### UNITED STATES ENVIRONMENTAL PROTE C T I ON AGENCY WA S HINGTON , D.C. 20460



## MEMORANDUM Date: J ul y 14, 20 1 5 011FIC E OF C HEMI CA L SAFETY A N D POLLUTION PREVENTION



## SUBJECT: H ydro ge n Cyanam id e (REV ISE D)

- Factors Affecting Hydrog e n Cyanamid e Ri sk Assess ment: Respon se to Draft Risk Assessm e nt fo r Regi s tration Review 

## PC Code: 014002 

## Decision No.: 502516 

## Petit ion No.: NIA 

## Risk Assessment Type: NIA 

## TXRNo.: NIA 

## MRID No.: 49 52200 I 

## DP Barcode: D4 26320 

## Reg istration No . : 7005-1 

## Regulatory Actio n: NI

## A Case No.: 7005 

## CAS No. : 420-04-2 

## 40 

## CFR: NIA 

## FROM : Abd a ll ah Khasawinah , Ph . D ., Toxico logist J ess ica Kidwell, Risk Assess ;a r Ivan N i eves , ORE Assessor Registration Ac tion Branc h I Healt h Effects Di vis io n (7509 P) 

## THROUGH: Charl es Smi th , Actin g Bran c h C hi ef 

# c ·**6~-** Ri s k Assessment Branch IV H ealth Effec ts Division (75 0 9 P) 

## TO : D ana Fri ed man , Ri sk Man age r R eviewer Ri sk Manage me nt and Impl e mentation Branch II Pes ti cide Re-Evaluation Division (PRD) (7508 P ) I. 

## ACT I ON REQUESTED The Health Effec ts Division was asked to rev iew and respond to " Facto rs Affecti ng H ydro ge n Cyana mid e Ri s k Assess ment " (M RI D 49 52200 I), w hich was prep a re d by the re g istrant and their consu ltant s fo ll owi ng the Draft Ri s k Assessment com me nt period. This re v is ion includ es the add iti o n of the revised quantification of the sp ray drift ri s k estimates fo ll owing the revision of the dermal absorptio n factor.

Page I of8

## II . RESULTS/DI SCUSS I ON The registrant 's comments address .. key factors in risk assessment" as it relates to hydrogen cyanamide. These are: A. 

## Co mment #/: Metabolism and Toxicokinetics. A number of published s tudi es includin g human o ral/iv metabo lism s tudies as well a g uideline metaboli s m study are di sc u ssed. Nacetylamide was the major metabolite by all mammalian species tested including man. Oral bioavailab ility is similar in dogs, rats and human s. T he regist rant felt th at this information shou ld have b ee n includ e d in th e risk assessment. HE D 

## Res p o n se: The published human stud ies were not discussed in the preliminary risk assessment. These would require review b y th e Human Studies Revi ew Board (HSRB) before being considered for use and they do not imp act our conclusions. HED agrees that N-acetylam id e was the major met abolite by all mammalian species tested and we agree r egard ing its rapid absorption and excretion. No new information is prese nted by the registrant except for the hum an studies. 

## B. Commen t #2: Dermal absorption.factor . The reg istrant di sagrees with the dermal ab so rption 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 / cm 2 ). 

## The derma l absorption increase d with increa si ng do se (24 hour absorption was 1.8 , 2 .8. 11 %, respectively). The registrant is requesti ng a DAF that corresponds to reallif e exposu r es (a OAF of 1.8% from the 

## in vivo rat dermal penetration study). The registrant c ites a published human study to support their position. 

## HE D R espo n se : After checking the magnitude of the ex pect ed occupational exposures, HED is revising th e OAF to 2 .84 % from the 

## in vivo rat dermal penetration study resulting from application of 80 μ g/c m 2

. 

## The published human stud y referenced by the registrant would need 1-ISRB r eview before being considered for use in the hydro ge n cyanamide ri s k assessment. Given the revised dermal absorpt ion factor from the rat penetration study, HED does not plan on taking the referenced human study to H SRB review. C. 

## Commen t # 3: Toxicology Benchmark. The reg istrant is requ estin g that the point of departure (POD) for assess in g risks from short

- and intermediate-tem1 exposu res be ba se d on more realistic studies of durations co mparable to these exposure durations. Th e registrant a l so provided a r efe renc e (Ross and Driv er 20 14) supporti n g applicator expos ure durations of S 7 days. Thu s the registrant requests that the POD be based on the rat developmental s tudy (MRID 41288806) of 5 m g/kg/day (NOAEL) rather than the s ub c hroni c/ chronic dog (M RJD 41390501 /41288802) of2.0 m g/ kg/day (NOAEL) curre ntl y being used.

Page 2 of 8

## H ED Res pon se : B ased on the in formation (Ross and Dri ver 20 1 4) provided by the re g istrant , H EO is revisi ng the POD fo r assess in g ri sks from sh ort- and intermediate-term expos ures to 5 mg/kg/day (NOAE L) based on maternal toxicity in the rat d eve lopme nt a l study. The maternal effects see n in thi s s tud y at the LO AEL of 1 5 m g/kg/day we re decreased body we i ght gain (L 

## 18 %) , decreased food co n s ump t io n (!8%) and hypoactivity in one third of the treated an im a ls. It 

## is noted that a similar NOAEL/LOAEL was seen in the developmental rabbit study. In the rabbit deve lop me nt al study (M R1D 41288805) , body we i ght gai n was also depressed (! 1 09%) at the LOAEL of 18 mg/kg/day with a NOAEL of 6 mg/kg/day. The u se o f the developmental rat study more clo sely matches the real world exposu re duration for worke rs. Table 1 shows dermal and inhalati o n exposu re ri sk estimates with a point of departure of 2.0 mg/kg/day (NOAEL) from the s ub c hronic/c hronic do g s tudy and a DAF of 11 % as pre vious ly used. Table 2 prese nt s th e same risk es timates rev ised with the rat developmental st ud y of 5 mg/kg/day (NOAEL) and a DA F of2.84% . Th e comparison results in a I 0-fold difference , however , the majority of dermal sce nario s for airblast applicators still do not reach HED ' s LOC of 1 , 000 with the rev i sed toxicological e ndp oints and points of departure. Tables 3 and 4 presents a revised quantification assess ment of sp ray drift exposure to ch ildren ( l to 2 years old) and ad ult s who have co nt ac t w ith turf w here residues are ass um ed to have d epos ited via spray drift thus res ultin g in an indirect exposure sce n ari o. For children d erm a l and incid e ntal oral ri sk estimates we re co mbined becau se the to x icity e ndpoint for eac h ro ute of exposure i s the same. The total app li cable leve l of co ncern is l 000 so MOEs < I 000 would be of concern. Ad ult an d chil dren 's (I <2 yea r old) d ermal and ch ildre n incidental ora l risk estimates from indirect exposure to hydrogen cyanamide related to spray drift result in buffers of 75 to 300 feet. Exposures were considere d for 50 feet wide lawns whe re the nearest side of the property was directly adjoini ng the treated field (at field edge) and at varied d i stances up to 300 fee t downwind of a treated field. Results indicate that there are risks of co nc ern from g roundb oo m app lic atio n s (for some nozz le types) even 300 feet downwind of the treated field for c hildre n 1 <2 year s old.

Page 3 of8Tab le 

### I. S h ort-Term Occu p ationa l Expos u re a nd Ri sk Estimates for Hydrogen Cya n nmide Handler Airblnst Sce nario (P REVIOUS ASSESSMENT) Maximum Dermal Do s e MOE I nhalation Do s e MOE C r op o r Applicatio n D er mal Un it (ml!.fkl!/day) Inh a l ation U ni t ( ml?fkl?l'day) LO C: I OOO Target Rate (lb Ex po s ur e (ug/lb Arca Tr ea ted (A) Arca Treated (A) Exposu r e Arca Treated (A) Area Treated (A) nil A) a i) 20 30 40 20 30 40 ( u g/ lb ni) 20 30 40 20 30 40 Mixer /Loader SL/N o G : 220 0.040 0.060 0.080 

# so 33 2S No-R : 0.219 0.00036 1 O.OOOS43 0.000723 

# ssoo 3700 2800 Nectarine 6.6 SL/G : 37.6 0.0068 0.0 1 02 0 . 0 1 37 290 200 ISO PFS R : 0.0438 0.000072 0.000 108 0.000 1 4S 28000 19 000 1 4000 and Pet1e h DL / G : 29. 1 O.OOS3 0.0079 0 . 0 106 380 2SO 190 PFIO R : 0.02 1 9 0.000036 0 . 000054 0 . 000072 

# ssooo 37000 28000 EC : 8.6 0.00157 0.00234 0.00312 1 300 85 0 640 E C: 0 . 083 0.000138 0.000205 0.000274 1 4000 9800 7300 SUNo G: 220 0.080 0. 120 0. 160 2S 1 7 13 No - R : 0.219 0.00072 0.00108 0.00 14S 2800 1900 14 00 Blackberries SL/G: 37.6 0.0 1 37 0.0205 0 . 0274 150 98 73 PFS R : 0.0438 O.OOO I S 0.00022 0.00029 14 000 9300 6900 and 1 3.2 Blueberrie s DL/G : 29. 1 0.0 1 06 0.0 158 0 . 0212 190 130 94 PFIO R : 0.0219 0.00007 0.000 11 O.OOO I S 28000 19000 1 4000 EC : 8.6 0.003 1 2 0.0047 0.0062 640 43 0 320 E C: 0.083 0.00027 0.0004 1 

# o.oooss 7300 4900 3600 Apple s, S L/No G : 220 0.106 0. 1 60 0.2 1 3 19 1 3 9.4 No-R : 0.219 0.00 1 0.001 0.002 2 100 14 00 1000 Grapes. S L/ G : 37.6 0.0 18 2 0.0274 0.0364 110 73 SS PF S R : 0.0438 0.0002 0.0003 0.0004 10000 6900 S200 C herries . 17 . 6 DL/G : 29. 1 0.0 140 0.0212 0.0282 140 94 7 1 PF I OR :0.02 19 0.000 1 0.0001 0.0002 2 1 000 1 4000 1 0000 Kiwi Fruit.

and Fi gs EC : 8 . 6 0.0042 0.0062 0 .0083 480 320 24 0 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 1 9 0.0078 0.0 11 7 0.015S 260 170 1 30 SL/ G : 37.6 0.289 0.433 0.58 6.9 4.6 3.5 PFS R : 0.0438 0.00 1 6 0.0023 0.0031 1300 850 640 N ectarine D UG : 29.1 0.268 0.403 0.54 7.S 

# s 3 . 7 PFIO R : 0.02 1 9 0.00078 0.00 12 0.00 16 2600 1700 1300 and Peach 6 .6 SL/G/C RH: 2 15 0.039 1 0.059 O.Q78 SI 34 26 

### NIA OL /G/C RH: 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 0.000 1 7 0 . 00023 18 000 12000 8900 S L/ No G : 220 0.64 0.96 1.29 3. 1 2.1 1.6 No- R : 0.2 19 0.0 16 0.023 0.03 1 130 8S 64 S L / 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 Blackb e rri es DL/G : 29.1 0.54 0.8 1 1. 07 3.7 2.S 1.9 PFIO R : 0.02 19 0.00 1 6 0.0023 0 . 003 1 1 300 8S O 640 and 1 3.2 Blueberries SUG/C RH : 21 S O.Q78 0. 11 7 O. IS 7 26 1 7 1 3 

### N I A DL/ G /C RH: 141 O.OSI 0.077 0. 102 39 26 20 

### NIA EC: 8.6 0.0053 0.0080 0 . 0 106 380 250 190 E C : 0.0 8 3 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 1 9 0.020800 0.03 1100 0.04 1500 96 6 4 48 Apples. SL/G : 37 . 6 0.77 1.16 1.54 2.6 1. 7 

### 1.3 PFS R : 0.0438 0.00 4150 0.0062 10 0.00 8290 480 320 240 Grape s . DL/G : 29.1 0.72 1. 07 1. 43 2.8 1.9 1.4 PFIO R : 0.02 1 9 0.002080 0.003 11 0 0.004 150 960 640 480 Cherries. 1 7.6 SL/G/C RH: 2 1 S O . I S7 0 . 208 19 9.6 Kiwi Fruit. 0. 104 13 N /A and Fi gs DUG/ CR H: 141 0.068 0. 102 0.137 29 20 15 N IA EC : 8.6 0.0071 0.0 106 0.0 142 280 190 140 EC : 0.083 0.000299 O.OOO .t49 0.000 599 6700 4500 3300 

### Pa ge 4 of8Table 2. Sho r t - Term Occupational Expo s ure and Ri s k E s timates for H ydroge n Cy ana mide H and ler A irb l a s t S cena ri o (REV I S E D NUMBERS ) D e rm a l Do s e MOE Inh a l at ion Do s e MOE C rop or M ax imum D ermal U nit (mg/kg/day) I n h a lation Unit (m1?/k1?/ da v) LO C: IOOO Target Application Expo s ure (ug/l b A r ea Treated (A) Area Treated (A) Ex posure Area Treated (A) Area Treated (A) R ate ( lb ai/A) a i) 2 0 30 40 20 3 0 40 ( u g/ lb ai) 20 30 40 20 30 40 Mixer / Lo a der S I/No G : 220 0 .0 09 0.0 14 0.0 19 530 350 260 No

- R : 0. 219 0 .000361 0.0 0 0 54 3 0 . 00 0723 1 400 0 92 0 0 69 00 Nec tari ne 6 . 6 S L/G : 37.6 0.00 16 0.0024 0 .0 0 32 3 100 2 100 1500 PFS R : 0.0438 0 . 000072 0 . 000 I 08 0.000 145 69000 46000 34000 a nd Peac h DL/G : 29 . 1 0 . 0013 0 . 0019 0 .0 025 4000 27 00 2000 PF I O R : 0 . 02 1 9 0 . 000036 0. 000054 0 . 0000 72 140000 9 2000 69000 EC : 8 . 6 0 . 00 037 0.0 0055 0.0007 4 1 30 0 0 9000 6800 EC : 0. 083 0.0 00 1 38 0.000 2 0 5 0.0 0 02 74 3 6000 24 00 0 1 8 000 S I/No G : 2 20 0.0 19 0.028 0.038 26 0 1 80 1 30 No- R : 0. 219 0.0 0072 0.0 0108 0.0 01 45 28 00 1 90 0 14 00 Blackb erri es S L/G : 37 . 6 0.003 2 0 .0 048 0 .00 6 5 1500 1 000 770 PFS R : 0.0438 0 . 000 15 0. 00022 0 . 00029 14000 9 3 00 6900 and 1 3.2 B lueberrie s DL/G : 29. 1 0 . 0025 0 . 0037 0 . 0050 2000 1 300 1 000 PF I O R: 0 .02 19 0.00 007 0 . 000 11 0 . 000 15 2 8 000 19000 14 000 EC : 8 . 6 0 . 00074 0 . 00 11 0.0 0 15 6800 4500 3400 EC : 0 . 083 0 . 00027 0. 0004 1 0 . 00055 7300 4900 3600 Appl es . SI/N o G : 220 O.D25 0.03 8 0.050 200 1 30 99 No

- R : 0. 2 19 0.00 1 0.00 1 0.002 21 00 14 00 1000 Grapes. S UG : 37.6 0.00 4 3 0.0065 0.0086 1 20 0 770 580 PFS R : 0.0438 0.00 0 2 0.0003 0.0004 10 000 6900 5 200 C herri es . 17.6 DL / G : 29 . 1 0 . 0 0 33 0 .0 050 0 . 0 0 67 1500 1 000 7 5 0 P F IO R : 0.02 19 0 . 000 1 0. 000 1 0 . 0002 2 1 000 1 4 000 1 0000 Kiwi Fruit. and Fig s EC : 8 .6 0.00 10 0 . 00 1 5 0 . 0020 5 100 340 0 2500 EC: 0.083 0.0004 

### 0.0005 0.0007 5 500 3600 2700 A ppli cator S I/No G : 2 20 0.076 0. 114 0. 1 5 66 44 33 No- R : 0. 2 19 0 . 00 78 0.0 1 17 0.0 155 6 4 0 430 320 S UG : 3 7.6 0.06 8 0. 1 0 2 0. 14 73 49 36 PFS R : 0. 04 3 8 0.00 1 6 0.00 2 3 0.003 1 32 00 2 100 1 60 0 Nectarine 6.6 DL/G : 29 . 1 0 . 06 3 0. 095 0 . 1 3 79 53 39 PF10 R : 0.02 19 0.00078 0 . 00 1 2 0.00 1 6 6400 4300 3200 and Peac h SUG/ C RH: 2 15 0.0092 0 . 0 14 0.0 19 540 3 60 2 70 NIA DUG/ CR H : 14 1 0 . 1 2 7 0. 127 0. 1 9 39 39 26 N/A EC : 8.6 0.00063 0.0009 4 0.00 1 3 8 0 00 5300 4000 EC : 0.0 8 3 0.000 11 0.000 1 7 0.00023 45 000 30 00 0 22 000 S L/ N o G : 2 20 0. 15 0. 23 0.30 33 22 1 6 No- R : 0 . 2 1 9 0. 0 1 6 0.023 0.03 1 3 20 2 10 1 60 SU G : 37 . 6 0 . 1 4 0.2 1 0. 2 7 36 2 4 1 8 PFS R : 0. 0 438 0.003 1 0 . 0047 0.0062 1 600 11 00 8 10 Blac kber ri e s DL/G : 29 . 1 0 . 1 3 0. 1 9 0 . 25 39 2 6 20 PF I O R : 0 . 02 19 0.00 1 6 0 . 0023 0 . 00 3 1 3200 2 100 1600 and 1 3. 2 Blueb e rri es S U G/ C RH : 2 15 0.01 9 0.0 28 0 .0 3 7 2 70 1 80 1 30 

### NI A DUG/ C RH : 1 4 1 0 . 012 0.0 1 8 0.0 24 4 1 0 2 8 0 2 10 

### N I A EC : 8 . 6 0.00 13 0 . 00 19 0 . 0 0 25 4000 2700 2000 EC: 0.083 0 . 00023 0 . 00034 0 . 00045 22000 1 5000 11 000 SI/N o G : 220 0 . 20 0 . 30 0.4 1 25 1 6 1 2 No-R: 0.2 19 0.02 08 00 0 . 03 110 0 0.04 1500 240 1 60 1 2 0 App l e s. SL/G : 37 . 6 0 . 1 8 0 . 27 0 .3 6 27 1 8 14 P FS R : 0 . 0438 0 . 004 1 50 0.0062 10 0 . 008290 1 200 8 10 600 Grape s. DUG : 29 . 1 0. 17 0. 25 0.3 4 30 20 1 5 P F IO R : 0 . 02 19 0.00208 0 0.003 1 10 0 . 00 4 1 50 24 00 1600 1 2 00 Che rr ies. 17.6 S L/G/ CR H : 2 1 5 O.D2 5 0.037 0.0 -1 9 200 1 30 1 00 Kiwi Fruit . 

### N I A and Fi gs D UG /C RH : 1 4 1 0 . 0 16 0. 024 0 .032 3 10 2 10 150 

### NI A EC: 8 . 6 0.00 1 7 0 . 0025 0 . 0034 3 0 00 2000 1 500 E C : 0 . 0 8 3 0 . 000299 0 . 000449 0 . 000 5 99 17000 11 000 8 3 00 

### Page 5 o f8Table 3 . Adu lt Spray Drift Expo s ure and Ri s k E s ti ma te s fo r Hydroge n Cyanamide (REV I SED N UMBERS ) C r op/RJltc S pra y T ype/ N om e Appli ca ti o n Rate Es tim ated or At Edge 1 0 Feet 2 S Feet SO feet 7S Feet 1 00 Feet 12S Feet I SO Fe et 200 Feet 2SO Feet 300 Feet Adjusted lTR Gro up C onfi guration (lb aV A ) ( o 2' cm2) Dermal MOE**~""-- ·** **V"t.ul~·** . .... 

# - ., ·--· ··· · f/ig ll B oo m Ve 1 J1 fi 11 e 140 290 480 760 1.100 1.300 1,600 1.900 2.400 3.300 3.800 to Fin e Low Doom Very line 1 0 310 830 1.300 2,100 2 ,700 3.300 3,800 4,400 5.300 6.700 8, 900 Fine Grou ndboom High Boom F i ne to Medium /Co arse 540 l .400 2. 100 3.000 3.800 4.400 5,300 5,300 6.700 8,900 8, 900 Low Doom Fine t o 17 . 6 1.96 Medi um /Co arse 810 2.200 3,300 4 , 400 5,300 6 ,700 8, 900 8,9 00 1 3,000 1 3,000 13.000 StJ(lr se 1 90 320 600 1 , 300 2,400 3.900 5 , 900 8.3 00 15.000 24.000 33,000 Airb las t Norma l 8,900 13,000 2 1.000 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 ,3 00 12 .000 15,000 1 8.000 Vi n evar d 3,300 6.500 12.000 22.000 33.000 44 , 000 53 . 000 67 , 000 89 .000 130,000 130,000



### ·-- ' 

# ...... - '

- Hi g h B oom Ve 1 :1 1

ji

11 e 190 380 630 1 .000 1 , 400 1, 800 2.100 2.500 3.200 4 .400 5 , 100 to Fi11 e Low 13 00 111 Very line 1 0 420 1.100 1, 800 2.700 3.600 4 . 400 5 , 100 5,900 7. 100 8 ,900 1 2.000 Fine Groundboom I ligh Doorn Fi ne 1 0 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 Fi ne to 13.2 1.-17

Medium / Coarse 1 , 100 3,000 -1 , 40 0 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 No nnal 12 , 000 18 .000 27.000 40.000 59.000 71,000 89 ,000 12 0.000 120 .000 18 0.000 180 .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 18 0,000 180.000

- A •**~~.,;** -- - - 

### - - 

## -- 

# -- ·-. 

### - .**~** . --

S

tJar se 500 850 1.600 3.600 6.500 10 .000 16 .000 22 ,000 40.000 65.000 89.000 Airb last Nonna I 6 .6 0.73 24.000 36.000 55.000 79.000 120 .000 1 40 .0 00 180 .000 240.000 240 ,000 360,000 360,000 Den se 1,700 2.500 4.100 7.100 11 .000 15 ,0 00 18.000 22,000 3 1 .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 of8Table 4 . C h ildr en 1<2 Co mbin e d ( Derma l 

### & H a nd -to -Mouth) Sp r ay Drift Expos ur e and Ri s k E st im ates for Hydrogen Cyanami d e (REVI SE D NUMBERS) C r o p / R

a t e S pr ay Type/ Ap pli catio n Es timated or At Edge 10 Feet 25 Feet SO F ee l 7S Feet 100 Feet 1 2S Fe el I SO Feet 200 Fe et 2SO Fee t 300 Feet Gr o up No zzle Rale A dju s te d 

### T fR , Co nfitrnrati on lib al/Al (ul!/cm2) Comb in ed MOE Ann i ""-**r.w.;~** 

## """'----' -Vlwlll' ..... ......... 

### .. -r' .

·- 

### - l. -·· 

### -- Hi

glt Boom Veryji 11 e to 26 52 86 140 190 240 280 340 440 600 690 Fine L

ow Boom Very fine 10 56 150 240 370 480 600 690 800 960 1 .200 1.600 Groundboom Fine Hi gh Boom

Fine to 98 250 370 530 690 800 960 960 1.200 1 ,6 00 1,600 Medium /Coarse 17.6 1.96 Low Boom

Fi ne t o 150 400 600 800 960 1,200 1.600 1,6 00 2.400 2.400 2,400 Me dium /Coarse Spa r se 33 58 1 10 240 440 710 1 , 1 00 1.500 2.700 4 .400 6.000 J\irb last No mial 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 11 0 180 260 320 380 460 580 800 9 1 0 Fine Low Boom Very fine to 75 200 320 490 640 800 9 10 I.I 00 1.300 1 .6 00 2. 1 00 Groundboom Fine High Boom

Fine 10 130 340 4 90 7 10 910 1,1 00 1 ,300 1,3 00 1,600 2. 1 00 2 , 10 0 Medium /Co arse 13 . 2 1.47 Low Boom

Fine to 190 530 800 1, 1 00 1.300 1.600 2.100 2.100 3.200 3.200 3.200 Medium/Coarse Sparse 45 77 1 40 320 580 940 1.400 2.000 3.600 5.800 8.000 J\i rbl ast Nomi al 2, 1 00 3,200 4 .90 0 7. 100 11 ,000 13 ,000 16.000 2 1.000 2 1 .000 32.000 32.000 Dense 1 50 230 370 640 960 1,300 1 ,600 2,000 2.800 3,600 4.300 Vineyard 800 1.600 2 , 900 5,300 8,000 1 1.000 13 ,000 16 ,000 2 1,000 32,000 32 , 000

.. ...... _ .. h . 

### . :**~-- 7·~,--~** **~.~JI.** - . 

## .. ,• .• I Spa r se 89 1 50 290 640 1,200 1,900 2,800 4 , 000 7, 1 00 12,000 16,000 1 \irbla s t Nomial 6.6 0 . 73 4 ,3 00 6.400 9 , 900 1 4.000 2 1 ,0 00 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, 1 00 5.800 11. 000 16 ,000 21.000 26 , 000 32.000 43.000 64 ,000 64.000



### Pa ge 7 of8

## D. 

## Comment # ./:Alternative analysis of interspecies and intraspecies toxicokinetics. Th e regi stra nt i s seeking to reduce the interspecies and intraspecie s unc erta inty factors (UF) based on published metabolism stud ies including a metabolism study in man. The registrant states that " toxicokinetic data are availab le for rats , dogs and humans. As a r esult it is possible to make direct inte rspec ie s comparisons of parameters affecting interspecies uncertainty. While there are both rat and hum an kinetic data available fo ll ow in g dermal dosing, the emphasis of those s tudies wa s bioavailability as opposed to classical toxicokinetics. However the human study does provide useful information on inter-human variabi li ty . " No PBPK m ode l is available and the re g istrant argues that it is not necessary, since there appears to be no primar y 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 wi ll be taken by HED o n this issue.

Pa ge 8 of8