UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: March 12, 2014 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Hydrogen Cyanamide: Preliminary Risk Assessment for Registration Review 

PC Code: 014002 

Decision No.: 453348 

Petition No.: Not Applicable (N/A) 

Risk Assessment Type: Single Chemical 

TXR No.: N/A 

MRID No.: N/A 

DP Barcode: 393086 

Registration No.: N/A 

Regulatory Action: Registration Review 

Case No.: 7005 

CAS No.: 420-04-2 

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

FROM: Jessica 

Abdalla

Kidwell, 

h Khasawinah, 

Risk Assessor 

ToxicoloBst 

~ 

-

~ , 

Bonnie. Cropp-Kohlli~ian, Che~ist ~nd Dietary Assessor j3~ nll\A/L- r-~ '\..r Ivan Nteves, Occupahonal/Restdenttal Exposure Assessor ..:.-...........-lr ~ 

Risk Assessment Branch 4 

Health Effects Division (7509P) 

THROUGH: Elissa Reaves, Ph.D., Branch Chief c (2___ Risk Assessment Branch 4 

Health Effects Division (7509P) 

TO: Dana Friedman, RM 52 

Kevin Costello, Branch Chief 

RMIB2, Pesticide Re-Evaluation Division (7508P) 

This document provides the Health Effects Division's (HED's) preliminary risk assessment for 

Hydrogen Cyanamide in support of Registration Review. 
Hydrogen Cyanamide 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 from 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 Consideration of Environmental Justice .................................................................... 13 

4.0 Hazard Characterization and Dose-Response Assessment.. .................................. ...... 13 

4.1 Toxicology Studies Available for Analysis ................................................................. 13 

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME) ............................. 14 

4.2.1 Dermal Absorption ................................................................................................... 15 

4.3 Toxicological Effects .................................................................................................... 15 

4.4 Safety Factor for Infants and Children (FQPA Safety Factor) ............................... 16 

4.5 Toxicity Endpoint and Point of Departure Selections .............................................. 17 

4.5.1 Dose-Response Assessment ...................................................................................... 17 

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment.. ... 18 

4.5.3 Cancer Classification and Risk Assessment Recommendation ............................ 18 

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment ..... ....... ....... ....... ........................................................................... .......................... 19 

4.6 Endocrine 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 Comparison of Metabolic Pathways ....................................................................... 22 

5.1.4 Residues of Concern Summary and Rationale .................. ........... ........ ................. 23 

5.2 Food Residue Profile .................................................................................................... 23 

5.4 Dietary Risk Assessment ................................................................. .. ...... .... ................. 25 

5.4.1 Description 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 Assessment ........................................................................... 26 

5.4.5 Cancer Dietary Risk Assessment.. ........................................................................... 26 

5.4.6 Summary Tables ....................................................................................................... 27 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................. 27 

6.1 Spray Drift .... ................................................................................................................ 28 

6.2 Residential Bystander Post-Application Inhalation Exposure ................................ 32 

7.0 Cumulative Exposure/Risk Characterization ............................................................... 32 

8.0 Occupational Exposure/Risk Characterization ............ .... .... ........................................ 32 

8.1 Short- and Intermediate-Term Non-Cancer and Cancer Handler Risk ................. 32 

9.2 Occupational Post-application Exposure/Risk Estimates ........................................ 50 

Page 2 of 75 
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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 Endpoint Selection.......................................................... 60

A.4 Executive Summaries................................................................................................... 64

Appendix B.................................................................................................................................. 73

Appendix C.................................................................................................................................. 74

Appendix D.................................................................................................................................. 75
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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 fruits, nectarines, and peaches. It 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. Applications would be made not less than 30 days prior 

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 exposures resulting from indirect 

spray drift of pesticide applications. Aggregate risk is not assessed since hydrogen cyanamide 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 route 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. Clinical signs of neurotoxicity 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, 

clinical 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 toxicity 

was limited to decreased body weight gain compared to disintegration of fetal liver structure and 

hemorrhagic appendix seen in the fetuses, suggesting qualitative susceptibility. 
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Hydrogen cyanamide was negative in a bacterial reverse gene mutation assay, 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 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 Q1

*

value of 6.64 x 

10-2(mg/kg/day)-1 was estimated. There was no evidence 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 endpoint, a point of 

departure (POD) of 5 mg/kg (maternal NOAEL) for the general population was selected from a 

rat 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 days of dosing. An uncertainty factor 

(UF) of 1000X (10X for intraspecies variation, 10x for interspecies extrapolation and a 10X

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 (DBUF) includes 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 studies (subchronic and chronic toxicity studies in 

dogs) were selected since they provided the most sensitive endpoints. 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 T4 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 

1000X (10X for intraspecies variation, 10X for interspecies extrapolation and a 10X database 

uncertainty factor for several datagaps, including ACN, SCN and immunotoxicity 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 1000 (10X for intraspecies variation, 10X for interspecies extrapolation and 

a 10X database uncertainty factor for five datagaps, including ACN, SCN, immunotoxicity, 28-

day inhalation and short-term dermal toxicity studies) is required for the incidental oral, dermal 

and inhalation exposures. 

Dietary (Water Only) 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 the drinking water 

assessment were from surface water. For surface water, the highest 1-in-10 year peak and annual 
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mean values were from the MI Cherries scenario and the highest 30 year mean value was from 

the CA Grapes scenario. Of significance, 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 yards (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%. 

The 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 assessments, respectively.

Acute and non-cancer chronic dietary risk estimates below 100% of the acute or chronic 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 99.9th percentile of 

exposure, 13% of the aRfD at the 99th percentile, and <1% of the aRfD at the 95th 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 99.9th percentile.

The chronic dietary exposure from hydrogen cyanamide in drinking water results in the 

estimated risk of ≤9.1% of the cRfD for all population subgroups. All Infants <1 year of age is

the most highly-exposed subgroup, utilizing 9.1% of the cRfD, while the General US population 

utilizes 3.5% of the cRfD. 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 Q1

*

value of 

6.64 x 10-2(mg/kg/day)-1 was estimated using a cross-species scaling factor for the administered 

dose based on equivalence of body weight to the 3⁄4 power per day (body weight3/4). The cancer 

risk estimate from hydrogen cyanamide in drinking water is 9.32 x 10-7.

Residential Exposure and Risk

There 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.
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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). 

Using 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 1200) 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 

is 40 A for airblast).

Cancer risk estimates: Default HED unit exposure values with refined treated acreage resulted 

in cancer risk estimates ranging from 1.4x10-6to 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 2.0x10-6to 5.3x10- 5. With 

open cabs, the resulting cancer risk estimates were 1.4x10- 5to 7.6x10-5.

 

Exposure data 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 1.4x10-6to 2.8x10-5. 

Using default HED unit exposure values, risk estimates for private applicators using closed cab 

airblast equipment ranged from 2.2x10-6to 1.2x10-5. HED default open cab assumption using 

double layer, gloves and a PF10 respirator resulted in cancer risk estimates ranging from 8.5x10-4 

to 4.6x10-3.
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Occupational Post-Application

A revised preliminary quantitative post-application inhalation exposure assessment was not 

performed for hydrogen cyanamide at this time. 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 hydrogen cyanamide.

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

does not 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 website1. 

2.0 HED Recommendations

HED has evaluated the toxicity and exposure 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 currently 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
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by the registrant. These 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 geometric 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 yards (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

The use of chemical-resistant suits 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) immediately 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 reentering the cab”. HED recommends taking this requirement off the label.
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2.3.3 Recommendations from Residential Assessment

Not applicable.

3.0 Introduction

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, NCNH2 and HNCNH. The NCNH2 form 

predominates.

N C NH2HN C NH

Cyanamide undergoes dimerization to form dicyandiamide. According to Merck Index, 

formation of dicyandiamide begins at 122oC. Dicyandiamide exists between two or more 

tautomeric forms. Tautometic Form 2 shown below predominates.

C NH2

NH

HN

N C

C NH2

N

H2N

N C

 Form 1 Form 2

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

H2N N

Common name Cyanamide

Empirical formula CH2N2

Molecular weight 42.04

PC Code 014002

IUPAC name Hydrogen cyanamide

CAS name Hydrogen cyanamide

CAS registry number 420-04-2
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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 fruits (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 products 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 containing 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. 

The 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. Drinking water and occupational exposures 

are expected. Hydrogen cyanamide is not registered for use in residential settings. Nonoccupational exposure from indirect spray drift as a result of pesticide application is also being 

assessed. Moreover, all three (3) registered labels contain a RESTRICTED USE PESTICIDE

clause that states that these pesticides are “for 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 Certification.” 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. 
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Table 3.3.1. Registered Uses for Hydrogen Cyanamide

Application 

Timing, 

Type, and 

Equipment

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 

application 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 

budbreak 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 Fruit 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 is 

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
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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 activities that will result in significant exposures to workers.

There are no currently registered residential uses of hydrogen cyanamide, 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 Environmental 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 large 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 activities 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 assessments 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 subgroups 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 entering 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 and farm workers as well as lifestyle and traditional dietary patterns among specific 

subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

The 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 dehydrogenase which 

then causes an increase in blood acetaldehyde levels.

4.1 Toxicology Studies Available for Analysis

The toxicology database for hydrogen cyanamide is not complete but is adequate for evaluating 

and characterizing its toxicity and selecting endpoints for purposes of risk assessment. Studies 
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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), dog 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 battery (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# 0056857). The dermal toxicity 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 reflect 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 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. See Appendix A for the complete 

toxicology profile and executive summaries for hydrogen cyanamide.

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

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

administration demonstrated that 14C-hydrogen cyanamide was 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 major 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 route following i.v. administration. Recoveries 

in expired CO2 were higher in the males than in the females and were higher in the i.v. and single 

low-dose oral groups 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 CO2. 

Tissue bioaccumulation of hydrogen cyanamide was low for all groups. Most of the 14Chydrogen cyanamide was metabolized to form N-acetylcyanamide, which is eliminated in the 

urine and feces.

Published studies (summarized in TXR 0010591; MRID 42178407) 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 CO2. Following both oral and i.v. dosing in dogs, 62-83.1% of the dose was 

excreted in the urine within the first 24-27 hours. Negligible amounts of radioactivity were 
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excreted in the feces. The major metabolite of cyanamide excreted in the urine of rats, rabbits, 

dogs and humans was identified 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%-l2% 

of the dose in the dog urine). Rats excreted approximately 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 halflife 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 Dermal Absorption

A dermal penetration study indicated that 14C-hydrogen cyanamide absorbed was generally 

proportional to the dose and increased with exposure duration. At dermal doses of 0.1, 1, or 10 

mg (8, 80, or 800 μg/cm2, respectively) the average 14C-hydrogen cyanamide equivalents 

absorbed within 24 hours were 1.79%, 2.84%, and 11.1%. For all dose groups at all times the 

majority of the applied radioactive dose was recovered in the skin wash. The amount of 

radioactivity in the skin generally decreased 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 11% should be used based on the findings in this study.

4.3 Toxicological 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 from 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 morphological 

activation in the thyroids consisting of an increased number of small follicles lined by cuboidal 

epithelium and disappearance of colloid. The number of inter follicular cells was increased and 

occasionally accompanied by a marked proliferation of follicular epithelial cells. Chronic oral 

gavage exposure of rats resulted in reduced colloid in the thyroid and reduced T3 and T4 levels at 

week 14. Effects 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 reduced or inhibited spermatogenesis. 

Effects seen in dogs following oral gavage subchronic and chronic dosing included the 

following: decreased T4 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.
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There was no increased qualitative or quantitative fetal or offspring susceptibility in the prenatal 

developmental or postnatal reproduction studies conducted in 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 weight, 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 

disintegration 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 toxicity 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.

Clinical signs of neurotoxicity 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 available 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 micronucleus 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 cytogenetic 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 tumors 

in female CD-1 mice and hemangiosarcomas in male B6C3F1 mice. There was no evidence of 

carcinogenicity in rats. A Q1

*

value of 6.64 x 10-2(mg/kg/day)-1 was estimated using body 

weight3⁄4interspecies scaling factor based upon female mouse ovarian granulosa-theca tumor 

rates in a 104-week drinking water study (TXR No. 0014510). 

4.4 Safety Factor 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 
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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 Departure 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 1000X (10x for intraspecies variation, 10X for interspecies extrapolation and a 10X

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 (UFDB) 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 T4 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 1000X (10X for intraspecies variation, 10X for 

interspecies extrapolation and a 10X database uncertainty factor as described above) was applied 

to the dose to obtain a chronic reference dose (cRfD) 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 incidental oral endpoint 

was selected specifically for this assessment. The POD selected was the same as the POD for the 

chronic dietary endpoint. The residential level of concern for MOE is 1000. 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 1000 is required for both the short- and intermediate-term dermal and inhalation 
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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 dermal 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 Assessment

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, dermal 

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 cyanamide 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 evidence of carcinogenicity in rats. 

A Q1

*

value of 6.64 x 10-2(mg/kg/day)-1 was estimated using body weight3⁄4interspecies scaling 

factor based upon female mouse ovarian granulosa-theca tumor rates in a 104-week drinking 

water study (TXR No. 0014510). 
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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 

NOAEL= 

5 mg/kg/day

UFA= 10x

UFH= 10x

UFDB= 10x

Acute RfD = 

0.005 

mg/kg/day

Developmental Toxicity Study in Rats

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 

subchronic dog

UFA= 10x

UFH=10x

UFDB= 10x

Chronic RfD = 

0.002

mg/kg/day

Chronic Toxicity-Dog co-critical with 

subchronic toxicity dog study

MRIDs 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 T4 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 

on 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 spermatogenesis.

Incidental 

Oral ShortTerm (1-30 

days)

NOAEL = 2.0 

mg/kg/day from 

subchronic dog

UFA= 10x

UFH=10x

UFDB= 10x

Residential 

LOC for 

MOE = 1000

Chronic Toxicity-Dog co-critical with 

subchronic toxicity dog study

MRIDs 41288802 & 41390501

Same as chronic dietary exposure 

endpoint.

Dermal 

Short- and 

IntermediateTerm (1-30 

days and 1-6 

months)

NOAEL = 2.0 

mg/kg/day from 

subchronic dog

DAF = 11%

UFA= 10x

UFH=10x

UFDB= 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.
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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 

IntermediateTerm (1-30 

days, and 1-6 

months)

NOAEL = 2.0 

mg/kg/day from 

subchronic dog

UFA= 10x

UFH=10x

UFDB= 10x

Occupational 

LOC for MOE 

= 1000

Chronic Toxicity-Dog co-critical with 

subchronic toxicity dog study

MRIDs 41288802 & 41390501

Same as chronic dietary exposure 

endpoint.

Cancer (oral, 

dermal, 

inhalation)

Classification: “Group C chemical– possible human carcinogen.”

Q1

*

, for hydrogen cyanamide is 6.64 x 10-2(mg/kg/day)-1in human equivalents using a mg/kg body 

weight3⁄4/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 observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). UFL = use of a LOAEL to extrapolate a 

NOAEL. UFS = use of a short-term study for long-term risk assessment. UFDB = 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 and FFDCA, EPA reviews numerous studies to assess potential adverse 

outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and 

chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, 

reproductive, and general or systemic toxicity. These studies include endpoints which may be 

susceptible to endocrine influence, including effects on endocrine target organ histopathology, 

organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, 

and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and 

chronic studies that assess growth, developmental and reproductive effects in different 

taxonomic groups. As part of its reregistration decision for hydrogen cyanamide,

EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment 

scenarios from the existing hazard database. However, as required by FFDCA section 408(p), 

hydrogen cyanamide is subject to the endocrine screening part of the Endocrine Disruptor 

Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide 

active and other ingredients) may have an effect in humans or wildlife similar to an effect 

produced by a “naturally occurring estrogen, or other such endocrine effects as the 

Administrator may designate.” The EDSP employs a two-tiered approach to making the 

statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify 

the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or 
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T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the 

potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP 

where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available 

data. Tier 2 testing is designed to identify any adverse endocrine-related effects caused by the 

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

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between 

October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 

chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list 

of chemicals identified for EDSP screening was published on June 14, 20132and includes 

some pesticides scheduled for registration review and chemicals found in water. Neither of 

these lists should be construed as a list of known or likely endocrine disruptors.

For further information on the status of the EDSP, the policies and procedures, the lists of

chemicals, future lists, the test guidelines 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, the 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 plants (sugars, cellulose, amino acids etc.) via the formation of urea and further 

decomposition to ammonium and CO2. 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 significance relative to hydrogen cyanamide, if present. Taken together, data indicate that no 

residues of concern should be present at harvest for the registered crops and dormant use pattern. 

The metabolism of the 14C-hydrogen cyanamide was followed in young detached grape leaves 

from the Thompson Seedless (Vitus vinifera) variety. The leaves were labeled through the cut 

petiole with 14C-hydrogen cyanamide (2-3 μg 14C-hydrogen cyanamide per 0.4 g leaf, 0.7-0.9 

μCi in 10-25 μl distilled water) and allowed to metabolize in a controlled laboratory atmosphere 

(25C, Atlas xenon arc lighting) for 24 hours. During this period, volatile gases were collected 

 

2

See http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0477-0074 for the final second list

of chemicals.

3

http://www.epa.gov/endo/
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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 reverse 

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 CO2 through the formation of urea and that finally the CO2 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, cyanamide 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, under 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 adsorbed 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 readily 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 hydrogen 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 
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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 Knowledgebase Subcommittee (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 identify any potentially significant 

degradate/metabolite of the parent.

5.2 Food Residue Profile

Currently registered uses of hydrogen cyanamide have been determined to be non-food/non-feed. 

No residues 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, the 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 Interface 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 Exposure 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-in-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 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%. 

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 Henry’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. 

The 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, respectively.
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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 water 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 and 

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 KOC, 

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 the 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 an 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.
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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. 

Scenario

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 probabilistic, chronic, and cancer dietary 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 Health 

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 hydrogen cyanamide estimated drinking water concentrations (EDWCs) used in these 

dietary risk assessments were provided by EFED (DP# 403785, I. Abdel-Saheb, 10/4/12), and 

incorporated directly into the dietary assessments. Water residues were incorporated in DEEMFCID via entry into the food categories “water, direct, all sources” and “water, indirect, all 

sources.” No ground or surface water monitoring data were available 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 surface water incorporated 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 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%. 
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The 30 year distribution of daily surface water concentrations was input into the acute dietary 

assessment. The 1-in-10 year 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

The acute probabilistic dietary assessment for hydrogen cyanamide in drinking water results in 

an estimated risk of ≤110% of the acute reference dose (aRfD) at the 99.9th percentile of 

exposure, 13% of the aRfD at the 99th percentile, and <1% of the aRfD at the 95th 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 99.9th percentile. See Table 5.4.6.1 in Section 5.4.6.

5.4.4 Chronic Dietary Risk Assessment

The chronic dietary exposure from hydrogen cyanamide in drinking water results in the 

estimated 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 cRfD, while 

the general US population utilizes 3.5% of the cRfD. 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 granulosa-theca tumor rates in a 104-week drinking water study, a Q1

*

value of 

6.64 x 10-2(mg/kg/day)-1 was estimated using body weight3⁄4interspecies scaling factor (Lori L. 

Brunsman memorandum; March 22, 2001, TXR 0014510). The cancer risk from hydrogen 

cyanamide in drinking water is 9.32 x 10-7. See Table 5.4.6.3 in Section 5.4.6.
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5.4.6 Summary Tables

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)

95th Percentile 99th Percentile 99.9th 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 110

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)

Q1

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

surfaces where contact with residues can eventually 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 

assessment.

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 varying 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). 

Combined 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 should 

be aware and characterize these appropriately.
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 Groundboom applications are based on the AgDrift option for high boom height and 

using very fine 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 are 

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 children’s (1 to <2 years 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 groundboom applications even 300 feet downwind of 

the treated field. 
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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
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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
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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 December 2009, and received the SAP’s final report on 

March 2, 20106. 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 postapplication inhalation exposure assessment for hydrogen cyanamide.

7.0 Cumulative Exposure/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 mechanism 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 Characterization

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 task. 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 occupational 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
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 Mixing/loading for groundboom applications.

Applicators:

 Applying sprays with airblast equipment; and

 Applying sprays with groundboom 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

 Nectarine 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 standard 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 Table7”, which, along with additional information on HED policy 

on use of surrogate data, including descriptions of the various sources, can be found at the 

Agency website8. 

Area Treated or Amount Handled: HED normally would use a default of 40 acres per day for 

airblast and 80 for groundboom for treatment 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 participants 

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 day. 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 kg) 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
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developmental and/or fetal effects.

 

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

Since no inhalation 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 agricultural 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 clothing 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, chemicalresistant 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 applicators 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 seasonally 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.
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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

Potential 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 for 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:

Average 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 determined 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 the 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.
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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 of 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 presented 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 groundboom 

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 lbs ai/A to the 

highest application rate registered of 17.6 lbs ai/A. Non-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

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Table 9.1.1. Occupational Exposure and Risk Estimates for Hydrogen Cyanamide Handler Scenario

Crop or 

Target

Maximum 

Application 

Rate1

(lb ai/A)

Dermal 

Unit 

Exposure2

(ug/lb ai)

Dermal Dose4

(mg/kg/day)

Dermal MOE5

(LOC:1000) Inhalation 

Unit 

Exposure2

(ug/lb ai)

Inhalation Dose6

(mg/kg/day)

Inhalation MOE7

(LOC:1000)

Total Engineering 

Controls 

Combined MOE8

LOC:1000

Area Treated3(A) Area Treated3 

(A) Area Treated3

(A) Area Treated3(A) Area Treated3(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 0.0027 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
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Table 9.1.1. Occupational Exposure and Risk Estimates for Hydrogen Cyanamide Handler Scenario

Crop or 

Target

Maximum 

Application 

Rate1

(lb ai/A)

Dermal 

Unit 

Exposure2

(ug/lb ai)

Dermal Dose4

(mg/kg/day)

Dermal MOE5

(LOC:1000) Inhalation 

Unit 

Exposure2

(ug/lb ai)

Inhalation Dose6

(mg/kg/day)

Inhalation MOE7

(LOC:1000)

Total Engineering 

Controls 

Combined MOE8

LOC:1000

Area Treated3(A) Area Treated3 

(A) Area Treated3

(A) Area Treated3(A) Area Treated3(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, 

Cherries, 

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 on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2012); Level of mitigation: Baseline, PPE, Eng. Controls;

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

4.Dermal Dose = Dermal Unit 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 Conversion 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/Dermal MOE + 1/Inhalation MOE). Engineering controls combined MOEs presented the lowest exposure risks.
Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

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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 calculated and then compared with a Q1* that has 

been calculated for hydrogen cyanamide based on dose response data in the appropriate 

toxicology study (Q1* = 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 Q1* 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 calculated 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 annual 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 expectancy of an individual (78 years).

Cancer Risk Estimates: Finally, cancer risk estimate calculations were completed by comparing 

the LADD values calculated above to the Q1* for hydrogen cyanamide (Q1* = 6.64 x 10-2

(mg/kg/day)-1). The Agency considered 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 Cancer Risk Estimate = (Dermal LADD + Inhalation LADD) x Q1*

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 weight/day), and

Q1* = 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

The occupational private handler cancer estimated risks for airblast and groundboom equipment 

mixing/loading exposure ranged from 1.4x10-6to 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

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risk estimates ranged from 1.7x10-6to 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. Cancer 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.
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Table 9.1.2. Cancer Risk Estimates for Hydrogen Cyanamide for Applications.

Crop or 

Target

Dermal & 

Inhalation 

PPE

Dermal Absorbed 

Daily Dose1

(mg/kg/day)

Inhalation

Absorbed

Daily Dose1

(mg/kg/day)

Dermal LADD2

(mg/kg/day)

Inhalation LADD3

(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 3.30E05

6.60E05

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 5.60E06

1.10E05

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 4.30E06

8.60E06

EC 0.002 0.003 0.00014 0.00027 0.00002 0.000038 0.0000017 0.0000034 2.1E-05 4.2E-05 1.40E06

2.80E06

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 6.60E05

1.30E04

SL/G

PF5 R 0.014 0.027 0.00015 0.00029 0.00017 0.00034 0.0000018 0.0000036 0.00017 0.00034 1.10E05

2.30E05

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 8.60E06

1.70E05

EC 0.003 0.006 0.00027 0.00055 0.000038 0.000077 0.0000034 0.0000067 4.2E-05 8.3E-05 2.80E06

5.50E06

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 8.60E05

1.70E04

SL/G

PF5 R 0.018 0.036 0.00019 0.00039 0.00022 0.00045 0.0000024 0.0000047 0.00023 0.00045 1.50E05

3.00E05

DL/G

PF10 R

0.014 0.028 0.0001 0.00019 0.00017 0.00035 0.0000012 0.0000024 0.00017 0.00035 1.10E05

2.30E05

EC 0.004 0.008 0.00037 0.00073 0.000051 0.0001 0.0000045 0.000009 5.6E-05 0.00011 3.70E06

7.30E06

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 2.70E04

5.40E04

SL/G

PF5 R 0.29 0.58 0.0016 0.0031 0.0036 0.0071 0.000019 0.000038 0.0036 0.0071 2.40E04

4.70E04

DL/G

PF10 R 0.27 0.54 0.00078 0.0016 0.0033 0.0066 0.00001 0.000019 0.0033 0.0066 2.20E04

4.40E04

EC 0 0.01 0.00011 0.00023 0.000033 0.0001 0.0000014 0.0000028 3.4E-05 6.8E-05 2.30E06

4.50E06

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 5.40E04

1.10E03

SL/G

PF5 R 0.58 1.16 0.0031 0.0062 0.0071 0.014 0.000038 0.000076 0.0071 0.014 4.70E04

9.30E04
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Table 9.1.2. Cancer Risk Estimates for Hydrogen Cyanamide for Applications.

Crop or 

Target

Dermal & 

Inhalation 

PPE

Dermal Absorbed 

Daily Dose1

(mg/kg/day)

Inhalation

Absorbed

Daily Dose1

(mg/kg/day)

Dermal LADD2

(mg/kg/day)

Inhalation LADD3

(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 4.40E04

8.60E04

EC 0.01 0.01 0.00023 0.00045 0.000065 0.00013 0.000003 0.0000055 6.8E-05 0.00014 4.50E06

9.30E06

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 7.30E04

1.50E03

SL/G

PF5 R 0.77 1.54 0.0042 0.0083 0.0095 0.019 0.000051 0.0001 0.0095 0.019 6.30E04

1.30E03

DL/G

PF10 R 0.72 1.43 0.0021 0.0042 0.0088 0.018 0.000026 0.000051 0.0088 0.018 5.80E04

1.20E03

EC 0.01 0.01 0.0003 0.0006 0.000087 0.00017 0.0000037 0.0000074 9.1E-05 0.00018 6.00E06

1.20E05

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 2.50E05

4.80E05

SL/G 0.006 0.012 0.00023 0.00045 0.000071 0.00014 0.0000028 0.0000055 7.4E-05 0.00015 4.90E06

1.00E05

DL/G 0.005 0.009 0.00011 0.00023 0.000057 0.00011 0.0000014 0.0000028 5.8E-05 0.00012 3.90E06

8.00E06

EC 0.002 0.004 0.00014 0.00028 0.000023 0.000045 0.0000017 0.0000035 2.5E-05 4.9E-05 1.70E06

3.30E06

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 3.30E05

6.40E05

SL/G 0.008 0.016 0.0003 0.0006 0.000096 0.00019 0.0000037 0.0000074 0.0001 0.0002 6.60E06

1.30E05

DL/G 0.006 0.012 0.00015 0.0003 0.000075 0.00015 0.0000018 0.0000037 7.7E-05 0.00015 5.10E06

1.00E05

EC 0.003 0.005 0.00019 0.00038 0.000031 0.000061 0.0000023 0.0000047 3.3E-05 6.5E-05 2.20E06

4.30E06

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 expectancy );

4.Total LADD = total absorbed dose [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 * Q1*

, where Q1

*

= 6.64 x 10-2(mg/kg/day)-1.
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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. The registrant’s label amendment consisted 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 equivalent in 

protection to an enclosed cab. Consequently, 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 requirement 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 this 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 current 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 calculated using HED default assumptions. 

HED only assessed the applicator exposure since it was noted in the passive dosimetry study that 

there 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 they 

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
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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 needed. 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 one 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 assumed with double layer and gloves and a PF10 Respirator and chemicalspecific 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. HED 

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 ranged 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 estimates 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 exposure 

geometric mean 0.00103 (mg/lb ai)]9applying 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 passed tests for log-normality (D333780; M. Collantes; 2/9/07).
Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

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Cancer Risk Estimate Comparison (Passive Dosimetry Study)

Using the passive dosimetry study (MRID 454074-03) data, cancer risk estimates for private 

applicators using closed cab airblast equipment ranged from 2x10-6to 5x10-6. HED default risk 

estimates for the aforementioned scenario ranged from 2.2x10-6to 1.2x10

-5

. Passive dosimetry 

study open cab applicator with coveralls resulted in cancer risk estimates that ranged from 

1.4x10- 5to 7.6x10-5. HED default open cab assumption using double layer, gloves and a PF10 

respirator resulted in cancer risk estimates ranging from 4.6x10-3to 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) using chemical-resistant suits, resulted in cancer risk estimates ranging from 

1.4x10-6to 2.8x10-5. A summary of these results are provided Table 9.1.7.
Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

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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 

Rate1

(lb ai/A)

Test

Acres 

Treated2

(A)

Dermal Daily Dose3

(mg/kg/day) Dermal MOE4 Inhalation Daily Dose5(mg/kg/day) Inhalation MOE6

Dosimeters7 HED 

Data8 Dosimeters HED Data Dosimeters9 HED Data10 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

30 0.018 0.0040 110 500 No Data N/A

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

30 0.037 0.0079 54 250 No Data N/A

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

30 0.049 0.011 41 190 No Data N/A

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
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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 Treated (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 Exposures: 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, double 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, coveralls = 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 Studies1

(mg/lb ai)

Application

Rate2

(lb ai/A)

Acres

Treated3

(A)

Absorbed Daily Dose4

(mg/kg/day)

MOE5

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 Application 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

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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

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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 yrs life expectancy; it is assumed that 

private growers would be exposed 10 days per year and commercial 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 Dose1(mg/kg/day) LADD2(Private Applicator) Cancer Risk3(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 private growers would be exposed 10 days per 

year;

3.Cancer Risk = Q1*(6.64E-2 mg/kg/day)-1 x Lifetime Average Daily Dose (mg/kg/day).
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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 reentry 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 time 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 was not performed for hydrogen cyanamide at this time. However, there are multiple 

potential sources of post-application inhalation exposure to individuals performing postapplication 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 Scientific Advisory Panel (SAP) in December 2009, 

and received the SAP’s final report on March 2, 201010. 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 hydrogen cyanamide.

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 from 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 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.

 

10 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html
Hydrogen Cyanamide Human Health Risk Assessment DP No. D393086

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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 Protection 

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 Concentrations 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 (Q1

*

) 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: Request 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, Chronic, 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. Carcinogenicity 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. Hydrogen 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 (HASPOC) 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. D271362. 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

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Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 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

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A.2 Toxicity Profiles

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 LD50 Females 

= 313 mg/kg

II

870.1200 870.1200 Acute dermal toxicity: 

rabbits (TXR 5009273)

47469102

(2005)

LD50 = 1707 mg/kg 

♂

LD50 = > 5050 mg/kg 

♀

II

870.1300 870.1300 Acute inhalation toxicity

(TXR 5009273)

47469103

(2005)

LC50 >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.) 
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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 consisting 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 

mononuclear 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

Developmental LOAEL = 18 mg a.i./kg/day

(disintegration of liver structure) 
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Table A.2.3 Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3800 Gavage 

Reproductive 

Toxicity 

[ HED Document 

0010591, 

0014571]

41566504 (1990)

0, 2.5, 7.5, or 30 mg 

a.i./kg/day (F0 during 

premating) or 0, 1.25, 

3.75, or 15 mg a.i./kg/day 

(during F1 premating, F0

and F1 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 significant decreases in body 

weight/weight gain (↓8%/↓18%) in the F0)

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 T3 and T4 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 

study.]

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 T4 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; and 

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).
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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 carcinogenicity.

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 carcinogenic 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 2000 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/-

CarcinogenicityRat

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 333μg/plate with rat or 

hamster S9; negative without activation. 

Results consistent from two laboratories testing 

for NTP (CaCN)
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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 

ovary 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.

870.6200a 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. 
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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/NonGuideline

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. Negligible amounts 

are excreted as expired CO2. 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 cyanamide excreted in the urine of rats, 

rabbits, dogs, and humans was identified as Nacetylcyanamide. The conversion of 

cyanamide to N-acetylcyanamide in vitro is 

catalyzed by an acetyl-S-CoA-dependent Nacetyltransferase 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 14C-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 14C-hydrogen 

cyanamide on day 15. An additional group 

received a single I.V. dose of 1 mg/kg 14Chydrogen cyanamide. The study demonstrated 

that 14C-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 administered 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 the 14Chydrogen cyanamide is N-acetylated to form Nacetylcyanamide, which is eliminated in the 

urine and feces. 
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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)

NonAcceptable/Guideline

A single dermal dose of 0.1, 1, or 10 mg (8, 80, 

or 800 μg/cm2, respectively) 14C-hydrogen 

cyanamide, administered to three groups of 

male rats (24/group), is rapidly absorbed, 

distributed and eliminated. In general, as the 

dose level and the duration of exposure 

increased, the percentage of the dose absorbed 

also increased. Using the direct procedure to 

calculate skin absorption, the average 14Chydrogen cyanamide equivalents absorbed 

within 24 hours are 1.79%, 2.84%, and 11.1% 

of 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 appropriate for this scenario.

A.3.2 Acute Reference Dose (aRfD) - General Population

Study Selected: Developmental Toxicity Study in the Rat. 

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 

32% 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, 10X 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

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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 acute RfD (aRfD) is derived to address the risk from 

drinking water exposure only. 

 

 

 

 

A.3.3 Chronic Reference Dose (cRfD)

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, Guidelines 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 T4 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, 10X 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 chronic RfD (cRfD) is derived to 

address the risk from drinking water exposure only. 

 

 

 

 
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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, Guidelines 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 T4 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, 10X 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 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 

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, Guidelines 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 T4 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. 
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Uncertainty Factor(s): Occupational Level of Concern (LOC) for MOE = 1000 The 1000

includes 10X for intraspecies variation, 10X 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 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 

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, Guidelines 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 T4 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 for MOE = 1000 This includes 10X for 

intraspecies variation, 10X 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 

since 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.
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A.4 Executive Summaries

A.4.1 Subchronic Toxicity

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 13.5 mg a.i./kg/day) for 90 days. No deaths occurred and animals did not 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 hematological 

parameters, serum enzyme activities, serum protein or serum albumin values among treated and 

control groups. There were no differences in the urinalysis 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 material. 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 small 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. Males in the l80ppm group exhibited an increase in the number of small foci of 

necrotic liver cells with a slight degree 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 on 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 weighed 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 
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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 acceptable/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

870.3700a 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 controls) 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. Hypoactivity 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 non-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 on 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)
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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. The 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 other 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. The 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 (F0 during premating through week 12). Because of severe weight loss in 

the F0 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 toxicity (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 and 

body gain in both sexes in the F0 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 F1 parents, when the doses were 

reduced, these effects were seen only at the high dose of 15 mg a.i. mg/kg BW/day. Food 

consumption was reduced in both generations at the high dose too. Based on the decreased 

body weight/gain (-8%/-18%) in the F0 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. 
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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 F1 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 F2 generation and the decrease was not dose dependent, the pup body weight changes 

in the F1 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) aqueous hydrogen cyanamide was administered via oral 

gavage to male and female Crl: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 excessive 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 addition, the 

analysis of thyroid hormone levels revealed possible treatment-related effects on thyroid function 

as indicated by decreases in both thyroxine and triiodothyronine levels in males receiving 7.5 

mg/kg/day. Although a previous mouse oncogenicity study (cited in the study report as Hazleton 

Project No. 55613) identified the ovary as a potential target organ, there were no treatmentrelated 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 the study. A slight but statistically nonsignificant decrease in food consumption was noted in the high-dose males and females during 

the first 16 weeks of the study.

Numerous differences 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; these 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 LOAEL is 7.5 mg/kg/day active ingredient hydrogen cyanamide in 
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males and females. The NOAEL is 2.5 mg/kg/day active ingredient 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 gavage 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 for 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-dose, 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 T4

in high-dose males. 

Relative thyroid/parathyroid weights were increased 56% in high-dose females. Compoundrelated 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 males, 

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, desquamation of the skin, 

tremors, and salivation; decreased body weight gain; decreased T4 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)

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.
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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) based 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 females (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 NOAEL 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 increase (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 dosing 

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), groups 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 (approximately 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. An increase in 

malignant hemangiosarcoma was seen at 2000 ppm (HDT). The incidence of hemangiosarcoma 

was twice that observed in historical 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 was 

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. 
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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 ruffled 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.
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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 - MRID 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 14C-hydrogen cyanamide 

or administered daily oral doses of 1 mg/kg/day unlabeled hydrogen cyanamide for 14 days 

followed by a single dose of 1 mg/kg 14C-hydrogen cyanamide on day 15 (MRID 42906401). An 

additional group received a single intravenous (i.v.) dose of 1 mg/kg 14C-hydrogen cyanamide.

The study demonstrated that 14C-hydrogen 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 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 route following i.v. 

administration. Recoveries in expired 14CO2 were higher in the males than in the females and 

were higher in the i.v. and single low-dose oral groups compared to the repeated-dose and highdose groups. These findings suggest that there is a depletion of metabolic enzymes at the highdose group, and therefore, only a limited amount of the hydrogen cyanamide is metabolized to 

CO2. Tissue bioaccumulation of hydrogen cyanamide was low for all groups. Most of the 14Chydrogen cyanamide is N-acetylated to form N-acetylcyanamide, which is eliminated in the 

urine and feces. This study is Acceptable/guideline.
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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 

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 was excreted in the urine within the first 6 hours, indicating that 

hydrogen cyanamide 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 catalyzed by an acetyl-S-CoAdependent 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 μg/cm2, respectively) 14C-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 increased. Using the 

direct procedure to calculate skin absorption, the average 14C -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 be 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
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Appendix B

The Major (solid arrow) and Minor (dashed arrow) Metabolic Pathways

for Hydrogen Cyanamide (Source TXR 0010591; MRID 42178407)
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Appendix C
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Appendix D

Table 3.2.1 Physicochemical Properties of the Pure Hydrogen Cyanamide.

Parameter Value Reference

Melting point/range 45-46oC Merck Index, 9th 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, 9th 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, 9th edition

Vapor pressure (20°C) 3.75 x 10-3 mm Hg EFED DWA D403785, 

I. Abdel-Saheb, 10/4/12

Dissociation constant, pKa Not Available None

Octanol/water partition coefficient, log 

POW (20°C)

Not Available None