### UNITED ST ATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON , D

. C. 20460

MEMORANDUM

Date: December 10 , 2015 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION

SUBJECT: Diph e o y lamine. Hum a n H ea lth Assess me nt Sco pin g D o cum e nt in S upport of R eg i s trati o n R ev i ew. 

### P C C od es : 038 50 1 D ec i s i on No.: 5093 5 5 

### P e tition No.: NA Ri s k A ss e ss m ent T y pe : N A 

### TXR No

. : NA 

### MRIU No.: NA DP Barcode: D4 292 56 Regi s tration No .: R eg R ev - 22 1 0 -1 Regulatory Action : Re g i s trat ion R ev ie w Sc o p in g D oc um e nt Case No.: 22 1 0 CAS No. : 1 2 2- 3 9

- 4 40 CF R : 1 80 .1 90

FROM : 

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## ss**es so** **~** E li za b e th H o lm a n , Ph ys i ca l

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### )\'-- M a tth ew C r ow ley , Bi o log i s t Ri s k Assess m e nt Bran c h 

### II Hea lth Effec t s Di vis io n (7509P) Offi ce of Pes ticid e Pro g ram s THROUGH : C hri s ti n a Swartz , B ran c h C h ie R i s k A ssess ment Bran c h JI \ 

### <'" ,,,.,. D a n a Voge l , Di vis io n D i rec t o r 

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## ~ H ea lth E ff ect s Di v is ion (75 09P ) O ffice of Pes ti c id e Pro g ra m s TO: R oy Jo hn so n , C h e mi ca l Rev iew M a n age r Ri s k M a n age m e nt a nd Implem e nta t ion Bran c h 

### V ( RMIB V ) P es ti c id e Re -E va lu a ti o n Di v i s io n ( 7 5 0 8 P )

A tt ac h e d i s th e H ea lth Effec t s Di v i s io n 's ( H E D ) hum a n h e alt h ri sk assess m e nt scop in g d oc um ent fo r di p h e n y la min e to s upp or t r eg i s t ra ti o n rev iew.

P age I of 2 1Exec utive Summary The H ea lth Effec t s Di v i s i o n ( H E D ) h as eva lu ate d the database and th e m os t rece nt hum a n h ea lth ri sk assessme n ts for the plant growth regula t or diphenylamine. This evaluatio n was pe r formed in o r der t o determ in e the scope of wo rk necessary to s upport the estab li shed tolerances a nd exist in g reg istrations for diphen y lamine. Th e pr im ary sources of information were recent human h ea lth ri sk assessments ( 0339969 ; 

### T. Goodlow; 13 March 2008 a n d 0314006; K. Bailey; 8 August 2005); a nd th e H E D c h apte r of th e R e reg i st r a tion E li g ibilit y Dec i s io n (RED) do c um ent for diph e n y lamine 

### (T. Mye r s; I March 1 997). H ED has evaluated thi s informati o n for diphenylamine in association w ith updates t o toxicity , exposu re, and usag e databases to determine if sufficient data are ava il ab le and if further updat es a r e n ee ded to s upp ort reg i st ration review. Diphe n y lamine ( DPA ) i s currently re gis tered in the U.S. for post- h arvest use on app les and pears h eld in storage to prevent the a pp earance of skin discoloration known as storage sca ld , based on it s antioxidant propert ies. There are five e nd

- u se products , fo ur of which are liquid co n ce ntrat es rang in g from 10-31 % diphen y lamine and o n e 99% a i so lid / powder product. The liquid conce ntra t e products are applied to apples and pears v i a conveyo r drenc hin g/fl ooding, tru ck drenchi n g. or th e nnofog g ing at a rate of app rox im ate ly 0.26 lb ai/ton or 0.02 lb ai / ga ll on of di lut e so luti on . T h e so lid / powder formu l ation is a p plied to apples in wa rehouse s torage v ia th e m1ofo gg in g a t a rate of 0.026 lb a i / ton. Th e to x i co logy databas e for d iph e n y lam in e i s co mpl ete. Ac ute and s ub c h ro ni c n e urotoxicity , immunoto xic ity , and inh a lation s tudie s are not avai lable fo r diphen y lamin e. However , the Hazard and Sc ie nce Policy Co u nci l ( H AS P OC) determined that th e s tudie s are not required for dipheny la mine , based on a we ight of ev id e n ce approach , cons id e rin g the ava ilabl e h aza rd an d exposure informat ion ( TXR # 0057260). The hematological system, li ver , spleen , a n d kidneys are affected after oral exposu re to diphenylamine. Th ere i s no ev id e nce of incr ease d quanti t a ti ve or qua lit ative s u scept ibilit y of the yo ung in deve lop me nt al an d r epro du c ti on s tu dies; the FQPA factor h as been redu ced t o I X

. The re i s no carc in ogenicity or mutagen ic ity concern after exposure to diph e n ylami n e. However, diphenylnitrosamine , an impurit y of diphenylamine , i s classified as a probable human carcinogen , with a calcu lated cance r potency factor (Q l *)of 4.9 x I 0 ( m g / kg/day)" 1 • Th erefore, cancer ri s ks associated wi th n itrosan1 in e h ave been considered in previou s r i sk assessments and s h o uld co ntinu e to b e cons ide r ed durin g registration review fo r dieta ry, occ u pa ti ona l handl e r and postappli cat ion cancer assess m en ts.

In the previous assessments, endpoin t s and poi nts of departure ( POD s) were selected for chro nic die t a r y a nd occ u pationa l s ho1t - and inter m ed iate -te rm der m a l a n d inh a latio n ex p os ure. No ac ute dietary risk assessmen t was conducted. L ong- term dermal a nd inhalation ri sk ass ess ment s were n o t co ndu c t e d s in ce the se ex p osures a r e not a nti cipated ba sed on the existi n g use s. HED ha s not re v i sed the endpoints, doses, a nd safety facto r s for th e purpo se of thi s scop ing assess m e nt for reg i stra ti o n r ev iew . T h erefo r e , futu r e assess m e nt s s h o uld take into co n s id erati o n

P age 2of2 1the appropriateness of th e ex i s ting endpoint s a nd doses se lec t e d for risk asse ss m e nt , based on sc ienc e polic ies and ri sk assess ment m e th o d o log ies in place a t the tim e of reg i st ration review. The FQP A fa cto r should also be rev i s it ed in li g ht of an y rev i se d e ndpoint s and po in ts of departure. The res idu e c h e mistr y datab ase i s adequate lo s upport re g i s tration r ev iew re quire m e nt s . Adequate m e t abolism (cro p s a nd li vestock ), s torage stabi lity, magnitude of th e residue , and proc ess in g data a re availabl e t o s upport th e reg i s te red use s. A d eq uate meth o d s a r e ava il ab le fo r e nforce m e nt of th e cu rre ntl y establi s he d to l e ra nc es. Th e tolerance ex pre ss io n n ee d s to be upd ated to includ e b o th coverage a nd com pli ance stateme nt s. l n addition, th e re i s a n ex i s tin g diph eny la rnin e t o leran ce fo r pears , but it is unclear w h eth e r a u se o n pears i s st ill s upported by th e r egis tra nt

. T he di e tary ex po s ure datab ase , includin g the p o t e nti al for re s idu es in food, i s adequate t o s upport curre nt reg i s trati on re quire ments. B ased o n th e postharv es t u se pattern , drinkin g w a te r ex posur e to diph e nylamin e i s not anticipated a nd has not b ee n includ e d in pri o r assessments. The las t risk assessment p rovided c hronic di e t a ry expos ure es timat es fo r diphen y lami n e th at are n ot of concern for all pop ulati o n subgro up s. Ri sk est i mates fo r the impurity dipheny lnitrosamine , we re also n o t o f co nce rn . T h e re are n o proposed or c urre nt reg i s trati ons fo r product s co nt a inin g diphen y lam in e that allow res ide nti a l u se . T here fo r e , res id e n tial handl e r a nd post-appli ca ti o n expo s ur e assessments w ill n o t be needed dur in g R egistration Re v iew. U nli ke ae rial o r a irbl as t appl ications to agric ultur a l fi eld crops. post-harvest dre n c h trea tm e nt is n o t a use that is typ i ca lly cons id e red for risk assess men t of s pray drift a nd volati li zation. In co rporati o n o f th ese assessments durin g Re g i strati o n Rev ie w shou ld b e determin e d in the co n text of thi s us e patt e rn. Th ro u g h u se o f s urroga te datasets and th e c h e mical- s p ec ifi c data s ubmitt e d by th e re g is trant s , th e occu p at io n a l expos ur e d atabase i s a dequ a t e t o s upport reg i s tr a ti o n re v iew o f diph e n y lamin e. The most rece nt occupatio n al assess m e nt s are n ot r e fl ective o f c urre nt poli cies and data , so th ese assess m e nt s s hould be upd a t ed. For assess m e nt of exposure for dre nch operators , th e r egistration r ev iew ri sk assessment sho uld: a) r eco n s id er th e 2 005 assess m ent c haracterizati o n of drench o p era tor exposure as n eg ligible ; b) rev iew and uti li ze th e c h e mic a l- spec ifi c use a nd ex p os ur e information pro v id e d in the regi s trant s ubmis s ion s (M RJDs 4421 250 1 a nd 4453400 I ) ; and c) cons id er th e u se of o p e n- cab airblast a ppli cato r exposure as a s urroga te d ataset. For exposures t o wo rke r s who h and le th e treated co mm o diti es (e.g., sorte r s and packers) , the " P os tHarv est Sta nd a rd Operat in g Proced ure (SO P ) " (March 20 1 2) a nd th e refere n ced lit e ra ture s tudy ( Gagoulia , e t a l , 2 01 2) s h o uld b e used. Fo r a ll occu pati o n a l ex p os ure asses s m e nt s, a can cer ri sk assess m e nt for the impurity nitrosa min e s h o uld be co ndu cted. T h e s tru cture and chemical n ames , as we ll as th e chemical and physical pr ope rti es fo r dipheny la min e ca n b e fo u nd in the tables in A tta c hment I

.

Page 3 of21

### Haza rd ld en tifica ti o nffox i co l ogy The to x ic o l ogy database for d ipheny lamine i s comp let e. The H azard and Sc ience Polic y Council ( H ASPOC) based on a weig ht of ev ide nc e app roach , consideri ng the avai l able hazard a nd exposure information , concluded that th e immunotoxicity, n e ur o toxicity batte ry (acute and s ubchronic), a nd inhalation studi es are n ot re quired ( TXR #0057260). The hema to logical system , liver , sp l een , a n d kid n eys are affected afte r oral ex po s ure to diphen y lamine. The hem ato logical changes observed in cluded decreases in red b lood cell (RBC ), he m og lobin , and h e mat oc rit. Additionally , increa ses were seen in Mean Corpusc ul ar Volume (MCV), Mean Cell Hematocrit (MC H). platelets , and reticuloc yte s. D i sco loration of the spleen and li ve r was a l so observe d , along w ith increased li ver and sp leen weights, ex tram ed ull ary hem a t opo iesis, h e mo s id eros i s (l ive r ), and co n gestio n (spleen). In the kidney , discoloration. brown pigment deposits , in c r eased k idn ey weig ht s , and dark urin e we re observed

. Dark red foci in the stomach wer e seen in both sexes after dem1al exposure. No evidence of increa sed quantitative or qualitative susceptib il ity of the young to diphenylami n e was obse rved in developm e ntal/reproduction s tudi es. The FQPA fac tor h as been reduced to l X for diph e n y l a min e ba se d o n th e fo ll owing: 1 ) th e to x ico logy database i s adeq u a t e to assess preand post-nata l toxicity ; 2) th e re was n o evidence of increase d s uscept i bility fo ll owing 

### in 11te ro exposure to rat and rabbit s and pre/ post natal exposure to rats; 3) there was n o co n cern for potenti a l developmenta l n eu ro t ox icity , and a developmental n e urotoxicit y s tud y is not requi red: a n d 4) ther e are no res idual uncertainties identified 

### in the exposu re databases. The dietary (food and drinkin g water) expos ure assessment wi ll not und eres tim a t e potential exposures for in fa nt s and chi ldren , a nd non -die tar y expos ure is n o t ex pected b ased o n th e use patte rn . Diphen y lam ine i s clas si fied as ' ·not likel y t o be carc inogenic to humans ," and there i s no mutag e ni cily concern. H owever, diphenylnitrosam in e! an impurity of di phenylamine! i s class ifi e d as a probab le human carc inoge n , ba se d on bladder tu mors in ra ts and reticul um ce ll sarco m as in mic e, as we ll as a st ru ctura l re l a ti ons hip to ca r cinogen i c nitrosamines. The ca n cer pot e n cy factor 

### for diphen y lnitrosam in e i s 

### 4.9 

### x I 0 ( m g/kg/day)' 1 • Ca nc e r ri sks associate d w ith nitrosamine have been considered in prev i ous risk assessments and s h o uld continue to be co n s id e red durin g registration review for dietary , occupat ional hand ler and postapp li cation cancer assessme n ts. In acute leth a li ty studi es , dipheny lamine h as low toxicit y ( T ox ic it y Category Ill or I V) via th e ora l and derma l routes. 

### It i s s li g htl y i rrit a tin g t o th e s kin (Ca t ego ry 

### 111 ) a n d se verely irritat in g to the eye (Catego ry I ). For acute inhalation , a data wa i ve r was granted for the tec hni cal material due to i ss ue s w i th producing 

### a s mall particle s ize . H oweve r , l ow toxicity (Ca tegory Ill ) was observed in an acute inhalation s tud y w ith the formulation (EC -283 ; 31.0%). Diphen ylamine i s not a sk in se nsitizer. Me t abo li s m d a t a in th e rat ind icate th at abso rption 

### of diph e n y lam in e is rapid a nd co m plete w ith in 24- ho urs. Ur in e was the major ro ute of exc retion a t both low and high doses, with between 68 and 81 % of radioactivity bei n g re cove red for bo th sexes at s in gle or repea ted do ses. No significant t i ssue resid u e le ve ls were fou nd post exposure.

Page 4 of2 1Endpoints and points of departure ( PO O s) we re se lected fo r chron ic dietary and occu p ational short- a nd int ermediate -t e rm de rm al and inh a l at ion expos ure . Lon g-te rm derma l and inh alation expos ure is n ot a nt ic ipate d based on th e ex i s tin g use s . No acute diet a ry r i sk a ssess m e nt ha s b ee n co ndu c ted fo r diph e n y lamin e. The need fo r an acute d ie t ary assessme nt s hould be re-eva lu a t ed duri n g registration review si n ce an appropriate e ndp o in t/P O D cou ld possibly be se lected from the 

### in vivo m ouse mi c ronucleus s tud y. H oweve r , it sho uld be noted that the effec t s observed in th e study after ac ut e expo s ure were seen a t th e limit d ose. For chro ni c dietary ri s k assessment , th e end p o int se lec t e d was b ase d o n a lt e r a ti o n s in clini ca l c hemistr y a n d kid n ey effec ts at th e lowes t observed a d ve r se effec t s level of 50 mg/kg/ day in a c hr on i c dog st ud y , wi th a n o o b served ad v er s e effects leve l of 

### l 0 m g/ k g/day. For dermal exposu re , a 

### 2 1 day de rmal toxicity s tud y with 

### a NOA EL of 500 m g/kg/day was se lected , based on s to m ac h effec ts o b se r ve d at th e LOAEL 1 000 m g/ kg/ d ay . For inhalation ex posure , a rat dev e l o pm e ntal s tud y was u sed wit h a NOAEL of 50 m g/kg/day , based on s pl ee n effec t s obse rved at the LOAEL of I 00 mg/k g/day. (A ttachm e nt 

### 2 )

. While th e s e en dp o int s and d oses are consi dered ap prop riat e , during regis tra ti o n rev iew th ey s h ou l d be r eexa min e d in light of cune nt 

### HED g uid a n ce , a nd in th e eve nt n ew data b eco m e ava il ab l e . 

### Conclu s ions.for Hazard lde nt[fi c ation / Toxicology Th e toxicology database fo r d iph enylamine i s complete , a nd n o n ew data are n ee d e d. H owever, durin g reg i s trati o n rev i ew th e e ndpoint s , p o int s of d e parture and safety factor s u sed for ri s k assessme nt purposes s h o uld be reexam in ed based on c urren t HED p o li cy , as we ll as a n y n ew data received. Furthermore , the n eed for a n acute dietary assessmen t sho uld be re-eva lu ated during registrat i o n r ev iew s in ce an appropriate e ndp o in t/POD co uld be se lec ted from th e 

### in vivo mouse micronucl e u s s tudy. 

### Diet a r y Ex p os ure Tolerances for diphe n ylamine a r e li s ted in 

### 40CFR§180. 1 90 and range from 

### 0.0 I to 

### 30 ppm. Th e res idue chemist ry databa se i s adequate to suppo rt r eg istration r ev iew. Adequate metaboli s m (cro p s and li vestock) , storage s t ab ilit y , magnitude of th e residue, and processing data are availab le to support the regi s tered uses. Adequate methods are avai lab le for e n fo r ce m e nt of th e cu rre ntl y establi s hed tolerances. No residue chemistry data deficiencies were c it ed in th e prev iou s risk assess m ent. 

### H E D h as pr ev io u s ly d e termin e d tha t th e res idue of concern in plant s and li vestoc k co mmoditi es for both t o le r a n ce e nforc e m e nt and ri sk assess m e nt purp oses i s parent diphenylamine. No acu te endpoint wa5 pr ev i o u s ly id e ntifi e d in e arlier ri s k a ssess m e nt s; therefor e, no acute di e ta ry ex po s ure assess ment was p e rform ed. The chron ic dietar y exposure estimates in th e previous ri sk assessme nt ass um e I 00% percent crop treated a nd to lerance- leve l residues fo r a ll regi s tered commodities 

### (03 1 9225 , D. D o tso n , 8/ 8/ 2005). Ba sed o n the pos t- harvest u se p atte rn assoc ia ted w ith d iph e n ylamin e, drinking wa te r exposure i s not a nti cipa te d and no drinkin g wa t e r est im a tes h ave bee n provid ed , nor h ave a n y been in c lud e d in pre vi o u s r i s k as sess m e nts

. Th e chro ni c d ieta ry ri sk estimates we re n o t of co n ce rn 

### for th e ge n era l 

### U.S. population and all population subgroups. A ll subgroups u se le s s than or equa l to 90 % of the c hroni c popu lation

Page 5 of2 Iadjusted dose (c PAD ). A die t ary risk assess m ent was a l so conducted for diphenylnitrosamine , to determine th e cancer ri s k from ex po s ure to the impurity ; th e risk est im ates were n ot of conce rn. Since the l ast dietary assess m e nt , I-JED updated it s d ie tary m o d e l t o in corporate m ore recent cons umpti o n data fr o m the National H ea lth and Nutr iti on Exami nati on Survey (N H ANES). A n ew d ie t a ry assessment m ay b e n eede d i f o ne o r more of the fo ll owi n g occur: n ew data a re identified w hi c h imp ac t di e ta ry exposure est im a t es; n e w t ox ico log i ca l po in ts of d epa rture a re identified , includin g revision s to the FQPA SF; OPP dietary ex posure p o li cies and procedures are revised. Conclusions for DielaJJ' Exposure The dietary expos ur e da t abase i s a d equate t o support th e existi n g registrati o n s and tolerance s. No new res idue c h e mi s try data are re quir ed. A new die t ary assess m e nt m ay be n eede d if one o r more of the following occur : new data are identifi ed which impact dietary ex p osure estim a t es ; new toxicological p oi n ts of departure are identified , in cluding rev ision s to the FQPA SF or the id e ntifi ca ti o n of a n acu t e dietary en dpoi nt ; OPP dietary ex p os ure p o li c ies a nd procedures are rev i sed

. Drinking water r esidues were n ot previou s l y included in th e die t a r y expos ure assess ment based on the postharves t use pa tt e rn . 

### It i s not anti c i pated th at this dri n king wa t er res idu e s ituation w ill c h ange dur in g re g i stra tio n rev iew. 1-I E D rece n t l y up d ated it s d ietary m o del to incorporate more r ece nt co n sumption data fr om th e Nat iona l Health a nd N utriti o n Exa minati o n Survey (NHANES). Thi s n ew vers io n of the model w ill be used du rin g reg i st ration review if a new di etary assessment i s needed. 

### Re s id e nti a l Expos ure There are no proposed o r cu rr e nt registrations for products co ntaining diphenylamine that allow r es identi a l use. Th e refo re , resident i al h and le r a nd post-app li ca tion exposure asses s ments w ill not be needed durin g Registration R eview. Unl ike ae ri a l o r a irbla st app li cations t o agr icu ltu ra l field c ro p s, post-harvest drench treatment is n ot a use that is typ ica ll y co n sidered fo r risk assess m e nt o f s pra y d ri ft a nd vo l atili za ti o n . ln corp o ra ti on of these assessments du rin g Registration Review s h o uld be determi n e d in th e co ntext of this u se pattern. 

### Agg re ga t e Risk Ass ess m e nt In acco rd a n ce wit h th e F QP A , HED mu st co n s ide r and aggregate (add) pestic id e ex posure s a nd ri sks from three m ajor so urces: food, drinking wa t er, and re side ntial exposu res. In an aggregate assessment , exposu res from re levant so urces are added t ogethe r a nd compared to q u antit at i ve es tim ates of ha zard (e.g., a NOAEL o r P A D), o r th e ri sks th emse l ves can be aggrega t e d. Wh e n agg regat in g exp osures and ri sks from var ious sources , H ED co n s i de r s both the route a nd d u rat io n of expos ur e. As diphenylamine h as no residential uses , and no exposure is expected for drinking water sou rces, agg regate exposu r e and ri sk i s equiva le nt to the dieta r y (food) expo s ure and ri sk. Risk es tim ates for the US population a n d all popul at i o n subgro up s are be low H ED ' s leve l of conce rn. 

### Occupational Ex p os ure

P age6of21Diphen y lamine i s reg i s tered for post -h ar vest us e o n apples and pears . There are fi ve end-use products , four of which are liquid concentrates rang ing from 10-31 

### % diphenylamine and one 99% ai so lid / powder product. The liquid conce ntrat e produ c t s are applied to appl es and pear s v ia conv eyo r drenchin g/floodin g, truck dren c hing , o r thermo fogging at a rate of approximate ly 0.26 l b ai/ton or 0.02 lb ai/gallon of dilute so lution. The so lid / powd e r formulat ion is appli e d to app le s in warehous e s torage via thermo fogg ing at a rate of 0.026 lb ai / to n. Each u se is de sc ribed in more d e tail below.

• T ru ck drenching: Sim il ar to an auto mated ca r washing process, a truck loaded wlth 20- 96 bins, each co ntainin g approx im ate ly 900 lb s of apples or p ear s , drive s into the drenching area , s uch that the truck cab i s beyond/outside the treatment area . The driver s ta ys in th e ca b while th e o perato r turns on the hi g h-fl ow flood nozzles and then s lowly drives throu g h as the apples or p ea rs are dr e nched. The nozzle s are turned off until the n ext truck pulls up . • Co n veyo r drenching/flooding: Direct spray of the apple or pe a r bins in a s tationary po s iti o n or as they m ove past the s pray no zz les on a cha in or track driven conveyor b e lt. • T h e rmo fogging: Appl e bins are placed in a s torage room / chan1ber (from 500 to 6 , 000 bins per roo m ). The roo m is cl osed and a ri gid pip e and no zz le ex t ending from a th e m1ofoggin g machine e nters the s torage room through an access hatch or portho le. Dipheny lamine i s load ed into th e maclline , flash heated , and a fog i s app li e d through th e ma c hine into the enclosed room. Twe lve h o ur s prior t o and during treatm e nt , room coo lin g systems. and humidifier s are turned off. Circulation fan s are turned off immediatel y prior to and during treatment. Once th e fogger i s opera tional , a n individual m onitors th e machin e to ensu re it i s functi o ning prop e rl y. The fogg ing process tak es about 1 h our to treat 1 25 tons of fruit. Based on the r egiste red use patterns , s h o rt- / interrn ediate- ter m dermal a nd inhalati o n expos ures during the ap plicati o n proce ss ( i .e . , mi xi n g/ loa din g , applying) are anticipated. ln additio n , there i s al so p o te ntial s hort-/ intermediate -t erm post-appli c ation exposure for peo ple handling trea t e d app les and pears. Long-term occupationa l expos ures a re not a nticipat e d

. 

### Occupa lional Handl e rs Afte r the diphenylarnine r eregis lr at ion e li g i bi li ty decision (RED) in 1 998, which a sses sed occ upati o n a l handler expos ur es fo r po s t-h a rvest truck drenching treatm e nt of apples only , an occ upati ona l handl e r ex po s ure assess ment was conducted in 2005 to address 

### FIFRA Section 3 n ew use reg i s tration s for th e nn ofogging and th e add ition of u se on pears . In both assess m e nt s s hort-/ in te rm ediate-term dermal a nd inh a la ti on handl e r non- cancer ri sks were quantified and no ri s k s of conce rn were identified. A lthou g h a cancer ri s k assess ment h as not been previou s ly co nduct ed fo r diphen y lamine due to it s c la ss ification as ' ·n o t likely to be ca rcin ogenic " to humans , a n occ up at io n a l h and le r cancer ri s k asse ss ment for the impurity diphenyl nitro sami n e was conducted in th e 1998 R ED. No cancer ri sk estimates of concern were id en tifi e d. All assessments con s idered the label- required work att ire and persona l protectiv e e quipm e nt ( PP E) of lo n g pant s, lo n g s le eve shirt, s h oes/ socks, and chemical-resistant g lo ves. Full-fa ce res pirator s a re required fo r certain acti v itie s related to the thermofoggin g ope ration.

Page 7of 2 1The previ o u s ri sk a ss e ss m e nt s do not re fl ec t the m os t up-t o -d ate exposure data or input s fo r occ upati o n a l handl e r sce nari os. Durin g R eg i s trati o n R ev iew , updated n o n- ca n ce r a nd canc e r occ upational handl e r de rmal a nd inh a l at i o n risk assessme nt s s h o uld b e co nduct e d to r e fl ec t c urre nt p o li cies and data set s. The follow in g sce n a rio s s h o uld b e asse sse d:

• Mi x in g/loadin g liquid co n ce ntrates fo r conveyo r d re n c hin g/fl ood in g , truck drenchin g, a nd th e rrn ofogg in g. • Mi x in g/ loading so lid / p ow der s fo r thermofo gg in g a ppli ca tion. • Operator / App li cator ex p os ure during tru ck drenchin g and/or co n veyor dre n c hin g (a lth o ugh n o t d ir ectly in vo l ved in th e ap pli cati o n pro cess, work e r s can expe ri e nce d e nnal a nd inhal a ti o n exposu res as b ys t a nde r s)

. Assess m e nt o f th e mixin g/load in g sce n ar io s s h o uld be fairl y s tra ig ht fo rward and d o ne usin g the m os t c urre nt s urrogate data se t s. H owever , drench o p e r ato r ex po s ure i s a scen a ri o for w hich ther e i s n o c urr e nt s tandard m e th o dol ogy . [n th e 1 99 8 RED , s in ce n o ex po s ure dat a we re av ailabl e , thj s scenar i o was assesse d u s in g ex po s ure data for ae rial " fl agge r s" a s a s urro ga te dataset. T h e 1 998 RED assessme nt a l so includ e d a pplicati o n in fo rmati o n from th e reg i s tran t ri s k assess m ent s ubmi ss io n "Es timation of De rmal and Inhalati o n Exposure at A ppl e Drenchin g S it es fo r Diph e n y lamin e " ( MRlD 442 1 25 0 I ). While that regi s trant s ubmi ss io n also utili ze d surro g ate d a ta to assess dre n c h o perator ri s k s, it i s th e scenario - s p ec ific u se inf or m atio n th a t s h o uld b e rev iewe d during re g i s tration rev iew fo r assess m e nt o f th e dre n c h operat o r sc enari o. S imil a rl y, u se information provided b y the " DPA Task F o r ce" durin g a m ee tin g with E PA o n Augu s t 3, 20 1 5 ( FOCUS M ee tin g) m ay a l so be u se ful. An o th e r re g i s tra nt s ubmi ss io n , p e rh ap s more d irec tl y relat ed t o dre n ch operator exp os ure , "Mo nit o ring of D epos iti o n of Diph e n y lamine R esi du es Assoc iat ed with Pos tharvest Apple Trea tm ent" ( MRlD 445 3 400l) , thro u g h use of patc h es attac h ed to s tationary s t a nds , mi g ht pro vide additional c haract e ri z ation of the expo s ure potenti a l d urin g dr e n c h ope ra ti o n. T hi s s ubmissi o n has n o t bee n rev i e w e d b y H E D , but d oes a ppear t o h ave d etecte d re s idue s th at co uld be u se d to represe nt dren c h o perator ex po s ure. It s h o uld b e r ev iewed and co n s id e re d durin g reg i s tra ti o n r ev iew. Th e reg i s tration rev iew assess ment ma y al so co n si d e r e xposur e data from o p en- cab a irbl as t app li ca ti o n s as a reaso nabl e, if not co n serva tiv e , s urrogat e dataset t o rep resent th e dr ench o p e rator sce n a ri o. F in al ly , th e 200 5 assess m e nt did n o t include a dre nch opera to r ex p os ure scenario as th e truck dri ve r was a ss um e d t o vacate th e truck ca b and o p e ration of the drenchin g don e re motely

. This characterization s h o uld a l so b e co n s idered in th e co nt ex t o f th e q uanti ta ti ve 1 998 RED assess m e nt and relat ed regis trant data s ubmi ss ions reg arding dr e n ch o p era to r expos ure. Th e R eg i s tration R ev i e w proce ss s h o uld a l s o be s ure to re co nc il e bandi e r work att ire and PP E w ith co rrespo nd i n g diphen y la min e e nd-u se ac ut e t ox icit y -ba sed requ ire m ents and pot e nti a l re quire m ents bas e d o n the re g i s tration re v ie w oc c upational h a ndl er ri s k assess m e nt. 

### Occupational Post-app lica tion Ex p osu re In co mp a ri so n t o s ta nd a rd foliar a ppli ca ti o n o f agric ultural c ro ps , wher e wo rk ers e xperien ce p os t-appli cation expos ur e w hil e p erfo rmin g hand labor ta sks in th e fi e ld , ex po s ure followin g diphen y la min e po s t

- h arvest treatme nts ma y occ ur as a re s ult o f handlin g treated appl es , p e rh aps

P age 8 of2 1durin g th e p ac king proc ess . Th e 

### 1998 R E D did not includ e a quant itative po s t-application ex p os ur e assess ment , s ta tin g th a t " handlin g o f appl es and appl e bin s are d o n e b y fo rklift ma c h i n e ry th e re b y minimi z in g , i f n o t e limin a tin g, po ss ibl e wo rk e r e x po s ure . " H oweve r , in 2005 , a qua n tit a ti ve s h o rt- / int e nn e dia te -te rm p os t- a ppli c ati o n d e nn a l ex p os ure assess ment was co ndu c t ed based o n tra n sfe r coe ffi c ie nt s fo r tree crop harves tin g , ass umin g th a t wo rk e r s co uld e x p e ri e n ce ex p os ure via direc t ha ndlin g of trea ted po s t-harves t a ppl es and p ea r s. No derm a l risk s of co n ce rn were id e ntifi e d

. N eith e r th e 

### 199 8 RED n o r th e 2 005 assess m e nt quantitati ve l y a ddresse d p os t- a ppli ca tion inh a la ti o n expos ur e , c itin g bo th d iph e n y la min e ' s va p o r press ure a nd the lik e lih o od o f a irb o rn e aeroso l s t o se ttl e o ut b y th e tim e w o rk e r s wo uld contact trea ted fruit. F o r th e rm ofogg i ng in parti c ul a r , as d esc ribed in th e 20 0 5 a ssess m e nt , in which a) n o p e r s onn e l are in s id e the stora ge room s durin g a pplication , b) th e re i s typi c a ll y a multi-day p e ri o d before which worker s would handl e th e treate d fruit , a nd c) th e require m e nt fo r a full- face res pirator durin g tre atm e nt o r d e p e ndin g o n th e ex t e nt of ac ti ve ve ntil a ti o n , 9 to 2 4 h o urs fo ll ow in g a ppli ca tio n , p os ta ppli ca ti o n inh a lati o n ex p os ure i s unlik e ly. S ince the se assess m ent s we r e co mpleted , H E D ha s de v el o p ed a methodolo gy th a t m o re accurat e l y r e prese nt s handlin g po s t

- harve s t trea ted commod iti es . Based on a s tud y monitorin g d e rmal a n d inh a la ti o n fo r wo rke r s h a ndlin g ( i .e ., so rtin g , c ullin g , and pa c kin g) p os t-harves t tre a t e d pear s an d c itru s fr uit , th e .. P os t-Har ves t Co mm o dit y T rea tm e nt " S t a nd a rd O p e rat i n g P rocedur e (Ma rc h 20 1 2) s h o uld b e utili ze d to asses s po s t -ap pli ca ti o n ex p os ures to p os t-harves t diph e n y la min e -tr e at e d ap pl es and p ea r s . As th e b as i s fo r th e m e th o d o logy i s a s tud y that monit o red wo rke r s handlin g th e comm o diti es 

### imm ediate l y a ft e r th ey w e re tre ate d , it mi g ht n o t b e an e x a c t m a tc h for handlin g dipheny lamin e- trea te d comm o diti es , particularl y with res pect to inhal a ti o n ex p os ur e. A publi s h e d literatur e s tud y, " Determin a ti o n o f diph e n y la min e in co nt a minat ed a ir of agri c ultur a l buildin gs u s in g ac ti ve samplin g o n s olid so rb e nt s" ( G ago uli a, e t a l. , 20 12, I ntl 

### J En v A n a l C h e m , V ol 9 2, I ss u e 1 3) , may pr ov id e be tte r c h arac t e ri za ti o n o f p os ta ppli ca ti o n inh a la ti o n e x pos ure th a n u se of th e P os t-Harves t SO P

. There fore, durin g R eg i s trati o n R e view th e P os t-Harve s t SOP and th e ref e re n ce d li t e rature s tud y s h o uld b e co n s id e red t o assess n o n- c an ce r a nd canc e r ri s k s fo r p os t-applicati o n ex po s ure s . S p ec ifi ca ll y th e assess m e nt s h o uld a dd ress d e rm a l a nd inh a la ti o n ex p os ures fo ll ow in g tru ck and co n veyor -ty p e dre nchin g a n d o nl y d e rm a l expos ures fo ll ow in g th e rm ofogg in g trea tment s. Inhal a ti o n ex p os ure s foll ow in g th e rmo fogg in g tre a t m ent s are unlik e ly, fo r th e r eas on s outlin e d in the 2 00 5 assess ment. T o u se th e S OP , th e ex po s ure asse sso r w ill n ee d app li ca tion rate inform a ti o n in term s o f a)% diphenylamin e in th e treatm e nt s o l ution , b) lb s diph e n y lamin e p e r lb c omm o dity , a nd c ) lb diph e n y lamine p e r ga ll o n o f tr ea tm e nt so luti o n , all o f w hi c h can b e de t e m1in ed fro m th e p ro du c t la b e l s . Th e R eg i s tra ti o n Rev iew p rocess s h o uld a l so be s ure to re co n c il e w heth e r res tri c te d e ntry interva l s ( R E l s) bas ed o n ac ti ve ingredient a c ute to x icity-b a s e d r e quire m e nt s a re a pplicabl e fo r diph e n y la min e . 

### Conclu s ions.f or Occupational Exposu re As sessm en t

Page 9 of 2 1Through u se of s urroga te da t asets and th e chemi ca l- s p ec i fic data submitted b y th e reg i strant s. the occ upa t io n a l exposu r e database i s adequate t o s up po rt reg i s trati on rev iew of diphenylamine. T h e m os t rec e nt occ up a tional assessments are n o t r e n ec ti ve of current p o li c ies and d a ta , so these assess m e nt s s h ou ld be upd ate d. For assessment of expos ure for dr e n c h o p era to r s, th e registrat io n rev iew ri sk assess m e nt s hould: a) reco n s i der the 2005 assess m e nt c h arac te ri za ti o n o f drench opera to r expos ure as n eg li g ibl e; b) rev iew a nd co n s ider th e c he mi cal-spec ifi c inform a t ion provided in the regi s tra nt submissi o n s des c ribed above ( MRIDs 442 1250 I a nd 4453400 1 ), and c ) consider the use of open-cab airblas t applicator expos ure as surroga te d ataset. Fo r exposures to worke r s who handl e the treated co mm odities (e.g., so rters and packe r s) th e " P os t-H arvest 

## so p ·•(Marc h 20 1 2) and the r efere n ced lit eratu re study shou ld be u sed

. For a ll occupation al expos ure assessment s a ca n ce r ri sk assess m en t for th e i mpurity nitrosamine s hould be conducted. Public H ea lth a nd Pe s ticide E pid e miolo gy Data For the eva lu a ti o n of p es ticide in c id e nt data for diphenylam ine, both the OPP In c id ent D a t a Syste m (ID S) and the Cente r s for Disease Cont r ol and Prevention/National In s titute fo r Occupatio n al Safe ty and Health (CD C/N IO SH) Se ntin el Event Notification Sys tem for Occ up ati ona l Ri sk-Pesticides (SENS OR) da t abases we re consu lt ed. Th e purpose of th e database searc h was to identify po t ent ia l patterns in the freque n cy a nd seve rit y of th e health effec t s attributed t o diphenylamine expos ure. Diph eny la min e is n o t includ e d in th e A H S , and ther efo re the s tud y do es not p rovide u se fu l information. The re we re no in c id e nt s i n vo lv in g d iph enylaminc r epo rte d to eith er Main o r Aggregate ID S , from J a nu a ry 1 , 2 010 to May 27, 2 015. A review of SENSO R-P est ic ides 1 998

- 20 11 id e ntifi es n o in c id e nt s in vo l v in g diph e n y la min e. There are n o in ciden t cases reponed fo r diph e n y lamine in ID S a nd SENSOR- P es ti ci d es. T h erefore , there does not appea r to be a concern a t thi s time that wou ld warrant further in vest igation. The Agency wi ll continu e to m o nit or th e in cident in fo m 1at ion and i f a concern i s tri ggered, add iti o n a l ana lys is w ill be includ ed in th e risk assessment. To le r a n ce Assess m e nt a nd Int e rnational Harmonization As s tat e d above , fo r diphenylamine are li sted in 40CFR§180.190 a n d r a n ge fr o m 0

. 0 I to 30 p pm . HED has previo u s ly determined that the r esid u e of conce rn in plants a n d li ves t ock commod iti es fo r bot h tol era nce enforcement and ri sk assess m ent purpo ses is pare n t diphenylarn in e. Acceptable a nal yt ica l method s are ava il able to e nfo rce to lerances for residues o f diphenylamine in p lant a nd l i vestock com m od iti es. Acco rdin g to H E D 's 

### Int e rim Guidance on Tole rance Express ions (S. Kn iz n e r ; 27 May 2009) , the to le ranc e expression for dipheny lamine c it ed in 40 CF R § 180.19 0 s h o uld be r ev i sed to sta t e: T o lera n ces a r e estab li s h ed fo r residues of diphenylamine , in c lu ding it s metabolites a nd degradates, in o r o n the commodi ti es li s t ed in th e table be low. Comp li a n ce wi th the to l era nce lev e l s spec ified bel ow is to be dete r mi n ed b y measuring only diphen y lamin e, in or on th e commo di ty

.

P age 1 0 of2 1f

### n addition, durin g th e r eg i st rati o n re v iew ri sk assess m e nt , 

### HED will rev iew th e language for th e ex i s tin g to l era nces a nd make reco mmendati o ns to update the to le rances to be co ns is te nt w ith current pra c tic es. SpecificalJy , HED will recommend that th e fo ll owing be removed in th e 40 C FR § 

### 180.190: All references to preharvest and po s tharvest use, and impregnated wrap s n ee d to be removed fr o m th e appl e and pear tol e ranc e co mmodity li st in gs. The prehar ves t a nd impreg nat ed wraps ref e renc es are in the appl e tolerance co mm o dit y li s ting. and the pos tharves t use r efe re nce is in both the appl e and pear to l e rance co mm od ity li st in gs. It 

### is noted that on ly pos th arves t u ses of d iphenylam in e are c un- ently reg istered. wi th the preharvest a nd impregnate d wraps refe r ences being based o n uses that ha ve been ca nce led (USEPA , Final 

### RED, April 1998 ). Si mil arl y , all references to pre ha r ves t uses a nd impregnated wrap u ses nee d to be r e mo ve d from the c urre ntly registered lab e l s. The re s idue definition for both Co dex and Canada is parent diph enylam in e , and is th erefore id e nti cal to th a t of th e U.S. Th e int ernational res idu e limit s tatu s s hee t ca n be found in Att ach ment 

### 4. Co d ex 

### MR Ls have been es t a bli s hed fo r th e postharvest u se of diphenylamine on both apples and pears. The apple MRL is 1 0 ppm and th e pe ar MRL is 5 ppm , whi c h i s identic a l to th e establi shed U.S. tolerances. Can ada has a n apple MRL o f 5 ppm fo r postharvest treatm ent. T h e r esi du e data used to es tab li s h th e U.S. t o le r a nce a r e based on th e curre nt U.S. use pattern , and indicate that th e I 0 

### ppm tolerance is appropriate. As a result , the U.S

. will con tinue to ha rm o nize with Codex a t I 

### 0 ppm , and will n o t reduce the cun-ent tol e ranc e to th e Canadian MRL o f 

### 5 ppm . E n v ir o nm e ntal Justice 

### Poten ti a l areas o f environmental justice c on ce rn s, to th e extent possible , were co ns id e red in the hum a n healt h ri sk assess me nt , in accordance with U.S. Executi ve O rd e r 1 2898 , · ' Federal Actio ns to A ddre ss Environmental Ju stice in Minority Po pulati o ns and Low-Income Po pulations , " http: // www . eh .d oc. 1wv / ne pa/tools/ guidance/ Yolume 1 / 2

- 6

- EO 12898e nv j

ustice.pdf). As a part of eve r y pes ti c ide ri sk assess ment, OPP co nsiders a lar ge va ri e ty of co nsumer s ub gro ups according t o well-estab lish ed proc e dure s. In line with OPP policy , HED estimates ri sks to population s ub g ro up s from pe s ticid e ex pos ur es that ar e ba se d on patterns of that s ubgroup's food and wa ter consumption , a nd activities in 

### and ar o und th e ho m e that in vo lve pes ti cide use in a reside nti a l sett in g. Ext en s i ve data o n fo o d consumption pa tte rn s are compiled by the US DA under th e Con tinuing Survey of Food f

### ntak es b y 

### Indi v idual s (CS FIT) and are used in pesticide risk assessments for all regi s tered food uses of a pe s ticid e . Th ese d a ta are anal yzed a

nd cat ego rized by s ub g r o up s ba sed on age, seaso n of th e year, e thni c g r o up , and reg i on of th e co untry . Addition a ll y , O PP is ab le to as se ss di e tary expos ure to smalle r, s p ec ialized s ub gro up s, a nd ex po s ure a ss e ss ment s are performed when condi tion s or c i rcum s tanc es warrant. The Office of P es ti c id e P rog ram s (O PP ) typi ca ll y co ns ider s the hi ghe s t po tenti a l exposures from the legal u se of a pesticide w hen conducting hum an hea lth ri s k assessme nt s , including , but not li mited to , peop le wh o obtain drinking water from sources near ag ricultural areas , the variabilit y of diets w ithin the U.S. , and people w ho mi gh t be 

### exposed when harvest in g crops. Should these

Page 11 of2 1hig h est exposures indi ca t e p o t e nti al ri s k s o f co n cern, OP P furthe r r e fin es the risk assessments t o e n s ure that th e ri sk estimates are based on the b es t avai la ble in format io n. 

### E ndocrine Disruptor Sc reenin g Program As r eq uir e d b y FIFRA and FFDCA , EPA rev i ews num ero u s s tudi es to assess pote nti a l adverse outcomes from expos ure t o chemical s . Co ll ecti ve ly , th ese s tudie s includ e ac ut e , s ub ch ronic and chron ic tox ic ity , includin g assess ment s of carc ino ge ni c it y , n e urotoxic it y , developmental , reproduct i ve , and ge n era l or sys t e mic toxicity. T h ese st udi es in clude endpo int s w h ich ma y be s u sceptible to e nd ocrin e influence, in cluding effects on e nd oc rin e t arge t o rga n histopathology , o rga n we i g ht s , es tru s cycl i c it y , sex ual m a tura ti o n , f e rtilit y , pregnan cy rates , reproduct i ve lo ss , a nd sex r at i os in offsp ring. Fo r eco logica l h aza rd assess m e nts , EPA eva lu a t es ac ut e t ests and c h ro ni c s tudi es that assess gro wth , de ve lo pm e ntal and r epro du ct ive effec ts in differ e nt taxo n omic gro up s. As part o f its m os t r ece nt r eg i s t ra ti o n decision fo r diph e n y l a min e, EPA rev iewe d th ese d at a a nd se lec ted t h e m ost se n s i tive e ndpoint s for re leva nt ri sk assessme n t scena ri os from th e ex i s tin g h azard database. However , as req uire d by FFDCA sectio n 408(p) , dipheny lamine is subject to the e n docrine sc r eening part of the E nd ocr in e D i srup t or Scree ni ng Program (E D S P ). E P A has de ve loped th e E D S P to detern1in e w h e th e r certain substances ( in cl udin g pestic id e ac ti ve and other in g red i e nt s) may hav e a n effec t in hum a n s o r w ildlif e s imil a r t o a n effect produced by a " n a tura ll y occ urrin g es tro ge n , o r o th e r s u c h e nd oc rin e effec t s as the Ad mini s t rator m ay de sig n ate." Th e EDS P e mpl oys a two-tiered approac h to makin g th e statut o ril y req uire d determinations. T i er 1 co n s i s ts of a battery of I I sc reen in g assays to identify th e potential of a chemica l s u bstance t o interact wit h th e es troge n , a nd roge n , o r thyroid (E, A , o r T) hormo n a l sy stems

. Che mi ca l s th at go through Ti e r 1 scree nin g and are fo und t o h ave the po tential to interact wit h E , A. o r T h o rm ona l systems will proceed to th e n ext s t age of th e E DSP whe re EPA w ill dete rm ine w hi ch, i f an y , of the Tier 2 tests are ne cessary base d o n the avai lab l e d ata

. T ier 2 testin g is d es i g n e d t o ide nti fy any adverse e nd oc rin e-relate d effects caused by th e s ub stance , and es tabli s h a do se -r espo n se re lati ons hip b e tw ee n th e do se a nd the E , A , o r T effect. Und er FF D CA sec ti o n 408(p) , th e A ge n cy mu s t scree n a ll p es tici de c h e mi ca l s. B e twee n October 2009 a nd Feb ruary 20 10 , E P A i ssued t est o rd e r s / data ca ll-in s for the fir st gro up of 67 c h e mi cals , w hi c h contains 58 pesticide act ive ingredien ts and 9 in e rt ing redie nt s. A seco nd li st of che mical s identified fo r EDS P screening was pub li s h e d o n Jun e 14 , 2013fl I a n d includ es some pesticides schedu led for reg i strat i on review and chem ical s fou n d in wate r. Ne ith e r of these li sts s h o uld be const ru ed as a li st of known or lik e ly endoc rin e di s rupt o r s . Fo r further infonnati o n o n th e s tatus of th e EDSP , the policies a nd p r oced ures , the li s t s of ch emical s, future li s t s , th e tes t g uidelin es and th e Ti e r I sc r eenin g batt e ry , pl ease v i s it our we b s ite. 

### Cu mulativ e Ri s k A ssess ments

Ill S ec http: // www.r c g u lati o n s.gov/# !doc um e ntD c tail;D = EP A- H Q-OPPT-2009-0.t 77-0 0 7 .t for the final s econd li s t of c h emica l s.

P age 12 o f 2 1Un li ke other pesticides for wh ich 

### EPA ha s followed a cumu lative ri sk approach based o n a co mm on mechanism of toxicity , EPA has not made a common m ec hanism of toxicity findin g as to diph e n y l amine and any other substances, and diphenylamine does not appear to produce a toxic metabolite produc e d b y othe r s u bstances. For the purpo ses of this action , therefore , EPA has not assumed that diphenylamine has a commo n mechani s m of toxicity with o th er subs tan ces. For information regarding EPA ' s efforts to determine which c h e mi ca l s ha ve a commo n me cha ni sm of toxicity a nd to eva lu ate th e c umu lat ive effec ts o f s uch chemica l s, see the policy statemen t s re leased by E PA' s Office of P esticide Program s concerning common mechanjsm determination s and procedure s for cumu lat in g effects from substances found to have a common mechani s m on EPA 's website at http: //www2.epa.gov /pesticide-science

- and-a sscss ing-pesticiderisks/cumulntive-assessment-risk-pesticides 

### Human Studi es The previou s diphenylamine risk assessments relied in p art on data from studies in wh ich adult human s ubj ec t s were i ntentionally exposed to a pesticide or other chemical. Studies such as the Pesticid e Handlers Exposure Database , Outdoor Residential Exposure Task Force , and the Agr icu ltura l H a ndler Exposure Task Force have been r eviewed by the Agency and found, on the basis of availab le evidence , to have been n e ith er fundament a ll y unethical n or s ig nificantl y deficient rela ti ve to standards of ethica l research conduc t prevailing when they were conducted. There is no barrie r 

### in E P A 

### ' s " Protection of Human Subjects" Regulation t o re li ance on these studies. 

### If u sed for the purpo ses of regist r ation review , nvo data sources not ed in this scopi n g document (MR fD 4453400 I and Gagoulia, et al) s hould be reviewed for comp lian ce wi th human s tudi es regulations. The ot h e r referenced submissio n ( MRlD 44212501) was a r eg i stranta uthored ri sk assessment 

### and was not comprised of any re sea rc h in volv in g hum a n s .. 

### Data Requ ir e m e nts There are no outstanding toxicology , residue chem i stry, or exposure data requirements. 

### Reference s A uth or B arco de Date Tit l e S. Recore 0429308 6 / 23/2015 Diphenylamine: T ier l (Sco ping) Review of Human Lncidents and Epidemiology T. Goodlow 0339969 3/ 13 /2008 Diph e ny lamine: Proposed Section 3 R egistrati on of a New Formulation for Use on App les. K. Bai l ey 0314006 6 / 8

/ 2005 Hum an I lea Ith Risk Assess m e nt fo r the Prop osed Section 3 Use of Diph e ny l amine o n P ear a nd for the Registration of a New Product and Method fo r the Aoolication of Diphenylamine to Aooles. T

. Meyers N I A 3/ 1 /1997 Th e HED Chapter of the Reregi stration Eligibi lit y Decision Docum e nt ( RED) for Diph e n y lamine 

### Attac hm e nt s Attachment 

### 1

. Diphenylamine C hemic a l Prope rt ies Attachment 2. Diphenylamine Endpoint Se lect ion Tabl es Attachme nt 

### 3. Diphen y lamin e Toxicity Profil e Tables Attachment 4. International Re s idue Limit Status

P age 1 3 

### of2 1Attachment I. Oiph e n y la min c C he mical Propertie s Table I.A

. Oiphenylamine Chemica l ld e nti ty Tab le Co mp o und H

# D
Co mm o n name Diph eny lamin e Co mp any expe rim ental DP A name s lUPAC nam e Diph e nylamine CAS na m e Diph e nylamine CAS # 1 22

- 39-4 E

nd-u se product s / EP DPA s up er re fin ed ; Decco No Scald ; DPA Ae rosa l ; Shield DP A 15 %; No Scald DPA EC

-2 83 ; EFOG-100; E GOG-1 70
Tabl e 1.8

. Ph ys icoc h e mi ca l Pr o p e rti es o f the T ec hnical Grade Test Co mpound

. Paramet e r V a lu e R efe re nc e Me ltin g poin t/ range 52

. 7

- 54

. 7 ° C 42716501 pH 5.9 42716501 Den s ity absolute den s ity = I. 18 g/c rn 3 at 25 ° C 427 1650 1 Water so lubilit y (25 ° C) 0.038-0.042 m g/ml.. Solvent so lubilit y (a t 25 ° C) acc 1 o ni1ril e a t 808-897 mg/ml , 42898801 m

e th anol at 454-492 mg/ mL. octanol at 204

-237 mg/ ml , and hexa ne a t 53 -66 mg/ ml Vapor press ur e Pascal torr 42876201 25 °C 8.52 

### x 10 · 2 6.39 

### x 10 4 35 ° C 3 .09 

### x 1 0 · 1 2.32 

### x 10· 3 45 ° C 9.46 

### x 10 · 1 7.09 

### x 1 0· 3 Di ssocia ti o n co nsta nt , pK

. pK a = 1 .03 at 20 ° C in 4

.75 % E tO H 42716401 Octano l/ wat e r pa1tition coefficien t , 3.6 4 282660 1 Log(K ow) UV / visible absorption spectrum not avai lab le

Pa ge 14 of21Att ac hm e nt 2. Di p h cny la min e En dp o int T ab l es . Table 2

. A. T ox ico l ogica l Dos es a nd E ndpoints for Diphen y la min e for Use in Di eta r y Hum a n Hea l t h Risk As sess ments. RID , PAD , Expos ure/ Point of Unce rtain ty/ FQ L eve l of PA Safety Conce rn for S tud y and Toxicological Effects Sce nario Departure Facto r s Ri s k Assess ment Acu te Dietary An approp ri at e endpo int a ttribu table to a sing le do se wa s no t identified. (A II po pu la tion s C hr on ic Di e tary NOAE L = 10 UF " = I Ox Ch ro ni c Rm= C hronic Toxicity- d og (A ll Populations) m g/kg/ day UF11 = I Ox 0. 1 m g/

k

g/

day LOAEL ( m g/k g/day): 50 FQ P A S F = I x c PAD =O .I base d on alteration s in cl ini cal c h e mi s try m

g/ k g/da y param eters ( in crease d BUN , cho lestero l, tota l bil iru bin) and in c r ease d absolute/ re lat i ve kidne y weights. D

e rm a l NOAEL=500 U F" = I Ox Re s id e nti a l LO C 2 1 Day Dermal-Rabbit Sho rt

-Ter m m g/kg/da y UF11 = IOx for L OA EL: (m g/ k

g/day) I 000 ( I

- 30 days) and FQ P ASF = I x MOE = 100 ba se d on effec t s in th e s t o mac h {dark red Int e rm ed iate- foc i in both sexes) Tenn ( I

- 6 M

o nth s) Inh a lati o n NOAEL = 50 UF " = IOx R esiden tial LO C D e ve lopme nt al Toxici t y- R a t S hor t-Te rm m g/

kg/ da y UF11 = IOx fo r LOAEL= IOO m g/ k g/day ( I

- 30 d ays) and FQPA SF= Ix MOE = 1 00 ba se d on increased s pleen we ig ht s a nd Int er mediate

- di sco loration o f th e s pl ee n Tenn ( I

- 6 Month s) Ca nce r (o ral , C lassifica ti o n : D i ph

eny lam in e is cla ss ifi ed as " Not lik e ly to be Carc in ogen ic t o Hum ans. " de rm a l

. Diphenylnitro sa mine ( impurit y) is c l ass ifi e d as a probable human carcinogen, inhala t ion ) QI* = 4.9 x 1 0 m g/

k

g/

da y. Po mt o f Departur e (PO D) = A da ta point o r an es tim ated point that is derived from obse rved d ose- r es ponse data and used t o mark th e be g in nin g of ex trapo la tion to d et e rmine ri sk assoc iated w ith lowe r enviro nm e nt a ll y r e l

evant hum a n expo s ure s. NOA EL = no obse rved adverse eff ec t lev e l. L OAEL = l owest obs e rved adverse effect l e vel. UF 

## = unc e rt a int y factor

. UF , , = ex trap o lati on from ani mal to hum a n ( int ers pecie s). UF11 = potential variation in se nsi ti v iry among members of th e human populati o n (i ntraspecie s). UF L= use of a LOA EL t o extra polate a NOA EL FQP A SF = FQP A Sa f ety Factor. P AD = popula tio n adju s ted dose (c =chronic). Rm = refere nce do se. MO E = m

ar

g in of e xpo s ure . LOC = l e ve l of co nce rn . N / A = not a pplic able.

Page 15 of2 1Table 2

. B. Toxico logical Do ses an d Endpoints for Diph e ny lamine for Use in Occupationa l Hum a n Health Ri s k A ssess ments. RfD , PAD , Ex p os ure/ Point of Unce rta int y / FQP Leve l of Co ncern for Stud y and To x ico logica l Effects Sce n a rio D e p a rtur e A Sa fe ty Factors Risk Assess ment Dermal NOAE L= 500 UFA = IOx Occupational 21 Day Dermal-R ab bit S ho rt-Term m g/

k

g/day UFM = IOx LOC fo r LOAEL: ( m g/

kg/day) 1000 (I

- 30 da ys) MOE = 100 ba se d on effec t s in the s tomach (dark red and foc i in both se xes) Inte rmediateTerm(l -6 Month s) I nhalation NOAEL = 50 UFA= ! Ox Occ upatio na l Deve lopme nt a l Toxicity-Rat Short-Tem1 mg/k g/day UF11 = !O x LO C for LOAEL= IOO mg/ k g/da y ( I

- 30 da ys) MO E = 100 ba sed o n increased s pleen weights and and di sco loration of the s pleen Int ermediateTerm( l -6 M

o nth s) Cancer (oral, C la ss ification: Dipheny lamin e is classified as " Not likel y t o be Carc in oge ni c to Human s." demial. Diphenylnitro sami nc (impuri ty) i s classified as a probable human carcinogen, inhal ation ) Q I* = 4.9 x I0 ( m J.?/kg/ day)" 1 • Point of Departur e (PO D)= A data point or an est imat ed point th at is derived from observed do se- res ponse data and used to mark the beginning of extrapolatio n to det e rmin e ri sk associated w ith lower envi ronmentally relevant hum a n exposures. NOA EL = no observed adverse effec t level. LOA EL = lo west observed adverse effec t level. UF = unc e rtainty factor

. UFA= extrapolation from animal to human (i nterspeci es). UF11 = potential variation in se n s itivity among members of the human population (intraspecies). MOE = margin o f exposure. LOC = level of co ncern. NIA = not app li cable. Atlac hment 3. Diphe n y lamin e T ox icit y Profil e Tab l es. Tab l e 3.A

. Acute To x ic it y Profil e - Di phenylam in e Tec hni ca l Guideline No. S tud y Type MRlD( s) R esu l ts Toxicity Calel!orv 870. I 100 Acute oral-rat 00148523**LD~ o=** **2720mg** (2490

-2980) m Q/kQ. Ill 870. 1 200 Acute dermal-rabbit 00 1 48524 LD so > 2000 m g/

kg II I 870. 1300 Acute inh alation-rat 43794201 LC5 0 = 1

.46 m g/ L 111 870.2400 Acute eye irr it ation-rabbit 00148525 Slight eye irritation Ill 870.2400 *Acute eye irritation-rabbit 41899404 Co rr os i ve: Corneal Opacity I 870.2500 Acute dermal irritation -rabbit 00 1 48526 S li ght sk in irrit ati on Ill 870.2600 Skin se nsitizati o n- g uinea pig 43540801 Not a dem1al se ns itizer NI A

• A s required by the Pesticide A ssess ment Guideline s (Subdivision F. 81-4) the eye irritation s tudy failed to include an observa tion peri od (2 I days) which was s uffi c ie nt to evaluate fully the r eversibility or irreve r s ibility of th e effects observed. The ob se rvation pe ri od in the s tu dy o nl y las ted 7 day s.



### Page 16of21T ab l e 3. B S ub c hro ni c, C hr o ni c a nd Oth e r Toxic ity Pr o fil e- Di ph e ny la mio e T ec hni ca l G D LN S tud y T y p e Dose L eve ls MRID Res ult s 870 .3 1 00 1 992- 13 WEEK ppm = 0 , 150, 1500 , 7 500, 4 233970 1 NOA EL ( mg/k g/d ay): 75 LOA EL ( mg/ kg/da y): 375 FEED I NG -R AT 15000 based on decreased body

mg/kg/ da y= weight a nd body weig ht gain, dark urin e, in crease d 0 , 7

. 5, 75, 375, 750 abso lut e sp leen and l iver wei g hts, congestion in Acceptab le/Guideline s ple e n, kidney , and live r, di sco loration and a lt era ti ons in he rnarological a nd clinical che mi stry param e t e r

s. 870.J 100 1992- 1 3 WEEK ppm 

### = 0, I0 , 525 , 2625, 5250 4254 280 1 NOA EL ( mg/kg/day): 2 FE ED I NG-MOUSE LOAEL ( mg/kg/day): mg/kg/day = M / F : 941107 , based on M:O , 2, 94 , 444, 926 l ive r /s pleen alteration s F: 0 , 2, 107, 556 , 1 10 1 (ex tr amed u l lary he matopo i es is in th e li ve r, disco lora ti o n and Acc e ptable / G uid e l ine hemo s iderosis of th e l iver, conges t i o n and ex tram edul lary he mat opo ie s is in th e s pleen). 870 .3 150 1 992- 13 WEEK ppm = no1 g iven 4233980 1 NOA EL ( mg/k g/day): 50 FEED I NG-D OG LOAEL ( mg/kg/day): not m

g/

k

g/day 

### = determined 0 , 5 ,25, 50 Acccptable/Nongui deline 870.3200 199 2-2 1 DAY m g/kg/da y = 4230490 1 Sys t e mi c: NOAEL D E RMAL-RABBI TS 0, I00 , 500, 1000 ( m g/ k g/da y):500 LOA EL : ( mg/ k

g/da y): I000 Acceptable/No ngu id e lin e based o n effec t s in the s to ma c h ( dark foci -r ed foci in both se xes-6/ I0) D

e rm a l : NOAEL (mg/kg/day): I000 LOA EL ( m g/

k

g/day) : not determ in ed 870.3700 1992- m g/kg/da y = 4229200 1 Materna l : NOAEL DEVELO PMENTAL 0 , 10 , 50, 100 ( m g/k g/day): 50 T OX- RA T LOA EL ( m g/

k

g/da y): I 00 Acceptable / Guideline based o n increased s pleen weig hts and discoloration o f th e s pleen. D

eve lop me nt a l : NOAEL ( mg/ kg/day): I00 LOA EL ( mg/kg/day): not



### Page 17 of2 1Tab le 3.B Subc hro ni c, C hron i c a n d Other To xic it y Profile-Diphen y l amine Tec hni ca l COLN Stud y Type Dose Leve ls MRID Results de t e rmined 870

. 3700 1983- mg/k g/day = 00 1 48521 Maternal: NOAEL DE VELOPMENTAL 0.33 , 100,300 (m g/ kg/day): I00 TOX-RABBIT LOAEL ( mg/k g/day) : JOO ba se d on decr eased body weight ga ins and food Acceptable/Nongu i d el in e con s umption. Developmental: NOAEL (mg/kg/ d ay): 300 LOA EL (mg/kg/day): not determined 870.3800 1993-2-G E NERA T ION ppm = 0, 500 , 1500 , 5000 42638101 Parental: REPRODUCT ION-RAT NOA EL ( mg/kg/day): not mg/kg/ da y = de t e rmined M : 0 , 40, 115 , 399 L OA EL ( m g/k g/day): F: 0 , 46 , 131. 448 M / F: 40 1 46, based on gross pathological finding s in the spleen and mi cro s copic findin gs in the kidn ey , liver , Acce ptable / Guideline and s pl ee n. Reproductive: NOA EL (mg/k g/day) : M

/F: I I 5113 I LOA EL (mg/kg/day): M/F: 399/448 decreased litter size in both generations Offsprin g: NOA EL ( mg/ k g/day): M

/ F: 40/46 LOAEL (mg/k glday) : M/F: I 1 5

/ 13 I based o n d ec rea sed body weight of F 2 pup s in late lacta ti o n 870.4100 1 993- 1 YEAR ppm = not given 43000601 NOA EL (m g/ k

g/day): I 0 FEEDING-DOGS LOA EL ( mg/kg/day): 50 m

g/kg/day "' based on a lterat io ns in 0 , 10 , 50

. 100 clinica l chemistry par ame ters (i ncreased B UN , cho les terol. Acce pt able/ Guideline total bilirubin) and increased abso lut e/re lati ve kidney. live r a nd s ple e n weights. 87 0.4200 19 94- 18 MONTH ppm = O. 525, 2625 , 5250 4336950 1 NOAE L ( m g/kg/day): not CA R C I NOGEN I C I

TY

- dctem1ined MI CE mg/k g/day = LOAEL ( mg/k g/ da y) :



### Pa ge 18 of2 1Tab l e 3. B S ubchron i c, C hro ni c a nd Oth er Toxicity Profile-D ip h e n y l am in e Tec hni ca l 

### G

DL N Stud y T y p e Dose Leve l s MRID Resu l ts M: 0 , 73, 368, 756 M / F: 73 / 91 F: 0, 91, 455, 937 based on histopathological l es ions in the sp leen No evidence of carc inogenicity Acceptable/ Gu ideline 870.4300 1994-2 YEAR ppm = 0 , 200, 750, 3750, 43401401 NOAEL (mg/kg/day): TOXICITY/ 7500 M/ F: 29/ 25 CARC I NOGENICITY- LOA EL (mg/kg/day): RAT mg/ kg/day = M/ F: 147/ 1 38 M: 0, 8, 29, 14 7, 302 based on reduced body weight and body weight ga in s, changes in hematological parameters , ppm = 0 , 1 50, 500 , 2500, sp leen and kidney les ion s 5000 a nd increased clinical s igns of toxicity. m g/kg/ day = F: 8, 25, 138 , 286 No evidence of carcinogenicity Acceptable / Guideline 870.5 100 1 992 -BA CTER IAL 6.7 , 10.0, 33.3, 66.7, and 100 42312101 Negative REVERSE MUTATION μ g/ plate (Salmonella typhimurium) in the absence of metabolic activation (S9); 10.0, 33.3, 66.7, I 00 , and 333 mg/plate in the presence of metabol ic activation. Acceptab le / Guideline 870.5300 1992-/N VITRO 5-80**~1 g/m** **L** in DMSO both 42332101 Weakly mutagenic in the MAMMALIAN CELL in the presence and absence presence of metabolic GENE MUTATION of rat liver metabolic activation TEST activation ( ± S9). Acceptable/Guideline 870.5395 1992-MAMMALIAN mg/kg/day = 250, 500 , or 42312001 Negative E RYTHROCYTE 1000 (males) or 375, 750, or MICRONUCLEUS 1500 (females) s in gle ora l TEST gavage Acceptable/ Guideline 870.7485 1993-METABOLISM mg/kg/day = 42994801 Tem1inal distribution data AND Low dose: 5 showed no s ign ifi ca nt PHARMACOK I NET ICS res idu a l activity in tissues -RAT Repeated low dose: 1 68 hrs oost-dose for both



### Pa ge 1 9 of21Tabl e 3. B S u bc hr o ni c, C hro ni c and O tb c r To xic ity Prolile-Diph e ny la m ine Technical C OLN S tu dy Type D ose Le vel s MRIO Re s ults 5 for 1 4 days , th e low a nd hi g h ora l d ose grou p s: urine was the major Si n gle hi g h dose: 750 route for excretion. Acceptablc / G u idel ine Recovery after 168 hrs : s ingle/ repea ted low do se= urin e 68-81 % (bo th sex e s) s in g le high do se = 73

- 74 % Male r ais excreted a g reater percentage of diph eny lamin e derived act ivity at the l ow dose , wh il e femal e rat s s howe d greater excretion in foccs at thi s do se. At th e high dose , the percent age e liminated in urine wa s equiva lent in both male s and females. Attachment 4. Intern atio nal R es idue Limit S tatu s ( Diph en y htmine (0 38501 ; 09/ 1 7/20 1 5) Table 4. Su mm ary of US and Int e rn at io nal Tol e rance s a n d M axi mum Residue Limit s R es idu e De fi11itio11: 

## us Ca nada Mex ico' Codex 2 40 C FR 180.190 : N- Diphenylarnine Plan t/ Liv estock : Diph e ny larn in e phen y lbenzenarnine Co mm od ity Tole ran ce (pp m ) ! Maxi11111111 R esidue Limit ( 111?.l kg) 

## us Ca nada Mexic o' Co dex 2 Apple , we t pornace 30 5 1 0 app l e Po Apple from preharve s t or po s th arvest 1 0 use , including use of irnpreP,na t ed wraps 0.5 a ppl e juic e PoP Cattle, fa t 0.01 Ca ttle, l iver 0.1 0.05 Ca ttle. meat byproduct s . exce pt liver 0.01 0.0 I (*) kidne y Ca ttle , meat 0.01 0.0 I ( * ) (fa t) Goa t , fat 0.01 Goa t , liver 0.1 Goat. mea t byproduct s, excep t liver 0.01 Goat, mea t 0.01 Horse, fat 0.0 1 Horse , liver 0 .1 Ho r se, meat b yprod uc t s. except l iver 0.0 1 Horse. meat 0.01 Milk 0.0 1 0

. 0 1 ( * ) Pear (p ostharvest) 5 Sheep. fat 0.01 Shee p , liver 0.1 Sheep , meat byproducts , exce pt liver 0.01 S he ep, meat 0.01 MRls wit// NO US Eq u ivalent



### Pa ge 20of2 1Tab le 4

. S umm a r y of US a nd I n ternat iona l To lerances and Max imum Residue Li mits Residue De{i11itio11: 

## us I Ca nada 

### I Mexico 1 

### I Codex 2 Pear 

### I I I I 5 Po Completed: M. Negussie; 09/ 25 / 15 1 M ex ico adopts US to lerances and / or Codex MRLs for its expo rt purpose s. 1 * = absent at the limit of quantitation; Po = postharvest treatment, suc h as tr ea tm ent of sto red grains. PoP = processed postharvest treated co mm odity, s uch as processing of treated stored wheat. (fat)= to be measured on th e fat portion of the sam ple. MRLs indic a t ed as proposed have not been finalized by the CCP R and the CAC.



### Pa ge 2 1 of21