UNITED STATES ENVIRONMENTAL PROTECTION AGENC Y WASHINGTON , D .C. 20460

O FFI C E OF CHEMI C AL SAF ETY AND POLL UTI ON PRE V ENT I ON



### F ebrua ry 29 , 201 6 MEMORAN D UM SU BJECT : P e t iti o n N o .: IN- I 0 77 7 ; Sa li c y la ld e h y d e . H um an H e a lt h Ri s k A ss e ss ment a nd E co log ica l E ff e c ts A ss e ss me nt t o S upp ort Pro p o se d Ex e mpti o n fro m th e R eq uirem e n t o f a To l eran c e W hen U sed a s a n In e rt In g re di e nt in Pe s ti c ide Fo rmul a ti o n s .



### F RO M: P C Co d e: 730944 

### Deci s ion N o.: / A

P e tition N o.: IN -1 0777 

### In e rt T r a ckin g N o. : N/A DP B a rc o d e : /A Re g ul a t ory Ac tion : Ine rt To le ra nce Exe mpt i o n ; 4 0 C FR 1 80.9 1 0 

### CAS Re g. N o . : 90-0 2

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T HRO UG H: C he mi s try , ln e rt s a nd To x ic o l o gY. Asses e nt Bra nc h (C I T A B ) R eg is tr at ion Div is ion ( RD * ( 7 50 P) Kerry L e if e r , Tea m Le ade · 

## Av 

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TO: C IT A B / RD (75 0 5 P ) P v S h ah , Bran c h C hi ef C I T AB /RD (75 0 5 P )

### EXECUTIVE SUMMA RY Ag

- C hem Co nsultin g LLC , o n b eh a l f of O mex Agritlu id s , subm itted a petition request in g , pursuant to sec tion 408 ( d) of t he Fe dera l Food , D ru g, and Cos m e ti c Act (FF D CA) , 2 1 U
. S.C
. 346a(d), that E P A ame nd 40 C FR part 1 80.9IO to estab l ish a n exemp tion from th e re quirement of a tol e rance for re s idu es of sa li cy l a ld e h y d e (2

- hyd roxy benza ld ehyd e; CAS R eg. No
. 9 0-02-8 ) when u se d as an inert in g redi e nt (penetration aid) in p est ici d e form ul ations app li ed to grow in g c ro p s o r to raw agricultural commod it ies after h arves t at a co nce ntr at io n n ot to exceed I4 % b y weight of t he pesticide formulation
. T h e acute o ra l tox i city of sa li cy lalde h y de was ex amin e d in m a l e rats a nd mic e. T he ge nera l lethal a m o un t o f sa li cy la ld e h y de i s es tim a t e d to b e 5 00mg/ kg in mice. The dermal LD so for sa li cylaldehyde was d e te rmined t o be great er than 23 g/kg. D e rm a l irrita tion st udi es found sa li cy laldehyd e to be irrita ting , w i t h esc h a r fo rmation a nd scarr in g 14 days afte r ad mini s tra ti o n. In a combined r epe at e d d ose to x icity s tud y with the re productio n/d eve lo pm e n ta l toxicity scree nin g t es t , t ox icity was n ot observe d in parenta l anima ls n or in repro ducti ve parameters at doses up to I 60 m g/k g/day , th e hi g h es t do se t es ted
. Fe ta l s u scep tibility was observe d
. R ed uc ed bod ywe ig ht and offspr in g mortality after 4 d ays of nur s in g were observe d a t 1 60 mg/k g/ d ay . The NOAE L was 40 mg/ kg/day. Sal icylalde h y de was negati ve for mutage ni c ity in th e Ames t est and gave a positive response in the chromoso m e aber r at io n s tes t u s in g C hin ese ham s t er ce ll s ( in v itro). An in vivo micronucleu s as say was negati ve. Since th e in v i vo s tud y i s m ore reli ab le than th e in v itro assays, th e we ig ht of evide nce s u gges t s that sa l icy la ld ehyde i s unlik e ly to be mutagenic.
T here are no cancer stud i es ava il ab l e for sa li cy l a ld e h yde
. According t o a D ERE K (Nex u s) (s tru c tur a l ac ti v ity rel a tion s hip) report , there are no s tructural a le rt s fo r ca r c ino genicity. Based o n pre di cted rapid m e tab o l ism a nd exc r eti o n , lack of spec ific target organ toxicity in t he repeat d ose toxicity st ud y , l ack of mutagen icity co nc ern s , a nd l ack of a ny s tructural a le rt s for carc in ogen icit y , sa li cy l a ldehyde i s n o t expected t o be carc in ogen ic to human s at a nticip a ted dietary concentratio n s. T he m e t abo li s m of sa li cy la ld e hy d e in r abb it s d e mon s trated that 75 % of si n g le dose of sa li cy la ld e hyde was exc re te d in the ur ine as g lu curon ic ac id and s ulfat e co nju gates of van illi c ac id
. The FQ P A Safety Fac to r (as r e quired b y th e Food Q u ality Pro t ec tion Ac t of 1 996) is intended t o provide an add iti o n a llO -fo ld safety factor ( I OX) , to protect for s p ec ia l se n sit i v ity in inf ant s and children. B ase d on ava ilable info rmation , th e FQPA safe ty factor s h o uld be reduced to IX.

3Occupationa l handler and post
- app li cat ion exposure may occur by the dermal and inhalation routes of exposure on ly. RD initiall y assessed handl er exposure and risks for salic y laldeh y de in pestic id es at baseline personal protective equipment (PPE; long pant s , a lon g - s l eeved s hirt , s h oes, soc k s, no chemical-re s i s tant gloves, an d no respiratory protecti o n) wh i ch the Agency considers to be the typical minima l worker clothing. Typically , th e Agency character izes the risk estimate in relation to the re s tricted entry interval (REI) for a particu l ar act ive ingre di e nt
. Whi le REis for s pecific products are not discussed in this ri s k assessment , occupatio n a l po s t-application s c e nario s assessed generally result in margin s of exposure (MOEs) that do not indic a te ri s k s of concern on Day 0 ( the day of app li cation) except for ten po stapplication scenarios
. Typically , the Agency characteri zes the risk estimate in re l ati on to the res tricted entry interval (REI) for a particular acti ve ingredient. Whi le REis for s pecific products are not discussed in this risk assessment, occupationa l post-application scenarios assessed re s ult in MOEs that do not indic a te ri s k s of concern o n Day 0 (the day of application)
. Salicy l a l de hyde has been tested for ecolog ica l toxicity. T he chemical is readil y biodegradab l e and not expected to have adverse ecological effects due to dilution factor and biodegradability potential Taking into consideration a ll availab le information on sa lic y laldehyde , E PA concludes that there is a rea so nab le certa inty that no harm to any population s ubgroup will result from agg regate exposure to sa li cy laldehyde when consider in g occupation , dietary exposure and a ll othe r nonoccupational so urce s of pesticide exposure for which th e re i s reliable information. Therefo re, the Agency recommends for the establishment of an exempt ion from tolerance for residue s of sa li cylaldehyde when u se d as a pesticide in ert ingredient in pe s ticide formu lations under 40 CFR § 180
. 910 with the limitation that the e nd-u se concentration n ot to exceed 14 %. 

### I. BACKGROUND Ag-Chem Consu ltin g LLC , 1 2208 Quinque Lane , Clifton VA 20124 on behalf ofOmex Ag r ifluids, 24730 Aven u e 1 3, Madera CA 93637, submitted a petiti o n reque s tin g, pursuant to sec tion 408 ( d) of the Federal Food , Drug , and Cosmetic Act (FFDCA) , 21 U.S.C. 346a(d), that EPA amend 40 CFR part 180.910 to establish an exemption from the requirement of a tolerance for re si dues of sa lic y l aldehyde (2- h ydroxy benza ld e hyde; CAS Reg
. No. 90-02-8) when used as an inert ingredient (so il penetrant) in pe sti c ide formulations applied to growing crops or raw agricu1tLrral commodities at no more than I 4% of the pe s ticide formulation II. INERT INGREDIENT PROFILE A. Summary of Uses The propo se d use of sa li cy la ld ehyde i s as an in e rt in gred ie nt in pe s ticide formu l ations wh ich include u se on crop s fo r pre- and post-harvest to help the act ive in g redient properl y penetrate and remain avai l ab le to act in the so il at a maximun concentration in the pe stic ide formu l ation of 14 % b y we ight. 5five gu in ea pigs tested fo r a ll e rg ic sk in reac ti o n s ex hibited a po s itive re s p onse (Let ter fro m East man Kodak Co mp a n y to USEPA s ubmittin g Toxicit y a nd H aza rd S umm a ry and Tox icity Report on Salicy la d ehyde with A tt ac h emen t s, I 0 / 221199 1 )
.
Eye irri tat io n tests were n ot don e, h owever, based o n th e seve re sk in reac tion , 

### it i s ass um e d that thi s compound wo uld prod uce seve r e eye irritation
. Metabo li s m A s in g le dose of 400 m g/ kg/day sa li cy la ldehyde was ad mini s tered to a fasted rabb it. A pprox imatel y 75 % of the dos e was excreted in th e urine co ll ecte d ove r 24 hr. Urin e ana lys i s revea le d m ai nl y e th e r so luble ac id s , wi th 27% and 3% accounted for as g lu c uro ni c acid and s ulfate conj ugates of va nilli c ac id , respectivel y (T h e FEMA GRAS assessme nt of hyd roxy - and a lk oxy - s ub st itut e d benzyl deri vati ves u sed as fl avo r ingredients, T. B
. Adams eta!. , Food a nd C h e mic a l Tox icolo gy 4 3(2005) 1241 1 27 1 )


### A .2 . Co mbined Repeated Dose Toxicity Stud y with the Reproductive/Developmental Toxicity Screening Test

To p e rform th e repeated d ose tox ic ity a nd reproductive de ve lop m e nt al tox icity combined tes t ba se d o n o ra l a dmini s tra ti o n u s in g sa li cy l a ld e h y d e rat s (C rj: C O (S D ) type S PF ) , we u se d dosages of 0 (co ntr ast g roup ), 2.5, I 0 , 40, and 1 60 m g/k g / day t o di scove r the ge n e ra l toxico l ogica l effec t s in m a le and fema le an im a l s due to repeated d oses , an d a l so to di scover t he effec t s on go nad a l pe rformance, m a tin g behavior, impregnati on , and partur iti o n and ot h er re pro du c t ive development. R epeated D ose Toxicity No effects of administration of th e tes ted s ub s tanc e to m a l e r a t s we re fo und in genera l co nditi ons , weight , feed vo lum e, h e mato log ic a l te st val ue s , bl oo d chemistry test va lu es, a utop sy findin gs , a nd o rga n w e i g ht. In th e t es te d s ub s tanc e adm in ist r ati o n gro up s of 40 m g/kg/ day o r m o re , th e d eg ree of lob ul ar p erip h e ral a dip os it y in th e li ve r a nd th e fre qu e nc y of app e arance was less than in th e co ntr as t gro up . T hi s i s not co n s id ered to be a n adverse effec t. In the te st on female r ats, as id e from o n e mother in t he 40 m g/ kg/day ad mini st rati o n g ro up th a t was partwa y through parturition o n preg n a ncy D ay 22, a nd o n e mother in th e 160 mg/kg/day a dmini s trat io n gro up that died o n preg nanc y Day 22, n o changes were obse rved in the genera l condit ion . I n th e 1 60 m g/kg adm ini s tratio n group. the li ver weig h t showed a hi g h va lu e ( 1 5.36 ± 1. 02 g vs 1 3 -13. 6 g), and the ova ri es a low value (4 7 ± 7 m g vs 50

- 63 m g). Howeve r, n o effects of ad mini stration of the tested s ub sta nc e we re f o und in we i g ht , feed vo lume , and a utopsy findin gs. In th e tes ted s ub stance administration g ro up s of 40 m g/ kg / da y or more , a s li g ht increase in th e g lycoge n vo lume was o b se rved in s ide li ve r ce ll s. T h e p a rental NOAE L was 160 m g /kg/ d ay, the h ighest d ose tested. 7clastogenic ity in rat bone marrow cells. C hro m oso m e Aberration The proliferation s uppre ss ion concentration exceeding 50% for sa lic y la l dehyde CHLI IU ce ll s was 0.020 m g/mL in t he co ntinuou s process ( 48 hour s) , and in the s h o rttime process (6 ho ur s) un der S9 mi x existence and non-exi s tence , 0.20 m g/ mL for both. As a re s ult , the concentrations of 0.020 mg/ mL for the continuou s proce ss, and 0.20 m g/ m LI for the s hort-tim e proce s s , were set as the maximum proce ss c o ncentration for this test. One-h a lf and one -f ourt h conc e ntrati o n s of the m a'< imum proce ss co ncentrat io n we re se t as the medium conc e ntrati o n and low concentration , respectively. In the co ntinuou s proc ess g roup, s pecime n s after 2 4-hour and 48 -h our processi n g were m anuf ac ture d under S9 mi x n o n- ex i s tence , a nd c hrom oso me analy s is performed. In th e s h ort-time process group , 6 -h o ur processing was perfo rmed under S9 mi x ex i s tenc e and non-existence , followed b y 18 hour s culturin g in a f re s h cu lturin g so lution to m a nu facture a spec im e n , and c hromo so me analysi s was perf o rmed. As a result of 24-hour and 48-hour continuous proces s in g , the C H L/ IU cells s howe d a s ig nifi c ant incr ease of ce ll s hav ing chromosome s tructural aberrations , in the 24- h o ur process high

- concentration g ro up (0.020 mg/ mL ), and sig nific a nc e was obtained in the trend test as we ll. In additio n , in the 48-hour proce ss high-concentration g roup ( 0.020 mg/ mLI) , a s ig nifi cant incr ease of c ulture d ce ll s was see n , and a significant differe nce in the trend t es t was obtained as wel l. Meanwhile , the g roup s w ith 6- hour proces s ing under S9 mi x ex i stence and non-e x i stence were both depend e nt o n th e concentration, with a s ig nifi ca nt incre ase in ce ll s with structural aberrations
. In additi o n , the grou p und e r S9 mi x ex i s t e nc e was d e pendent on the concentration , wi th a s ig nific a nt increase in polyploid y cel ls. Reverse Mutation For the assay bacteria , five bac t e rial s train s were used , including 

### Salmonella t yphimurium TAIOO , TA1535 , TA98, TA1537 , and 

### Esc h erichia coli WP2 

### uvrA , and a d osage set tin g tes t was perform e d f o r thi s t es t u sing the plate method w ith S9 mi x noadd iti ve and additive conditions. When the dos age se ttin g te s t was performed at a do sage of 50 to 5000 u g / plate , in th e S9 mi x no-additive , antibiotic action was found a t do sages of 1 500 ug / plate or more (T A 100 at 500 ug/ plate or more, and WP 2 

### uvrA a t 5000 u g/plate or more), while in the S9 mi x additive, it was found at 1 500 u g/pl a t e o r more (TA 100 at 500 u g/ plate or more). In this te s t , the S9 mi x no-additiv e te st was set a t do sages in a ran ge of 3 1 .3 to I 000 u g/plate (TA 100 at 15.6 to 500 u g/ pl ate, and WP2 

### uvrA at 12 5 to 4000 u g/ plate ), and th e S9 mi x addi ti ve te s t was set at 62.5 to 2000 u g/plate (TA 100 at 15. 6 to 500 ug/p late , a n d WP2 

### uvrA at 1 25 to 4000 u g/p la t e), and th e te s t was implemented
. As a result, in both of the two ro und s of te s ts , s ince no increase was found in th e revertant colony number s that were m o re th a n doubl e th e so l ve nt contrast va lu e in all d osages of the fi v e types of assay s train u se d , we concluded that sa lic y laldeh yde d oes not ha ve an y mu tag enicity (negative) in the te s t sys tem used. B. C hronic Toxicity 9expos ure assessme nt s Res idu a l Unc erta int y in th e Expos ure Database The dietary ri s k assessment for sa lic y la ld ehy d e i s ba se d on co n serva t ive, hi g he nd ass umpti ons and as s uch th e ex p os ure assessment i s not like ly to und eres tim a t e act u a l ex po su res Based on above cons id e ra tion s, the FQPA Safety Factor ( SF) ha s be e n reduced to 1 X. T he acute and chronic p o pu lation-adjusted do ses (aPAD and cPAD) would be e qual to the acute and chronic RtD s, res p ec ti ve l y. 

### D . Toxicity Endpoint Selection No ac ute toxicological e ndp o int of concern h as been id e ntifi ed for sa l icy la ld e h yde. On th e basis of the rep eated dose a nd reproductive/ developmenta l toxicity screening st ud y , a OAEL for offs prin g tox ic ity NOAEL for sa li cyla ld e hy de was 40 m g/ kg/day
. The LOAEL was 1 60 m g/ kg/d ay based o n red uced b odywe ig ht a nd in crease mortality in pup s a t 160 m g/kg/d ay. The s ta nd a rd 1

### OX fa ctor s for intr a- and int er- spec ies we re ap p li e d
. The chronic refe ren ce d ose (c RtD ) i s therefore 0.4 m g/kg (40 m g/kg b w/ d ay II 00). Since the FQ PA SF ha s b ee n re duc ed to 1 X, the chronic p o pulat ion a dju ste d d ose ( cPAD) e qual s the cRfD. T he chronic NOAEL i s also a ppli ca bl e to the derm a l and inh a la ti o n expos ure routes. The accep tab le MOE f o r de1m a l and inh a la ti o n expos ure routes i s 100 o r a bo ve. 

### IV. DIETARY EXPOSURE ASSESSMENT In conduc tin g the chronic di e tary expos ure assessme nt u s in g the Di eta ry Exposu re Evaluatio n Model D EEM-FC ID TM , Version 3. 1 8, E PA used food cons umpti on in fo rm ati o n from th e U.S. D ep art m e nt of Ag riculture's (US DA 's) 2003

- 2008 a ti o n a l Hea lth a nd N utri t ion Ex aminati o n Survey , Wh at We Eat in A merica (NHANES / WWEIA). As to residue leve ls in fo o d , n o re s idu e data were s ubmitte d for sa li cy laldeh yd e . In the a b se nce of s p ec ific re s idu e data , E PA ha s de ve loped an approac h w hi c h u ses s urrogate information to d e ri ve upper bound exposure estimates fo r the s ubj ect inert in g re dient. U pp e r bound expos ure es timate s are ba se d o n th e hi g hes t to le ra nce for a give n commodity f ro m a li s t of hi g h-u se in sec ticid es, herbici d es, a nd fungic id es. A complete de sc ripti o n of th e ge ne r a l a pproach take n to assess in ert ingredie nt risks in the absence of residue data is co nta i ned in th e m e m o ra ndum ent itl e d "A lk y l A min es Polyalkox y lates (C lu s te r 4): Acu t e and Chro nic Aggregate (Foo d and Drinking Water) Dietary Exposure a nd Ri sk Assess m e nt s fo r t he ln e rt s : · ( D 36 170 7, S. P ip er, 2/ 25 / 09) and can be found at htt p: //www.reg ul at i o n s .gov in docket ID number E PA-HQ-OPP-2008

- 0738
. In th e dietary expos ure assess m e nt, the Age nc y ass um e d that th e res idu e level of th e inert in gredie nt would b e no hi g he r th an th e hi g he st to l era nc e for a given co mm o dity. Implicit in thi s as s umption is that there would be s imil ar rates of degradation ( if any) betwe e n the active a nd i ne rt in g re di e nt a nd that the co nce ntr a ti o n of IIpopu la tio n and a ll population s ubgroup s . The chro nic d ie t a r y e xpo s ure from food a nd water to s al ic y laldehy de i s 1 3% oft he c P AD fo r the U.S. population and a l s o 49 % of the c PAD for c hildre n 1- 2 y ea rs o ld , the m o s t hi ghl y expo s ed population sub g roup. 

### C. Ca nc e r Di e ta ry Ex p os ure and Ri sk Th e Age nc y h as n o t identified an y c o ncern s fo r ca rc inogenicity relatin g to s alic y la l deh y d e; th erefore , a cancer dietary e xpo s ure a s se s smen t wa s n ot performed.



### Table 4. Dietary E xposure Assessment for Salicylaldehyde Population C hr o nic Ex po s ure S u bgro up Ac ute Expos ure Dietar y Ex p os ure Total fr om D EEM mg/ kg /day 

### I %aPA D m g / kg/day %cPA D US Pop
. N A 0.0 53 0 1 6 1 3 A ll Infant s ( < l y r) 0.110440 2 8 C hildre n l- 2y r 0
. 19 77 4 7 49 C h ildre n 3

- 5 y r 0
. 1 35 9 7 8 34 C hildren 6-1 2yr 0
. 0701 55 1 8 Y o uth 13 -19 y r 0
. 0 377 4 3 9 .4 A du lt 20 -49y r 0
. 0 4 0 527 10 Adult 50 -99 y r 0.04 25 0 1 II F

e ma le 1 3

- 4 9 y r 0
. 04097 3 10


### V. RES ID ENTIAL EX PO SURE AND RI SK ASSESSMENTS A s w ith th e propo se d a g ri c u ltura l u s e s , th e re i s unc e rtainty reg ardin g th e p os s ibility o f " res identi a l " u s e of t hi s in e rt
. T he A ge nc y conducte d a "s cree nin g " l e ve l a ss e ss m e nt o f pe s ticid e app li catio n act iv iti es known to res ult in hi g h e xpo s ures , re l ative ly s p e ak in g. T he
" home-owner " pe s ticide handl e rs are a ss umed to we ar s hort-p ant s , s hort- s le e v ed s hirt s and s ho es plu s s o c k s but no protectiv e g lo v e s . Th e re s u ltin g e s tim a te s o f ri s k a re con s idered c o n s erv ati v e , i. e. protecti v e. T he MO Es f o r res id e nti a l h andlers all ex c ee d I 00. 

### A . R es id en tial Mixer/Loader/Applicator Ta bl e 5. Es timat ed Re s idential Pesticide Handler (Mixer/Loader/Applicator) Ex po s ure a nd Risk

Mi x er / load er / U nit E x p o s ure A pp l icati o n U nit s B o d y Ave ra g e D a il y M a rg in of a ppli ca tor mg / l b h a n d le d R a te lb/ga l Treat e d we ig ht Do s e Ex p o s ure Ac re s / d a y kg mglkg/ d a y Ho s e e nd De rm a l 1 3.4 0
. 010 5 5 ga l /d a y 80 D e rm 0
. 00 3 08 1 2 , 9 27 Spray e r lnh a l. 0
. 0 22 Inh a l 0
. 00 0 0 1 44 Pum p -up h a nd- D e rmal 6 3 5 ga l / d a y D e rm 0
. 014 4 2
. 77 4 he ld s pra y e r l nh a l 0 .0 18 lnh a l 0
. 0000 1 8 Back pack D e rm a l 1 3 0 5 ga l/ da y De rm 0 .02 98 1. 33 8 S pra y e r In h a l 0. 14 Inh a l 0
. 0 000 9 2 C on ve nti o n Use d t o E s tim at e Ex po s ure = U nit Ex p os ure 

## * A pp li cat i on rate 

## * U nit s Trea te d -:- Bod y w e i g ht 1 3= 0.00085 lb in e rt in formul a ted so luti on/ d ay For trigger pump spray 0.13 gallon formulated solution * (8
. 3 4 lb/ ga l) 

## * (5 .0 %) = 0.00085 lb in e rt in f o rmul a t e d so luti on/ d ay B. Residential Post-Application
Table 7. Summary Recreational and Residential Post-Application Exposures and Risks Act i vity E x po s ure ( D o s e) MOE m g in ert/k g/da y T oddler s hort -term ora l h a nd to 0
. 00 3 6 I 1.111 mouth !Tom co nt a c ti ng tre ate d turf Todd ler ora l object to mouth 0
. 00023 17 3 .913 (turfgra s s) Adult derma l po s t appl ic turf co ntact 0
. 0172 2, 325 Todd le r denna l post appli c turf 0
. 033 1 , 2 1 2 co nt act A dult go lf e r post ap p turf co nt act 0
. 000119 33 6 , 1 34 C hild go lf er p ost ap p turf contact 0 .0 0 202 1 9 , 801 0
. 037 = hand to mouth + object to Todd le r comb in e d expo s ure mouth + turf po s t- applica t ion 1 , 08 I e x posure MO E = NOAEL .;.. Do s e . OAEL = 40 mg in ert/kg/ da y. A dult and A dole s cent Golfer Post-Application Dermal Ex posure may b e estimate d using th e co n ve nti o n state d in Science Adv i so ry Co un c il for Expos ure draft OP regarding

· ' Go l fer Expos ure Assessment For Ad ult s a nd C hildre n· ' (2 4 A u g u st 2000). T h e draft policy s tates that ad ult an d ado lesce nt go lfer d e rm a l po st
- applicat ion exposure m ay b e ca lcul a ted a s D E ( t ) ( m g a.i./kg bw/ day) = (TTR( t ) ( ).l g/ c m 2 )) 

## * TC (c m 2 

### /hr) 

## * hr / d ay + (CF ( I 000 ).l g/m g)) 

## * BW (bo d y we ig ht (kg)) Wh e re: D E( t ) = d e rm a l ex po s ure at tim e ( t) a ttribut a bl e to go lfin g o n pr e viously treate d tur f (m g a. i ./kg bw/ d ay). TTR( t ) = turf transferab le re s idu e at tim e 1 ( ).l g / cm 2 ) TC = Transfer Coeffic ient (500 cm 2/hr ) hr = exposure period (4 h o ur s) CF = co n ve r s io n factor to change ).lg to m g. BW = b ody weig ht (kg) (80 kg for ad ult ; a dju s te d (m ultiplied ) b y a factor of 1.7 for chi ld go l fers) and whe re TT Rt = AR 

## * F 

## * ( 1-D Y 

## * CF2 

## * CF3 A R = app li cat io n rate (lb in ert/ac re); 0.02 1 lb ai / ac re (taken from Tab l e 5 above w h e re 0.0105 l b i s app li ed to Y2 ac re) 1 5

### Children's short- term oral hand-to-mouth exposure= TTRt *SA* EX* FQ * ET * CF l where: PORt = potential dose rate o n day ·' t " (m g/kg bw / da y) TTRt = turf transferable residue o n day " t "**2** turf) ; 0.00056**~g/cm 2**  SA = s urf ace area oft he hand (c m 2/even t ; p a lm er s urfa ce a rea of3 fingers = 20 c m 2 EX = ex trac ti on factor from th e h a nd b y sa liv a = 50% FQ = freq ue nc y of hand-to-m o uth act iv ity (eve nt s/hr ); 2 0 events/ hr ET = expos ure time (hr / d ay); 2 hr s/ d ay CFI = we ig ht unit conversion fac t or to co nve rt**in** the TTR va lu e to mg for the daily exposu re (0
. 00 1**mg/~g).** 0.136**~g/cm 2**  * 20 c m 2/event * 0.50 %ex traction fac t o r * 20 events /hr * 2 hr / day * 0.001**mg ~g**  7 15 kg bw = 0.0036 mg ine rt/ kg/d ay. MOE = OAEL 7 D ose 40 m g in e r t/kg/ day 7 0.0036 mg in ert/ d ay = 11 , 111
. 

### C hildren 's object-to-mouth (turfgrass) = Grt * Ig R * CF 1 PORt = potential dose rate o n day " t " (m g/ kg b w/ day) GRt = g rass (and pl ant m a tter) residue o n day " t " ; 0.00056**~g cm** **2** Ig R = mo uthin g ra te of g ra ss (cm 2/ d ay); 25 cm 2 / day CF I = we ig ht un it conversion fac to r to co n vert**~g** unit s of res idu e o n the g rass to mg for the dai ly expos ure (0.00 1**g/ g).**  0. 1 36**g/c 2**  * 25 cm 2/ day * 0.00 I**g/ ~g**  7 15 kg bw = 0.00023 mg in ert/kg/day MOE = NOAEL 7 Do se and 40 mg inert/kg/day 7 0.00023 mg in ert/kg/day = 173 , 9 1 3.

VI. AGGREGATE RISK AND DETERMINATION OF SAFETY 

### A. Ac ute Risk T here was no h aza rd attributab l e to a s in g le ex po s ure see n the in th e tox ic ity database for sa li cy la ldehyde ; th e refo re , a n acute agg regat e risk asses s m e nt i s n ot require d. 

### A. Chronic Risk. Us ing the exposure assumpt io n s described in Section III for chro ni c dietary exposure , EPA has concluded th at chro ni c exposure to sa li cylaldehyde from food and water is conservative l y es tim ated to utili ze 49 % of the cPAD for c hild ren l- 2 y r s o ld, the population group receivi n g t he greatest expos ure . Chro ni c residential exposure to residues of sa li cy la ldehyde not expected. 

### B. Sho rt- and Inte rm ed iate-ter m Risk

1 7d ur ations. Ac t ive i n gre di e nt app li cat i o n r ates we re co rrecte d for the m ax im u m a m o un t of the in ert in g re di ent lik e ly to b e in th e fi n a l fo rm u la ti o n s to d e te rm ine ex p os ure a n d ri s k f ro m expos ure salicy la ld e h y d e. A s umm a ry of t he occ up a t iona l assessme nt i s p rese n ted be low . 

### A. H andler Risk

Ex p os ure Scena rio s
Ex p os ure t o p es ticid e han d lers i s lik e ly durin g th e o c c up a ti o n a l u se of p es ti c ides co n tai nin g sa li cy l a ld e hy d e as a n ine rt in g re di e n t. D e rm a l and inh a la ti o n expos ure was e s t i mated u si n g the P est ic id e H a n d l e r s Ex p os ure D a ta b ase ( PH E D ) a n d O utd oor Res ide nti a l Expos ure Tas k Fo rce (ORETF) da ta. T he qu an tit a ti ve exposure/ r i sk a ss essme nt develo p e d fo r occ upati o n a l h an dl e rs to s upport the req u es t e d to le ra nce exemp t ion for sa li cy l a l de h y d e i s b ased o n th e fo ll ow in g sce n ar ios. RD n otes th at t hese sce n ari o s we re se le cte d t o rep rese n t th e sce n a ri os w ith th e hi g hes t potentia l exposure. T he sce n ari os a re s umm a ri zed in Ta bl e 6 b e low. Assessme nt s ar e co n duc t ed u s in g sta n dard ope r a ti ng p roc e d ure d eve lo p e d b y t he Hea lt h Ef f ec t s Di v i s i o n , Office of Pes t ic i de Prog r am s. T h e me tri c u se d to ca lcul ate ex p os ure and ri sk i s : U nit Ex p os ure 

## * m g inert/ lb h a ndl e d A ppli cat io n R a t e 

## * U nit s Treat e d / d ay + B o d y we i g ht lb in e rt / unit A cr es e t c 80 kg Ri sk es tim ate s we re ca lc ul a t e d u s in g th e Ma rg in of Ex p os ure (MOE) w hi c h i s a ra ti o of t he tox ico log ica l P O D (m g/ k g/ d ay) t o th e d a il y d ose ( m g/kg/d ay). T he p o in t of d eparture is 40 m g/kg/d ay. D erm a l an d inh a la t io n a b sorp t ion are ass um ed to b e I 00%
. S h o rt
- t e rm ex p os ures ( 1- 30 d ays) we re es tim a ted. For t hese u ses. int erme d iat e -term exp os ures ( 1 -6 m o nth s) a re n ot expec ted and are typ ically lowe r thu s are not prese nte d . T he Age ncy ass u me s occ u pati onally ex p osed i n d i vi du a ls wear pro tec t ive g loves. To assess han d le r ri s k s , th e Age ncy u se d s urroga te unit ex p os u re d ata from th e P H ED , a n d ORETF d a ta.

Ri sk C h arac t e ri za ti o n : 

### Tabl e 9. Expo s ure and Ri s ks for Occupational Handlers of Salicylaldeh y de in Pesticide Products ( A ll Expo s ure Durations) with Baseline Plu s Gloves for High Acreage Mixer/ Loader S cenarios and Turf A

rea Dermal I n ha

lati on B as elin e+ Baseline Base line Base l i n e Total Ex p os ure Sce nar i o Appl. R atc 1 Treated U nit U nit Gloves Inhalati o n + Gloves Inhal atio n MOE 8 (Formulati on! ( lb inen/ Daily2 Expos ure Ex p os ure Dennal Dose Dcm 1al MOE7 App li c ati on / C r op) A) (acre s) ( m gllb ( u gll b Do se ( mg/kgl Mor:6 in e n )3 ine rt )3 ( mg!ko da y) 5 /day)4'

Mixer / Lo ader Scenarios Liqu id s / Ae ri a l 1. 456 0.57408 0
.029952 70 1300 66 Ap p l icat ion/ l li g h ' ,.. , ICTI 1200 0
.023 1. 2

L

iquids / Aeri al 0
.28 0. 11 04 0.00576 360 6900 340 App li cation / l l igh



### .. . ,.. , ,,,., Liquid s / 1.4 56 200 0.09568 0
. 004992 420 8000 4 00 r.rn u nrlh "" "' ' II' o h 19• Tall field/row crops (including sco utin g , weeding , hand harvesting sweet corn) • Turf (golf co urse/ sod farm) (including mowing , transplanting , hand weeding) • Vine/Trellis crops (includ in g sco uting , training, tying , thinning , and gra pe girding and cane turning ) Ex posure Data and Assumptions are li ste d in the foot notes of Tab le 8.0 below whic h are standard operating procedure and developed by the Health Effects Division , Office of Pesticides Programs
..
• Calcu lations of postapplication exposures are completed using maximum app li cation rates of pe s ticide product s for s hort
- term exposures and average application rates of pe s ticide products for intermediate-term exposures. • No postapp li cat ion data were submitted for sa li cy laldehyde ; a default 50% of the app li catio n rate (for agricu ltural crops) and 10 % (for turf) is considered ava il ab l e as a transferrab le residue with a l 0% defa ult daily diss ip ation rate. • Derma l absorpt ion i s ass umed to be 100 %
. Risks were calculated using the MOE app roach , which is a ratio of the exposure to the toxicological PoD. Risk C haracte r izat i on A variety of pe sti cide fo rmul at ions ma y contain sa lic y lald e h yde. PPE is u s uall y not required for wo rker re-entry , and th e refore the se postapp li cation ri s k es timate s are bas ed on the basel i ne exposure scenar io ( i .e., typical work clothing but no gloves). Typica ll y, the Agency characterizes the risk es timate in relation to the restricted e ntry interval (RE I) for a particu l ar active in gre di ent. Wh il e REis for specific product s are not di sc ussed in this r i sk assessment, occupationa l po s t-application scenar ios assessed genera lly resu lt in MOEs that do not indicate risks of concern on Day 0 (the day of app li cation) except for ten postapp l ication sce nario s . The resu l ts are s ummari zed in Table 8.0. l) T h e short-term worker postapplication activities invo l v in g herbicide s on corn, specificall y the hand-harvest in g harv est ing/ deta ss ling sce nario. That sce nario resulted in a s hort-term MOE of 7 on the day of app li ca ti on (Day 0). Assum in g an herbicide application at the maximum app lication rate , the short

- term MOE wou ld excee d 

### 100 for this sce nario at day 25 after app li cation. The Agency note s that it i s not expected to be typical agricu ltura l practice to app ly herbicides on the same day workers would be conducting hand harve s ting and deta ss lin g activities. As noted earlier in thi s assessment , herbicides are typicall y app lied re lative l y early in a growing seaso n . 2) The shor t-term worker postapplication activ it ies in vo lv in g herbicides on grape, tab le, s pecificall y the h arvest, pull , thin , prune , train , tie sce nario. That scenario resulted in a s hort-term MOE of 53 on the day of app l ication (Day 0). For the s hort-term , assw11ing an herbicide app li cation at the maximum application rate, the MOE wo uld excee d 

### 1 00 for this sce nario at day 6 after app li cat i on. The Agency note s that it i s not expecte d to be typ ica l agr ic ultural practice to app ly herbicid es on the same day workers wou ld b e conducting harve s t, pull , thin , prune , train, tie activities. As noted earlier in th i s assessment , herbicide s are typicall y app li ed re lative ly earl y in a growing season. 21t y pi ca l ag ri cu lt ura l prac ti ce to ap pl y f un g i c ide s o n th e s ame d a y wo rker s wo uld be co ndu ct in g h a n d h a rve s tin g a n d de t a s s lin g a c ti v iti e s . As n o ted earli e r in thi s a ss e ss m e nt , fun g ic id es a r e typ ic a ll y appli e d re la ti ve l y earl y in a g row in g s ea s o n. 9) The s ho rt-te rm wo rker p o s tapp li ca ti o n ac ti v iti e s in v o lvi n g fungic ide s o n grap e, tabl e , s pec i fica ll y th e ca ne turnin g , g ird lin g sc e n ario. Th at s ce n ar io re s ul ted in a s h ort
te rm MO E of 64 o n th e d a y of a ppli cat io n (D a y 0). Fo r th e s h o rt-t e rm , a ss um in g a fu n g ic id e a ppli c a tion at th e m ax imum a ppli ca ti o n r ate , th e MO E wo ul d excee d I 00 f o r thi s s ce n a ri o a t day 4 afte r a ppli cati o n. The Ag e ncy notes th a t it i s n ot e x p ec ted to b e t yp ica l ag ri c ultu ra l pract ice to a ppl y fun g ic ide s o n th e s ame d a y wo r ke r s wou l d be co n duc t i n g hand c an e turnin g, g irdlin g act iv iti e s . I 0 ) The s ho rt-te rm wo rke r p o s ta ppli cat io n ac ti v it ie s in vo lv in g f un g icide s o n turf , s p ecifica ll y t he tran s p la nt , we e d , h arve s t s ce n a ri o . T h a t s ce n a ri o res ult ed in a n MO E o f 94 o n t he day of ap p li cat io n ( D a y 0). A s s umin g a f un g i c id e a ppli cati o n a t th e m ax imum appli cat io n ra te , the MOE wo uld ex c ee d I 00 fo r thi s s ce n ar io at day I a ft e r a pplic a ti o n . T he A ge nc y n o tes th at i t i s n o t ex pec t e d to b e t y p ica l agri cu l t ur a l p rac ti ce to appl y fu n g icide s o n the same day w o rke r s wo uld be co n duc tin g tran s pl ant , wee d , h a rv e s t acti v iti es . As n o ted ea rli e r in thi s a ss e ss m en t , i n s ec ti c ides are ty pic a ll y app lied relat ive l y earl y in a g rowin g s ea s o n . A ll o th e r in se cti c id e pos tapplic a tion s c e n a ri os res ult in M O Es t h a t do n o t demon s tr ate r is k s of co nce rn o n t he d ay of a ppli ca ti o n ( D ay 0 ). A vari e ty of p es t i c ide f o r mu la ti on s m ay co nta in sa li cy la ld e hy d e . P P E i s u s u a l ly n o t re quired fo r w o r ke r r e -e nt ry , an d t herefor e th e s e po s tapp li c a tion ri s k es t imat e s ar e ba se d o n th e b ase lin e ex p os ure s ce n ari o ( i .e . , ty pic a l wo rk cl o th i n g b ut no g lo ves). T y pic a ll y, th e A g e n c y c h a rac te ri z e s th e r i sk e s tim a te in re l ati o n t o th e re s tri c t e d e ntry inter va l ( RE I ) for a p arti c u la r acti ve in g re di e nt. Whil e RE i s fo r s p e c ifi c pro du c t s are n ot d i s cu ss ed in t hi s ri s k a ss es s m e nt , occ upat io n a l po s t -a ppli cat i o n s c e n ar io s assesse d res ul t in MO Es th a t do n o t indi c a te ri s k s of conc e rn o n D a y 0 ( th e d a y o f a pp li ca ti o n)
. 

### Tabl e 10. S hort-T erm Occupational Po s tapplication D e rmal Ex po s ure s and Ri s k s for S ali cy laldeh y d e C rop & Appli c ation Tran s fer D ay after DFR, Dail y Do se E xpo s ure R a te W o rk A ctivity C oeffi c ient 1 Treatment 2 (1-1 g/cm 2) 3**da y)~**  MO E 5 Du r ation ( lb in e rt / A) (cm 2/ hr) H erb ic id e Pro du c t Sce nar ios Sco ut, wee d 100 0 0 .0327 1200 low f o l iage Sco ut , wee d 4 00 0 0
. 1 306 3 10 Co rn h ig h f o li a ge (S T ) 1 .45 6 Sc ou t , irr ig ate, 3
. 27 wee d h i g h 1 , 0 0 0 0 0 .3265 1 2 0 f o li age H ar ves t in g/ 17. 00 0 0 5.55 1 3 7 d e tass li ng Hedge, irri ga te ,

wee d , sco ut , 500 0 0. 0 754 530

tr a in , ti e Sco ut, tra in , t ie 1 , 000 0 0
. 15 0 7 270 23

### Table 10. Short-Term Occupational Postapplication Dermal Exposures and Risks for Salicylaldehyde C rop& Application Transfer Day after D F R , Ex po s ure Rate Work Activity Coe fficient ' Tre a tm e nt 1 ( ll g/ cm1)J Durati o n (lb in e rt / A) (c m 1 / hr) Mowing 500 0 Turf / s od 0
. 28 0.628 (ST) T ra n s pl a nt , 6 , 800 0 weed , harvest*



### . 1 The rc from th1 s expos ure sce nano use s /\ RTF data
- stu dy /\RF

- 035 (M RID 45432303)
. 2 Day after Treatment set to 0 by d efault Dail y Dos e**(mg ay)~**  0.03 14 0.4270

3 Dislodgable Foliar Re s idu e (Jlg/c m2 ) = AR * F * ( 1-0) ' • CF I • C F2. Where: AR = App l ication Rate (lb ine rt/acre), F = fraction of ai r etained on fo l iage or 20% for folia r c rop or 5% fo r turf ( unitl ess), 0 = fraction of residue that d i ssipates daily or I 0% (uni tl ess). t = numb e r of days after ap plic atio n day (days) , CF I = 4.54 x I 0 8 Jl g/l b, CF2 = 24.7 x I 

## o- 9 acre/cm 2 4 Daily Dermal Dose (mglkg/day) = DF R, 

### * CF3 

### * Tc 

### * DA 

### * ET/ BW (kg). Where: DFRt = di s lodgable fo li ar residue on day " t " (Jlg/cm 2 ) , CF3 = I x I 

## o3 mg/f..! g , Tc = tran sfer coeffic ien t (cm 2/h r), DA = dermal absorpt ion factor 100% (un it less) defau lt w ith n o data s ubmitt ed , ET = exposure tim e 8 ( hr /day) , BW = body we ig ht 80 (kg) ( H ED Hot S h ee t # 3 1 , 1 / 17 / 1 2) 5 Margin of Expos u re: MOE = POD (40 mglkg/day) I DOD (mglkg/day). MOE (uni t less) , POD = Point of Departure u s ually NOAEL = No Ob s erved Adverse Effec t Leve l : Dose level in a toxicity study. DOD = Dermal Dai l y Dose: the absorbed d o s e r eceived from expos ure to a pesticide in a given scenario. 

### VIII. CUMULATIVE EXPSOURE Cum ulativ e effec t sfrom subs tances wi th a com mon mechanism of tox icity
. Section 408(b)(2)(D)(v) ofFFDCA requires that , when cons id e rin g w he th e r to es tabli s h , modi fy , or revoke a to le rance , the Agency cons id er "ava ilabl e information " concerning th e cumu lative ef fects of a part icu lar pesticide' s res idu es and "o ther subs tances th at hav e a common mechanism oftox i ci t y." E PA ha s not found sa li cy la ld e hyde to s h a re a co mm o n mechani s m of toxicity with any other subs tance s , an d that sa li cy la lde hyde doe s not appea r to prod uce a toxic met abo li te produced b y other s ub s tance s. For th e purposes of thi s tolerance action , t heref ore , E PA h as assumed that sa li cy l a ld e hyde does not have a common mechanism of tox icity with othe r subs t a nces. For in format ion regardin g E PA' s ef fort s to de t e rmin e wh ich c hemica ls h ave a co mm on m ec h ani s m of to x ic ity and to eva lu ate the c umul a ti ve effects of s uch che mi ca ls , see E PA' s webs ite a t 

### http :// www. epa.gov l pes ti c id es/cum ulat ive. 

### IX
. ENV IRONMENTAL J UST ICE STATEMENT Potentia l areas of e nvi ronmen ta l ju s ti ce concerns , to the exten t po ssi bl e, were considered in thi s human hea lth ri s k assess me nt , in acco rdance w ith U.S. Exec utive Order 12898 , "Feder a l Act io n s to Add ress E nv ironm e nta l Ju s tice in Minority P op ul ati o n s and Low- In co m e Population s, " http: // www . e h.doe .gov / oepa/g uid ance/ju s tic e/eo 1 2898.pdf. As a part of every pesticide ri sk assessment , OP P considers a large variet y of consumer s u bgroups accord in g t o we ll- es t ab l ished procedure s. In lin e wit h OPP po li cy , RD esti m ates ri sks to popu lat ion s ub g roup s f rom p es ti c ide exposu res th at are ba sed o n patte rn s of t h at s ub gro up ' s food and water cons umpti on , a nd act iv iti es in a nd around th e 25 MOE 5
1300 94

### XII. RISK CHARACTERIZAT IO N Ag

- Chem Consulti n g LLC , o n behalf of Omex Agrifluid s is proposing to amend 40 CFR part 180.910 t o establ i s h an exe mpti o n from the req uiremen t of a tolerance for sa li cy la ld e hy d e (CAS# 90-02-8) in or o n food crops a t n o m ore than 14 % of the pesticide formu lat io n to help th e act ive ingredient properly penetrate and remain ava il ab l e to act in the so il. No adverse effec t s attribu ta bl e to a s in g le expos ure t o sa li cy l a ld e hyde were see n in t he tox i c ity databases; th erefore, a n ac ute dietary risk assess m e nt i s n ot a co nce rn . A chronic dietary ri s k assess m e nt takes into acco unt expos ure estim ates fro m c hronic dietary co n sumpt io n of food and drinking water. Mo d e l estim ates for ora l expos ure from the use of sa li cyla lde hyde in pe s ticidal formul a ti ons ( including expos ure through drinking water) resulted in chronic d ieta ry ex posure es timate s fo r food and drinkin g water below the Age n cy ' s level of co nce rn ( < 1 00% cPAD) for the US population and all population subgroups. T he chron ic d i etary exposure from food and water to sa lic y laldeh yde is 1 3% of the cPAD for the U.S. population and a lso 49% of the cPAD for c hildre n 1- 2 years old , t he m ost high ly ex posed population s ub group. The Agency ha s not id e ntified any concerns fo r carc in oge ni city re lat i ng t o sa li cy l a ldehyde; therefore, a cancer dietary exposure assessme nt was not performed
. These assess m e nt s are co n se rvative in nature and w ill not und er es tim ate the potential dietary ri sks to s alic y la ldehyde T he term " residential expos ure" i s u sed in thi s document to refer to nonoccupat io n a l, n on - dietary ex p os ure (e.g
. , fo r lawn and garde n pe s t co ntro l , indoor pe s t contro l , termiticide s, and flea and tick co ntro l on pet s). W hil e th e re are no curre nt or proposed res id ent ia l use s for sa li cy la l dehy d e , it i s po ss ibl e that sa li cy la lde hy d e may be used as an inert ingredient in pe s ticide product s for wh ich sho rt- term and inte rm ediate

te rm res id ent i a l exposu res m ay result. In th e absence of specific residential exposure scena ri os, risk esti m a te s for re s i dent ia l expos ure s t o sa lic y laldehyde can be mod e led based on occupatio n al exposure assessments for sa li cyla ld eh yde. Occupational expos ure assess m e nt s for sa lic y la lde hyde fo r occupatio n a l mixer / lo ad er / app li cato r exposu re and occupationa l po st -appli ca ti on expos ure for comparab le u se s cenario s (e
. g., l ow pressure hand wand t ur f app li catio n ) w it h o nl y ba se lin e p e rso n a l protective eq uip ment res ul t in MOEs of 500 or greater ( i .e. , ex p os ures are not of concern)
. Given the larger t rea tm en t areas and hi g her concentrations of sa li cy la ldehyde u se d in t hese occu p a ti o n a l u se pes ti c id e products th an would be see n in res id e nti a l u ses, MOEs for residential u se sce nario s wou ld exceed I ,0 00 o r more a nd therefore t here are no concerns for re s id entia l exposu res to sa li cy la ld e hyde. S h ort- and intermediate term aggregate exposure takes into accou nt s hort-term residential expos ure plus chro n ic exposu re through food and drinking water (co n s idered t o be a background exposure level ). Since it i s po ss ible t h at sa li cy la ldehyde may b e used as a n inert in gred ient in pes ti c ide product s for w hi c h s h ort-term and intermediate

- term res id e nti a l exposu res m ay res ult , the Agency has determined that it i s appropr iate to aggregate c hroni c exposu re through food and wate r w ith s h ort-t erm res id ent i a l expo s ures to sa li cy la ld e hy de
. Us in g the ex posure assumpt io n s de sc rib e d in thi s unit for s hort-term exposu re s, E P A h as co nc lud ed the co mbin ed s h ort
- term food, wate r , a n d re s id e nti a l exposu res res ult in agg rega te MOE s of 430 for ad ult s a nd 170 fo r c hildre n ( 1- 27app li cat ion. T he Agency notes that it is not expected to be typical agr icu l tura l practice to apply herbicide s on the same day workers wo uld be conducting hand cane turn in g , girdling activities
. · 4) The s hort-term worker postapplication ac ti v iti es in vo l v in g herbicides on turf, specifica ll y the transplant, weed , harvest scenar io. T h at scenario resulted in an MOE of 72 on the day of app li cati on (Day 0). Ass umin g an herbicide app li cation at the maximum applicat ion rate , the MOE wou ld exceed I 00 for th i s scenario at day 3 after app lic ation. T he Age n cy notes that it i s n ot expec ted to be typical agricu ltura l p r actice to app l y herbicides on the same d ay workers wou ld be co ndu cting transplant , weed, harve st activities. As noted earl i er in this assessme nt , h erb icid es are typically app li ed r e lative ly early in a grow in g season. 5) The short-term wo rke r postapplication acti vit ies in vo l ving in sect icide s on corn , spec ifica ll y the hand-harve s ting h arvesting/ detass lin g sce n ario
. T h at scenario res ulted i n an MOE of 20 on the day of app lic at i on (Day 0). Assuming an in sec ticide app li cati on at th e maximum app lic ation rate , the MOE woul d exceed 

### 10 0 for this sce nario at day 

### 16 after applicatio n . The Age n cy notes that it i s n ot expected to be typ i cal agricu ltural pract ic e to app ly in secticides on the same day workers wou ld be conduct in g hand harvesti n g and detassling act ivities. As noted earli er in this assessme nt , in sec ticide s are typicall y app li ed relatively earl y in a g row in g seaso n. 6) The sho rt- term worke r postapplication activities involving in secticides on grape , table , spec ifically the cane turning, girdling sce nario. That scena ri o res ulted in a short-term MOE of 37 o n the day of app lic ation (Day 

### 0). Fo r the sho rt -term, assuming an in sect icide app li catio n at t he maximum application rate , th e MOE wou l d exceed 100 for this sce nari o at day 1 0 after application. The Agency note s that it is not expected to be typica l agricultur a l practice to app l y in sec ti cides on th e same day wo rkers would b e conducting hand cane turning, gird lin g activ iti es. 7) The s hort-te rm worker po s tapplication activities invol ving insecticide s on turf , specificall y the transp lant , weed, h a rvest scenario
. That sce nario re s ulted in an MOE of 4 7 on th e day of app li cation (Day 0). Ass u ming an insecticide app li cation at the maximum application rate , the MOE wo ul d exceed I 00 for this sce n a ri o at day 6 after app li cation. The Agency notes that it i s not expected to be t yp ical agricu l tural practice to apply insec tic ides on the same day workers wo uld be conducting transplant , weed, harves t activ iti es. As noted earlier in thi s assessment , in sect icide s are typically app li ed relati ve l y early i n a grow in g seaso n. 8) T he s hm1-term worker po s tapplication activ iti es involving fun gicides on corn, s p ec ifically the hand-harvesting harvesting / deta ss lin g sce nario
. That sce nario resu l ted in a s hort- term MOE of 3 7 o n the day of app lic ation (Day 0)
. Ass umin g a fung i cide application at th e maximum app li cati on rate , the short-term MOE wou ld exceed I 00 for this sce nario at day 9 after app licatio n . The Agency note s that it i s not expected to be typica l agricultura l practice to app ly fung ic id es on th e same day workers wou ld be conduct in g hand harvesting and detass lin g act i v iti es. As note d ear li e r in thi s assessment, fungicides are typicall y app lied re lat ive ly earl y in a growing season. 9) The sho rt-term wo rker postapplication activities involvin g fungicides on grape , 29Appendix 1. Dietary Exposure Assessment

EPA Ver. 3.16, 03-08-d DEEM-FCID Chronic analysis for INERTS- SALICYLALDEHYDE NHANES 2003-2008 2-day Residue file name: J: \ IN-10777 \ INERTS 57ACTIVE

_ 100PPBH20REV.R08 Adjustment factor #2 used. Analysis Date 10

- 09-2015 / 13:54:20 Residue file dated: 10-09

- 2015 / 13:53:41 Reference dose (RfD, Chronic) = . 4 mg / kg bw / day COMMENT 1: Inert 57 active ingredients +drinking water (100ppb) ===============================================================================

Population

Subgroup Total US Populat i on Hispanic Non-Hisp-White Non

- Hisp-Black Non-Hisp-Other Nursing Infants Non-Nursing Infants Female 13 + PREG Children 1-6 Children 7-12 Male 13-19 Female 13-19 / NP Male 20+ Female 20+ / NP Seniors 55+ All Infants Female 13-50 Children 1

- 2 Children 3-5 Children 6-12 Youth 13-19 Adults 20-49 Adu l ts 50-99 Female 13-49 Total exposure by population subgroup
Total Exposure mg / kg Percent of body wt / day Rfd



### -- - -- -- - -- - - - ---------------- 0.053016 13.3% 0.057893 14.5%- 0
. 052024 13.0%- 0.049266 12.3% 0
. 062540 15.6%- 0.069497 17.4%- 0. 128725 32.2%- 0.046267 11.6%- 0.153068 38.3% 0.063675 15. 9%- 0.037453 9.4%- 0.038061 9.5%- 0. 039479 9.9%- 0.042885 10.7%- 0.042752 10.7%- 0.110440 27
. 6%- 0.040993 10.2%- 0.197747 49.4\ 0
. 135978 34.0%- 0.070155 17.5%- 0.037743 9.4%- 0.040527 10.1%- 0.042501 10.6%- 0.040973 10.2%-

3 1

## Submitted Compound - 

## Structure

Average Mol Mass 122.12 

## Predictions 

# 0

Smiles: C1 = CC=CC( =C1C( =O)[H])O Exact Mol Mass 122.0368 Log Kp -2 .1 8



## Knowledge Base: Derek KB 2014 1.0 Certified by Log P 1.81

Version 1.0 Last Modified Date 23 / 01/2014 07:14:42 Lhasa Limited , Leeds, Yorkshire, UK 

### Reasoning Summary 

## + Cardiotoxicity in mammal is EQUIVOCAL • Alert matched: RapidPrototype167 Sub s tituted benzaldehyde 

## + Hepatotoxicity in mammal is EQUIVOCAL • Alert matched: RapidPrototype019 A romatic aldehyde 

## + Mutagenicity in vitro in bacterium is INACTIVE • No misclassified o r unclassified features 

## + Skin sensitisation in mammal is PLAUSIBLE • Alert matched: 439 Substituted phe nol or precursor 

### Endpoints not firing any alerts at the selected reasoning level (53) Adrenal gland to x icity alp h a-2-m u -G i ob ul in nephropathy Anaphylaxis 33 Mitochondria I dysfunction Mutageni c ity in vivo Nephrotoxicity

## Alert Descriptions 

# CD Alert: 439 Substituted phenol or precursor (from KB: Derek KB 2014 1.0)
Alert Description Image R2 R3 

# R1-<l * R4

H R5
R1 =H. C H 3 R2 · R 5 =an t. except n,d ro x)l ethers

. arnnes . suphonJC aod

. sul!1lol'lc esters carbox )liC a oos a cy l halides

. add anh ) drides

. ttlioesters

. esters and their alpha bet a-l.llsaturated den 1 a trY es In addtJon R2-R5 camo t alll:le h ) drooen or a !K) I groups up**~** carbons**id rO** **JCy Quno~~s**  and phena are exclld ed
Comments Match with query compounc 

### 0

The activity of phenol s ha s been demonstrated in various sk in se n s iti s ation assays including the guinea pig maximisation test [Cronin and Basketter , Goh] and the human maximisation test [Opdyke]. Phenol itself is corrosive but not a sensitiser [Itoh, Ba sketter et al 1999a]. Oestradiol-type ste roidal structures l acking s ubstitution on, and carbon double bond conjugat i on of, the A ring are exc lu ded from the a l ert on the following basis : 1. Limited proprietary data provided by Bayer Schering Pharma AG indi cate no evidence of skin se n sitisation potential for compounds of this type in animal experiments

. 2. Oestradio l it s elf i s in w i de-sp r ead human u se in transderma ll y administered hormone rep l acement therapy. A l though isolated case reports have described allergic contact dermatitis to oestradiol (or in some cases are sugges t ive of it) following use of hormone rep l acement therapy [Boehncke and Gall, Carmichael and Fould s, Goncalo et al, Quirce et al], clinica l trial data indicate that in general dermal exposure to oestradiol under such conditions ha s no sensitising potential [Rozenbau m et al]

. 3

. For simp l e phenols, sk in se n s itisation i s thoug h t to a ri se as a result of formation of a phenolic radical which subse quently r eacts with sk in protein s, primarily at positions ortho to the phenol group [Barratt and Basketter]. QSAR studies have shown that for other toxic pathways also involving phenolic radical formation, the activity of oestrogens such as oestradiol appears to be adequately mode ll ed by approximating the st ructure to a dialkyl -s ubstituted phenol [ Z hang et a l ]. In thi s re spect, it is therefore worthy of note that si mpl e a lkyl pheno l s (such as 4 - tert - buty l ani s o l e [Cron in a n d Basketter] , 1,1,3 - tri -[2- 35• Carmichael AJ and Foulds IS

. (1992) Allergic contact dermatitis from oestradiol in oestrogen patches., Contact Dermatitis, 26, 194-195 DO!: 10.1111/j.1600-0536.1992.tb00293.x • Goncalo M, Oliveira HS, Monteiro C, Clerins I and Figueiredo A. ( 1999) Allergic and systemic contact dermatiti s from estradiol., Contact Dermatitis, 40 , 58-59 DOl: 10.1111 /j. 1600 -0 536.1999.tb05989. x • Quirce S, Garde A, Baz G, Gonza l ez P and Alonso Diaz de Durana MD. (1996) Allergic contact dermatitis from estradiol in a transdermal therapeutic syste m. , Allergy, 51 , 62-63 DOl: 10.1111/j.1398-9995.1996.tb00014.x Rozenbaum H, Birkhauser M, De Nooyer C, Lambotte R, Pornel B, Schneider H, Studd J and Thebault J. (1996) Comparison of two estradiol transdermal systems (Oesc lim 50 and Estraderm TTS 50 )

. II. Local ski n tolerability., Maturitas, 25, 175-185 DOl: 10.1016/S0378-5122(96)01074-2 • Zhang L, Gao H, Hansch C and Selassie CD. (1998) Molecular orbital parameters and comparative QSAR in the analysis of phenol toxicity to leukemia cells., Journal of the Chemical Society: Perkin Transactions II, I 2553-2556 DOl: 10.1039/a801684d • Zimerso n E, Bruze M and Goo sse ns A

. (1999) Simultaneous p-tert-butylphenol-formaldehyde resin and p-tert-butylcatechol contact alle rgi es in man and sensitizing capacities of p-tert-butylphenol and ptert-butylcatechol in guinea pigs., Journal of Occupational and Environmental Medicine, 41 , 23-28 DOl: 10.1097/00043764-199901000-00005 • Basketter DA, Flyvholm MA and Menne T. (1999) Classification criteria for skin-sensitizing chemicals : a commentary., Contact Dermatitis, 40, 175-182 DOl: 10.1111/j.1600-0536 .1 999.tb06029.x • Basketter DA, Lea U , Cooper K, Stocks J, Dickens A , Pate I, Dearman RJ and Kimber I. (1999) Threshold for classification as a skin sensitizer in the local lymph node assay: a statis t ic al evaluation., Food and Chemical Toxicology, 37, 1167-1174 DOl: 10.1016/S0278-6915 (99)00112-X • Opdyke DU. (1979) Fragrance raw materials monographs: alpha-methylanisalacetone., Food and Cosmetics Toxico logy, 17 , 863 DOl: 10

. 1016/SOOlS-6264(79)80072-3 • Andersen A. (20 06) Final amended report on the safety assessment of oxyquinoline and oxyquinoline sulfate as used in cosmetics., International Journal of Toxicology, 25 (supplement 1) , 1-9 DOl: 10.1080/10915810600716570 • Yamano T, Ichihara M, Shimizu M, Noda T and Tsujimoto Y. (2007) Immunomodulatory effects of mono-, di-, and trimethylphenols in mice

. , Toxicology, 232, 132-137 DOl: 10.1016/j.tox.2006.12.021 • Fiedler H, Novak M and Schwank R. (1971) Investigations on group sensitization to new hydro xychino l ine derivatives (German)., Dermatologica, 143 , 298-304 DOl: 10.1159/000252221
3 7- Mammalian skin sensitisation predictions in Derek associated with a reasoning level of equivocal or above have been considered positive ;

- Predictions do not take into account (i) the tautomeric forms of compounds or (ii) the individual components of mixtures;

- Compounds have been considered positive for skin se nsitisation if they have been clas s ified as extreme, strong or moderate sensitisers;

- Compounds classified as weak sensitisers have been excluded from the analysis;

- No account has been taken of other skin sensitisation alerts which may also be present in some compounds ;

- Informa t ion from the data sets may have been used pre v iously as supporting evidence for the derivation of some alerts; -S ome compounds may be present in more than one of the data sets analysed. 

# @ Examples for Alert 439 Substituted phenol or precursor Example 1: 4-styryl-phenol

0

CAS Number: 3839-46-1

391)

1) Test Data ( 4-allyl-anisole) Species guinea pig References Assay ma xi misation test

• Cronin MTD and Basketter DA. { 1994 ) Endpoint(s) Skin sensitisation Result moderate

Multivariate QSAR analysis of a sk in sensitization database. , SAR and QSAR in Environmental Research, 2 , 159 -179 DOl: 10.1080/10629369408029901 

### Example 4: phenol

CAS Number: 108-95-2 Test Data (phenol)

Species

mouse References Assay local lymph node assay Endpoint(s) Skin sensitisation Result negative

• Basketter DA, Lea U, Cooper K, Stocks J, Dicken s A, Pate I, Dearman RJ and K imber I. {1999) Threshold for classification as a ski n sensitize r in the local lymph node assay: a statistical evaluation., Food and Chemical Toxico logy, 37, 1167-1174 DOl: 10.1016/50278-6915{99)00112-X 

### Example 5: alpha-methylanisalacetone

:J 

## /

CAS Number: 104-27-8

41

# Q) Alert: RapidPrototype167 Substituted 6enzaldehyde (from KB: Derek KB 2014 1.0)
Alert Description Image

F

F·

F R l -R S 

### = H , OH , "' OC (al ky l) A

t l e a st o n e o f R l

- RS must be OH o r OC ( al kyl) Comments This alert describes the cardiotoxicity of substituted benzaldehydes. This is a rapid prototype alert derived using a proprietary data set of 1515 chemicals, classified on the basis of the presence or absence of histopathologic lesions in the heart in oral rat repeat dose studies mostly of 28-days duration. Two chemicals in this data set activated this rapid prototype alert and both of these were toxic to the heart. 

## Reasoning Details Cardiotoxicity in mammal is EQUIVOCAL (from KB: Derek KB 2014 1.0) The parameters that have influenced your prediction are: substructures in the input structure, which have a potential for cardiotoxicity, your selected species which is mammal. Rule 266: If [species mammal] is [certain] then [Species dependent variable 8] is [equivocal] • species mammal is CERTAIN In mammals the variable "Species dependent variable 8" is equivocal.

4 3

# 0

H

Details The query structure does not match any structural alerts or examples for ( bacterial in vitro) mutagenicity in Derek. Additionally, the query structure does not contain any unclass i fied or misclassified features and is conseq uently predicted to be inactive in the bacterial in vitro (Ames) mutag e ni city test.


## Skin sensitisation in mammal is PLAUSIBLE (from KB: Derek KB 2014 1.0) The parameters that have influenced your prediction are : substructures in the input st ructure , which have a potential for skin sensitisation, your selected species which is mamma l. Rule 243: If [species mammal] is [certain] then [Species dependent var iab le 22] is [plausible] • spec i es mammal is CERTAIN In mamma l s the var i able "Spec i es dependent variable 22" is plausible. Rule 914: If [alert 439] is [certain] then [Skin sensitisation] is [Species dependent variab l e 22] • alert 439 is CERTAIN • Species dependent variable 22 is PLAUSIBLE If a chemical contains a l ert 439 then it is considered plausible that the chemical wil l cause skin se n s itisation in mammals and impo ss ible in bacteria

. T h e variation in rule outcome with spec ies is achieved via use of the variable "Species dependent variable 22".

45