UNITED STATES ENVIRONMENTAL PROTECT ION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: Jul y 14, 2015 

011FICE OF CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Hydrogen Cyanamide (REVISED) - Factors Affecting Hydrogen Cyanamide 

Risk Assessment: Response to Draft Risk Assessment for Registration Review 

PC Code: 014002 

Decision No.: 502516 

Petition No.: NIA 

Risk Assessment Type: NIA 

TXRNo.: NIA 

MRID No.: 4952200 I 

DP Barcode: D426320 

Registration No.: 7005-1 

Regulatory Action: NI A 

Case No.: 7005 

CAS No.: 420-04-2 

40 CFR: NIA 

FROM: Abdallah Khasawinah, Ph.D., Toxicologist 

Jessica Kidwell, Risk Assess;ar 

Ivan Nieves, ORE Assessor 

Registration Action Branch I 

Health Effects Division (7509 P) 

THROUGH: Cha

Risk 

rl

Assessment 

es Smith, Act

Branch 

ing Bran

IV 

ch Chief c · 6~-

Health Effects Division (7509 P) 

TO: Dana Friedman, Risk Manager Reviewer 

Risk Management and Implementation Branch II 

Pesticide Re-Evaluation Division (PRD) (7508P) 

I. ACTION REQUESTED 

The Health Effects Division was asked to review and respond to "Factors Affecting Hydrogen 

Cyanamide Risk Assessment" (MRI D 4952200 I), which was prepared by the registrant and their 

consultants following the Draft Risk Assessment comment period. This revision includes the 

addition of the revised quantification of the spray drift risk estimates following the revision of 

the dermal absorption factor. 

Page I of8 
II. RESULTS/DISCUSSION 

The registrant's comments address .. key factors in risk assessment" as it relates to hydrogen 

cyanamide. These are: 

A. Comment # /: Metabolism and Toxicokinetics. A number of published studies including 

human oral/iv metabolism studies as well a guideline metabolism study are discussed. Nacetylamide was the major metabolite by all mammalian species tested including 

man. Oral bioavailability is similar in dogs, rats and humans. The registrant felt that this 

information should have been included in the risk assessment. 

HED Response: The published human studies were not discussed in the preliminary risk 

assessment. These would require review by the Human Studies Review Board (HSRB) 

before being considered for use and they do not impact our conclusions. HED agrees that 

N-acetylamide was the major metabolite by all mammalian species tested and we agree 

regarding its rapid absorption and excretion. No new information is presented by the 

registrant except for the human studies. 

B. Comment #2: Dermal absorption.factor. The registrant disagrees with the dermal 

absorption factor of 11 % derived from the in vivo rat dermal penetration study (MRID 

41504004). In this study, rats were treated with 0.1 , 1.0, or 10.0 mg/rat (8, 80 or 800 

μg/cm2). The dermal absorption increased with increasing dose (24 hour absorption was 

1.8, 2.8. 11 %, respectively). The registrant is requesting a DAF that corresponds to reallife exposures (a OAF of 1.8% from the in vivo rat dermal penetration study). The 

registrant cites a published human study to support their position. 

HED Response: After checking the magnitude of the expected occupational exposures, 

HED is revising the OAF to 2.84% from the in vivo rat dermal penetration study resulting 

from application of 80 μg/cm2. The published human study referenced by the registrant 

would need 1-ISRB review before being considered for use in the hydrogen cyanamide 

risk assessment. Given the revised dermal absorption factor from the rat penetration 

study, HED does not plan on taking the referenced human study to HSRB review. 

C. Comment #3: Toxicology Benchmark. The registrant is requesting that the point of 

departure (POD) for assessing risks from short- and intermediate-tem1 exposures be 

based on more realistic studies of durations comparable to these exposure durations. The 

registrant also provided a reference (Ross and Driver 2014) supporting applicator 

exposure durations of S 7 days. Thus the registrant requests that the POD be based on the 

rat developmental study (MRID 41288806) of 5 mg/kg/day (NOAEL) rather than the 

subchronic/chronic dog (MRJD 41390501 /41288802) of2.0 mg/kg/day (NOAEL) 

currently being used. 

Page 2 of 8 
HED Response: Based on the information (Ross and Driver 2014) provided by the 

registrant, HEO is revising the POD for assessing risks from short- and intermediate-term 

exposures to 5 mg/kg/day (NOAEL) based on maternal toxicity in the rat developmental 

study. The maternal effects seen in this study at the LOAEL of 15 mg/kg/day were 

decreased body weight gain (L 18%), decreased food consumption (!8%) and 

hypoactivity in one third of the treated animals. It is noted that a similar NOAEL/LOAEL 

was seen in the developmental rabbit study. In the rabbit developmental study (MR1D 

41288805), body weight gain was also depressed (! 109%) at the LOAEL of 18 

mg/kg/day with a NOAEL of 6 mg/kg/day. The use of the developmental rat study more 

closely matches the real world exposure duration for workers. 

Table 1 shows dermal and inhalation exposure risk estimates with a point of departure of 

2.0 mg/kg/day (NOAEL) from the subchronic/chronic dog study and a DAF of 11 % as 

previously used. Table 2 presents the same risk estimates revised with the rat 

developmental study of 5 mg/kg/day (NOAEL) and a DAF of2.84%. The comparison 

results in a I 0-fold difference, however, the majority of dermal scenarios for airblast 

applicators still do not reach HED's LOC of 1,000 with the revised toxicological 

endpoints and points of departure. Tables 3 and 4 presents a revised quantification 

assessment of spray drift exposure to children ( l 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. For children 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 l 000 so MO Es < I 000 would be of 

concern. Adult and children's (I <2 year old) dermal and children incidental oral risk 

estimates from indirect exposure to hydrogen cyanamide related to spray drift result in 

buffers of 75 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 indicate that there 

are risks of concern from groundboom applications (for some nozzle types) even 300 feet 

downwind of the treated field for children 1 <2 years old. 

Page 3 of8 
Table I. Short-Term Occupational Exposure a nd Risk Estimates for Hydrogen Cyannmide Handler Airblnst Scenario (PREVIOUS ASSESSMENT) 

Maximum Dermal Dose MOE Inhalation Dose MOE 

Crop or Application Dermal Unit (ml!.fkl!/day) Inha lation Unit (ml?fkl?l'day) LOC: IOOO 

Target Rate (lb Exposure (ug/lb Arca Treated (A) Arca Treated (A) Exposure Arca Treated (A) Area Treated (A) 

nil A) a i) 20 30 40 20 30 40 (ug/lb ni) 20 30 40 20 30 40 

Mixer/Loader 

SL/No G : 220 0.040 0.060 0.080 so 33 2S No-R: 0.219 0.000361 O.OOOS43 0.000723 ssoo 3700 2800 

Nectarine 6.6 

SL/G: 37.6 0.0068 0.0 102 0.0 137 290 200 ISO PFS R: 0.0438 0.000072 0.000108 0.00014S 28000 19000 14000 

and Pet1eh DL/G: 29. 1 O.OOS3 0.0079 0.0 106 380 2SO 190 PFIO R: 0.02 19 0.000036 0.000054 0.000072 ssooo 37000 28000 

EC: 8.6 0.00157 0.00234 0.00312 1300 850 640 EC: 0.083 0.000138 0.000205 0.000274 14000 9800 7300 

SUNo G: 220 0.080 0. 120 0. 160 2S 17 13 No-R: 0.219 0.00072 0.00108 0.00 14S 2800 1900 1400 

Blackberries SL/G: 37.6 0.0 137 0.0205 0.0274 150 98 73 PFS R: 0.0438 O.OOO IS 0.00022 0.00029 14000 9300 6900 

and 13.2 

Blueberries DL/G: 29. 1 0.0 106 0.0158 0.0212 190 130 94 PFIO R: 0.0219 0.00007 0.000 11 O.OOO IS 28000 19000 14000 

EC: 8.6 0.003 12 0.0047 0.0062 640 430 320 EC: 0.083 0.00027 0.0004 1 o.oooss 7300 4900 3600 

Apples, SL/No G : 220 0.106 0. 160 0.213 19 13 9.4 No-R: 0.219 0.001 0.001 0.002 2100 1400 1000 

Grapes. SL/G : 37.6 0.0 182 0.0274 0.0364 110 73 SS PFS R: 0.0438 0.0002 0.0003 0.0004 10000 6900 S200 

Cherries. 17.6 DL/G : 29. 1 0.0140 0.0212 0.0282 140 94 7 1 PFIOR:0.02 19 0.000 1 0.0001 0.0002 2 1000 14000 10000 Kiwi Fruit. 

and Figs EC: 8.6 0.0042 0.0062 0.0083 480 320 240 EC: 0.083 0.0004 0.0005 0.0007 ssoo 3600 2700 

Applicator 

SL/No G: 220 0.322 0.48 1 0.64 6.2 4.2 3.1 No-R: 0.2 19 0.0078 0.0 11 7 0.015S 260 170 130 

SL/G : 37.6 0.289 0.433 0.58 6.9 4.6 3.5 PFS R: 0.0438 0.0016 0.0023 0.0031 1300 850 640 

Nectarine DUG: 29.1 0.268 0.403 0.54 7.S s 3.7 PFIO R: 0.02 19 0.00078 0.0012 0.00 16 2600 1700 1300 

and Peach 6.6 

SL/G/CRH: 2 15 0.039 1 0.059 O.Q78 SI 34 26 NIA 

OL/G/CRH: 14 1 O.S38 0.538 0.8 1 3.7 3.7 2.5 N/A 

EC: 8.6 0.0026S 0.00397 0.0053 7SO 500 380 EC: 0.083 0.0001 1 0.00017 0.00023 18000 12000 8900 

SL/No G: 220 0.64 0.96 1.29 3. 1 2.1 1.6 No-R: 0.2 19 0.016 0.023 0.03 1 130 8S 64 

SL/G: 37.6 0.S8 0.87 1.16 3.S 2.3 I. 7 PFS R: 0.0438 0.0031 0.0047 0.0062 640 430 320 

Blackberries DL/G: 29.1 0.54 0.8 1 1.07 3.7 2.S 1.9 PFIO R: 0.02 19 0.0016 0.0023 0.003 1 1300 8SO 640 

and 13.2 

Blueberries SUG/CRH: 21 S O.Q78 0. 11 7 O. IS7 26 17 13 NIA 

DL/G/CRH: 141 O.OSI 0.077 0. 102 39 26 20 NIA 

EC: 8.6 0.0053 0.0080 0.0 106 380 250 190 EC: 0.083 0.00023 0.00034 0.00045 8900 6000 4SOO 

SL/No G: 220 0.86 1.29 1.72 2.3 1.6 1.2 No-R: 0.2 19 0.020800 0.03 1100 0.04 1500 96 64 48 

Apples. SL/G: 37.6 0.77 1.16 1.54 2.6 1.7 1.3 PFS R: 0.0438 0.004150 0.0062 10 0.008290 480 320 240 

Grapes. DL/G: 29.1 0.72 1.07 1.43 2.8 1.9 1.4 PFIO R: 0.02 19 0.002080 0.003 11 0 0.004150 960 640 480 

Cherries. 17.6 

SL/G/CRH: 2 1 S O.IS7 0.208 19 9.6 Kiwi Fruit. 0. 104 13 N/A 

and Figs DUG/CRH: 141 0.068 0. 102 0.137 29 20 15 NIA 

EC: 8.6 0.0071 0.0106 0.0 142 280 190 140 EC: 0.083 0.000299 O.OOO.t49 0.000599 6700 4500 3300 

Page 4 of8 
Table 2. Short-Term Occupational Exposure and Ris k Estimates for Hydrogen Cyanamide Handler Airblast Scenario (REVISED NUMBERS) 

Derma l Dose MOE Inha lation Dose MOE 

Crop or Maximum Dermal Unit (mg/kg/day) Inha lation Unit (m1?/k1?/dav) LOC: IOOO 

Target Application Exposure (ug/lb Area Treated (A) Area Treated (A) Exposure Area Treated (A) Area Treated (A) Rate (lb ai/A) ai) 20 30 40 20 30 40 (ug/lb ai) 20 30 40 20 30 40 

Mixer/ Loader 

SI/No G: 220 0.009 0.0 14 0.019 530 350 260 No-R: 0.219 0.000361 0.000543 0.000723 14000 9200 6900 

Nectarine 6.6 

SL/G: 37.6 0.00 16 0.0024 0.0032 3 100 2 100 1500 PFS R: 0.0438 0.000072 0.000 I 08 0.000145 69000 46000 34000 

and Peach DL/G: 29. 1 0.0013 0.0019 0.0025 4000 2700 2000 PF IO R: 0.02 19 0.000036 0.000054 0.000072 140000 92000 69000 

EC: 8.6 0.00037 0.00055 0.00074 13000 9000 6800 EC: 0.083 0.000 138 0.000205 0.000274 36000 24000 18000 

SI/No G: 220 0.019 0.028 0.038 260 180 130 No-R: 0.219 0.00072 0.00108 0.001 45 2800 1900 1400 

Blackberries SL/G: 37.6 0.0032 0.0048 0.0065 1500 1000 770 PFS R: 0.0438 0.000 15 0.00022 0.00029 14000 9300 6900 

and 13.2 

Blueberries DL/G: 29. 1 0.0025 0.0037 0.0050 2000 1300 1000 PF IO R: 0.02 19 0.00007 0.000 11 0.00015 28000 19000 14000 

EC: 8.6 0.00074 0.00 11 0.00 15 6800 4500 3400 EC: 0.083 0.00027 0.0004 1 0.00055 7300 4900 3600 

Apples. SI/No G: 220 O.D25 0.038 0.050 200 130 99 No-R: 0.2 19 0.00 1 0.00 1 0.002 21 00 1400 1000 

Grapes. SUG: 37.6 0.0043 0.0065 0.0086 1200 770 580 PFS R: 0.0438 0.0002 0.0003 0.0004 10000 6900 5200 

Cherries. 17.6 DL/G: 29. 1 0.0033 0.0050 0.0067 1500 1000 750 PF IO R: 0.02 19 0.000 1 0.000 1 0.0002 2 1000 14000 10000 Kiwi Fruit. 

and Figs EC: 8.6 0.00 10 0.00 15 0.0020 5 100 3400 2500 EC: 0.083 0.0004 0.0005 0.0007 5500 3600 2700 

Applicator 

SI/No G: 220 0.076 0.114 0.15 66 44 33 No-R: 0.2 19 0.0078 0.0 117 0.0 155 640 430 320 

SUG: 37.6 0.068 0. 102 0. 14 73 49 36 PFS R: 0.0438 0.00 16 0.0023 0.003 1 3200 2 100 1600 

Nectarine 

6.6 

DL/G: 29.1 0.063 0.095 0. 13 79 53 39 PF10 R: 0.02 19 0.00078 0.00 12 0.0016 6400 4300 3200 

and Peach SUG/C RH: 2 15 0.0092 0.0 14 0.019 540 360 270 NIA 

DUG/CRH: 14 1 0.127 0. 127 0. 19 39 39 26 N/A 

EC: 8.6 0.00063 0.00094 0.0013 8000 5300 4000 EC: 0.083 0.000 11 0.00017 0.00023 45000 30000 22000 

SL/No G: 220 0. 15 0.23 0.30 33 22 16 No-R: 0.2 19 0.0 16 0.023 0.03 1 320 2 10 160 

SUG: 37.6 0. 14 0.2 1 0.27 36 24 18 PFS R: 0.0438 0.003 1 0.0047 0.0062 1600 11 00 8 10 

Blackberries DL/G: 29. 1 0. 13 0. 19 0.25 39 26 20 PFIO R: 0.02 19 0.00 16 0.0023 0.0031 3200 2 100 1600 

and 13.2 

Blueberries SU G/CRH: 2 15 0.01 9 0.028 0.037 270 180 130 NIA 

DUG/CRH: 14 1 0.012 0.018 0.024 4 10 280 2 10 NIA 

EC: 8.6 0.00 13 0.0019 0.0025 4000 2700 2000 EC: 0.083 0.00023 0.00034 0.00045 22000 15000 11 000 

SI/No G: 220 0.20 0.30 0.4 1 25 16 12 No-R: 0.2 19 0.020800 0.03 1100 0.04 1500 240 160 120 

Apples. SL/G: 37.6 0. 18 0.27 0.36 27 18 14 PFS R: 0.0438 0.004 150 0.0062 10 0.008290 1200 810 600 

Grapes. DUG: 29. 1 0. 17 0.25 0.34 30 20 15 PF IO R: 0.02 19 0.002080 0.003 110 0.004150 2400 1600 1200 

Cherries. 17.6 

SL/G/CRH: 2 15 O.D25 0.037 0.0-1 9 200 130 100 Kiwi Fruit. NIA 

and Figs DUG/CRH: 14 1 0.0 16 0.024 0.032 3 10 2 10 150 NIA 

EC: 8.6 0.00 17 0.0025 0.0034 3000 2000 1500 EC: 0.083 0.000299 0.000449 0.000599 17000 11 000 8300 

Page 5 o f8 
Table 3. Adult Spray Drift Exposure and Risk Estimates for Hydrogen Cyanamide (REVISED NUMBERS) 

Crop/RJltc Spray Type/ Nome Application Rate Estimated or At Edge 10 Feet 2S Feet SO feet 7S Feet 100 Feet 12S Feet ISO Feet 200 Feet 2SO Feet 300 Feet 

Adjusted lTR Group Configuration (lb aVA) (o2'cm2) Dermal MOE 

~""-- · V"t.ul~· ..... - ., ·--···· · 

f/igll Boom Ve1J1 fi11e 140 290 480 760 1.100 1.300 1,600 1.900 2.400 3.300 3.800 to Fine 

Low Doom Very line 10 310 830 1.300 2,100 2,700 3.300 3,800 4,400 5.300 6.700 8,900 Fine Groundboom High Boom Fine to 

Medium/Coarse 540 l.400 2. 100 3.000 3.800 4.400 5,300 5,300 6.700 8,900 8,900 

Low Doom Fine to 17.6 1.96 

Medium/Coarse 810 2.200 3,300 4,400 5,300 6,700 8,900 8,900 13,000 13,000 13.000 

StJ(lrse 190 320 600 1,300 2,400 3.900 5,900 8.300 15.000 24.000 33,000 

Airblast Normal 8,900 13,000 21.000 30,000 44,000 53,000 67,000 89,000 89.000 130.000 130.000 

Dense 630 960 1.500 2.700 4.000 5.400 6.800 8,300 12.000 15,000 18.000 

Vinevard 3,300 6.500 12.000 22.000 33.000 44,000 53.000 67,000 89.000 130,000 130,000 ·-- ' ...... - - ' 

High Boom Ve1:11 ji11e 190 380 630 1.000 1,400 1,800 2.100 2.500 3.200 4.400 5,100 to Fi11e 

Low 1300111 Very line 10 420 1.100 1,800 2.700 3.600 4.400 5,100 5,900 7. 100 8,900 12.000 Fine Groundboom I ligh Doorn Fine 10 

Medium/Coarse 730 1,900 2.700 4,000 5.100 5.900 7,100 7.100 8.900 12.000 12,000 

Low Doom Fine to 13.2 1.-17 

Medium/Coarse 1,100 3,000 -1 ,400 5.900 7.100 8.900 12,000 12,000 18.000 18.000 18.000 

Soarse 250 430 800 1.800 3.200 5.200 7.900 11 .000 20.000 32.000 44.000 

Airblas1 Nonnal 12,000 18.000 27.000 40.000 59.000 71,000 89,000 120.000 120.000 180.000 180.000 

Dense 840 1.300 2.000 3.600 5.300 7.300 9.100 11.000 15.000 20.000 24.000 

Vinc~ ard 4.400 8.700 16.000 30.000 44.000 59.000 71.000 89.000 120.000 180,000 180.000 - A • 

~~.,; -- - - - - -- -- ·-. -. ~ . --

StJarse 500 850 1.600 3.600 6.500 10.000 16.000 22,000 40.000 65.000 89.000 

Airblast Nonna I 6.6 0.73 24.000 36.000 55.000 79.000 120.000 140.000 180.000 240.000 240,000 360,000 360,000 

Dense 1,700 2.500 4.100 7.100 11 .000 15,000 18.000 22,000 31.000 40.000 47.000 

Vim.:vard 8,900 17.000 32.000 59.000 89.000 120.000 140.000 180.000 240,000 360.000 360,000 

Page 6 of8 
Table 4. Ch ildren 1<2 Combined (Dermal & Ha nd-to-Mouth) Spray Drift Exposure and Risk Estimates for Hydrogen Cyanamide (REVISED NUMBERS) 

Crop/Rate Spray Type/ Application Estimated or At Edge 10 Feet 25 Feet SO Feel 7S Feet 100 Feet 12S Feel ISO Feet 200 Feet 2SO Feet 300 Feet 

Group 

Nozzle Rale Adjusted T fR, 

Confitrnration lib al/Al (ul!/cm2) Combined MOE 

Anni ""- r.w.;~ """'----' -Vlwlll' ..... ......... .. -r' . ·- - l. -·· -- Higlt Boom 

Veryji11e to 26 52 86 140 190 240 280 340 440 600 690 

Fine 

Low Boom 

Very fine 10 56 150 240 370 480 600 690 800 960 1.200 1.600 

Groundboom Fine 

High Boom 

Fine to 98 250 370 530 690 800 960 960 1.200 1,600 1,600 

Medium/Coarse 17.6 1.96 

Low Boom 

Fine to 150 400 600 800 960 1,200 1.600 1,600 2.400 2.400 2,400 

Medium/Coarse 

Sparse 33 58 110 240 440 710 1,100 1.500 2.700 4.400 6.000 

J\irblast Nomial 1.600 2.400 3.700 S,300 8,000 9.600 12.000 16,000 16.000 24.000 24.000 

Dense 110 170 270 480 720 980 1.200 1.500 2,100 2.700 3.200 

Vineyard 600 1.200 2.200 4.000 6.000 8.000 9.600 12,000 16.000 24.000 24,000 

-- -- .... - - ~ ' - .. . - . 

' -· High Boom 

VelJ' fine to 34 69 110 180 260 320 380 460 580 800 910 

Fine 

Low Boom 

Very fine to 75 200 320 490 640 800 910 I.I 00 1.300 1.600 2.100 

Groundboom Fine 

High Boom 

Fine 10 130 340 490 710 910 1,1 00 1,300 1,300 1,600 2.100 2,100 

Medium/Coarse 13.2 1.47 

Low Boom 

Fine to 190 530 800 1,100 1.300 1.600 2.100 2.100 3.200 3.200 3.200 

Medium/Coarse 

Sparse 45 77 140 320 580 940 1.400 2.000 3.600 5.800 8.000 

J\irblast Nomi al 2,100 3,200 4.900 7.100 11 ,000 13,000 16.000 21.000 21.000 32.000 32.000 

Dense 150 230 370 640 960 1,300 1,600 2,000 2.800 3,600 4.300 

Vineyard 800 1.600 2,900 5,300 8,000 11.000 13,000 16,000 21,000 32,000 32,000 .. ...... _ .. h . . : ~-- 7·~,--~ ~.~JI. - . .. ,• .• I 

Sparse 89 150 290 640 1,200 1,900 2,800 4,000 7,100 12,000 16,000 

1\irblast 

Nomial 

6.6 0.73 4,300 6.400 9,900 14.000 21,000 26,000 32.000 43,000 43.000 64,000 64.000 

Dense 300 460 730 1,300 1,900 2.600 3.300 4,000 5,600 7,100 8,500 

Vineyard 1.600 3, 100 5.800 11.000 16,000 21.000 26,000 32.000 43.000 64,000 64.000 

Page 7 of8 
D. Comment #./:Alternative analysis of interspecies and intraspecies toxicokinetics. The 

registrant is seeking to reduce the interspecies and intraspecies uncertainty factors (UF) 

based on published metabolism studies including a metabolism study in man. The 

registrant states that " toxicokinetic data are available for rats, dogs and humans. As a 

result it is possible to make direct interspecies comparisons of parameters affecting 

interspecies uncertainty. While there are both rat and human kinetic data available 

following dermal dosing, the emphasis of those studies was bioavailability as opposed to 

classical toxicokinetics. However the human study does provide useful information on 

inter-human variability." No PBPK model is available and the registrant argues that it is 

not necessary, since there appears to be no primary target organ. 

HED Response: As per HED policy, a vetted PBPK model is needed to reconsider the 

uncertainty factors. The registrant argues that a PBPK model is not necessary, since there 

appears to be no primary target organ. However, HED identified the thyroid and the 

testes are primary organs of cyanamide toxicity. At this time, no action will be taken by 

HED on this issue. 

Page 8 of8