- hydrogen cyanamide or administered daily oral doses of 1 mg/kg/day unlabele d hydrogen cyanamide for 14 days followed by a single dose of 1 mg/kg 14 

### C

- hydrogen cyanamide on day 15 (MRID 42906401 ) . An additional group received a single intravenous (i.v.) dose of 1 mg/kg 14 

### C

- hydrogen cyanamide. The study demonstrated that 14 

### C

- hydroge n cyanamide is rapidly absorbed, distributed, metabolized, and excreted following oral and i.v. administration in rats. Total recoveries of the radioactivity were high for all oral and i.v. groups (98.7

- 105.0% of administered dose); urine was the major rou te of excretion (66.9

- 97.7% of administered dose). The elimination of hydrogen cyanamide was sex

- , dose

- , and route

- related. The recovery of radioactivity in the feces was higher in the i.v. group (13.2

- 15.0% of administered dose) compared to oral groups ( 2.76

- 4.15% of administered dose), suggesting that biliary excretion is an important route following i.v. administration. Recoveries in expired 14 

### C O 2 

### were higher in the m ales than in the females and were higher in the i.v. and single low

- dose oral groups co mpared to the repeated

- dose and high

dose groups. These findings suggest that there is a depletion of metabolic enzymes at the high

dose group, and therefore, only a limited amount of the hydrogen cyanamide is metabolized to

CO 2 

### . Tissue bioaccumulation of hydrogen cyanamide was low for all groups. Most of the 14 

### C

hydrogen cyanamide is N

- acetylated to form N

- acetylcyanamide, which is eliminated in the

urine and feces. This study is Acceptable/guideline.

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 72 of 75 870.7485 Metabolism

- Literature studies/various species.

The metabolism of hydrogen cyanamide is summarized from information obtained from ten

different Acceptable/non

- guideline studies ( MRID 42178407 ). This summary concludes that

h ydrogen cyanamide is rapidly absorbed, m etabolized and excreted in the urine following oral, intravenous (i.v.), and intraperitoneal (i.p.) dosing in rats, dogs, or rabbits. Following i.p. dosing in rats, 93.4% of the dose was excreted in the urine within the first 6 hours, indicating that hydro gen cyana m ide is rapidly metabolized and almost completely eliminated from the body. Negligible amounts were excreted as expired CO2. Following both oral and i.v. dosing in dogs,

62%.

- 83.l % of the dose was excreted in the urine within the first 24

- 27 hours . Negligible amounts of radioactivity were excreted in the feces. The major metabolite of cyanamide excreted in the urine of rats, rabbits, dogs and humans was identified as N

- acetylcyanamide. The conversion of cyanamide to N

- acetylcyanamide in vitro is ca talyzed by an acetyl

- S

- CoA

dependent N

- acetyltransferase present in rabbit and dog liver.

870.7600 Dermal Absorption

- Rat

- MRID 41504004

In a dermal penetration study (MRID 41504004) a single dermal dose of 0.1, 1, or 10 mg (8, 80,

or 800 μ g/cm 2 

### , r espectively) 14 

### C

- hydrogen cyanamide, administered to three groups of male rats (24/group), was rapidly absorbed, distributed and eliminated. In general, as the dose level and the duration of exposure increased, the percentage of the dose absorbed also incr eased. Using the direct procedure to calculate skin absorption, the average 14 

### C

- hydrogen cyanamide equivalents absorbed within 24 hours were 1.79%, 2.84%, and 11.1% of the applied dose for the low

- , mid

- , and high

- dose groups, respectively. The data can b e utilized for risk assessment purposes as a

worst case scenario. This study is classified as Acceptable/guideline study.

A.4.9 Immunotoxicity

870.7800 Immunotoxicity

This study is not available and it is required.

A.4.9 Special/Other Studies.

None

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 73 of 75 Appendix B

The Major (solid arrow) and Minor (dashed arrow) Metabolic Pathways for Hydrogen Cya namide (Source TXR 0010591; MRID 42178407)

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 74 of 75 Appendix C

### Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

Page 75 of 75 Appendix D

Table 3.2.1 Physicochemical Properties of the Pure Hydrogen Cyanamide.

Parameter Value Reference

Melting point/range 45

- 46oC Merck Index, 9 th edition

pH Not Available None

Density Not Available None

Water solubility (20°C) 77.5 g/100 mL at 15oC 100 g/100 mL at 43oC Merck Index, 9 th edition

Solvent solubility (g/100 g at 20°C to 25°C) butanol 28.8 methyl ethyl ketone 50.5 ethyl acetate 42.4 Soluble in alcohols, phenols, amines, ethers, ketones. Very sparingly soluble in benzene, halogenated hydrocarbons. Practically insoluble in cyclohexane. Merck Index, 9 th edition

Vapor pressure (20°C) 3.75 x 10 - 3 mm Hg EFED DWA D403785,

I. Abdel

- Saheb, 10/4/12

Dissociation constant, pK

a Not Available None

Octanol/water partition coefficient, log

P OW (20°C) Not Available None